Metabolic Brain Disease

, Volume 32, Issue 5, pp 1335–1355 | Cite as

The putative role of environmental aluminium in the development of chronic neuropathology in adults and children. How strong is the evidence and what could be the mechanisms involved?

  • Gerwyn Morris
  • Basant K. PuriEmail author
  • Richard E. Frye
Open Access
Review Article


The conceptualisation of autistic spectrum disorder and Alzheimer’s disease has undergone something of a paradigm shift in recent years and rather than being viewed as single illnesses with a unitary pathogenesis and pathophysiology they are increasingly considered to be heterogeneous syndromes with a complex multifactorial aetiopathogenesis, involving a highly complex and diverse combination of genetic, epigenetic and environmental factors. One such environmental factor implicated as a potential cause in both syndromes is aluminium, as an element or as part of a salt, received, for example, in oral form or as an adjuvant. Such administration has the potential to induce pathology via several routes such as provoking dysfunction and/or activation of glial cells which play an indispensable role in the regulation of central nervous system homeostasis and neurodevelopment. Other routes include the generation of oxidative stress, depletion of reduced glutathione, direct and indirect reductions in mitochondrial performance and integrity, and increasing the production of proinflammatory cytokines in both the brain and peripherally. The mechanisms whereby environmental aluminium could contribute to the development of the highly specific pattern of neuropathology seen in Alzheimer’s disease are described. Also detailed are several mechanisms whereby significant quantities of aluminium introduced via immunisation could produce chronic neuropathology in genetically susceptible children. Accordingly, it is recommended that the use of aluminium salts in immunisations should be discontinued and that adults should take steps to minimise their exposure to environmental aluminium.


Brain Neuropathology Aluminum Alzheimer disease Autism spectrum disorder Autoimmunity 


Autism spectrum disorder (ASD) refers to an increasingly common group of heterogeneous disorders identified by the presence of impairments in social interactions and communication together with a restrictive range of repetitive and stereotypical behaviours (Zhubi et al. 2014; Ladd-Acosta et al. 2014). Recent analyses have consistently shown that the prevalence of ASD is increasing. Estimates vary between one in 68 (CDC) and one in 46 (Pelly et al. 2015) to one in 38 (Kim et al. 2011) during similar time periods. There is some debate as to the reasons for the precipitous increase in prevalence of ASD over the past two decades, with some concluding that this is essentially an artefact stemming from the development of broader diagnostic categories and increased medical awareness (Rutter 2005; King and Bearman 2009). However, analyses conducted by other research teams have suggested that other factors aside from diagnostic shift may contribute to this increase in prevalence (Grether et al. 2009; Hertz-Picciotto 2009). Although early heritability estimates for ASD were high (approximately 97%), multiple comprehensive genetic studies have failed to reveal reproducible candidate genes, and thus far no single gene can account for more than 1% of ASD cases, although there is a great deal of evidence that genetic abnormalities play a major role in the development of the disorders which is unsurprising given that this is the case with most if not all illnesses (Siniscalco et al. 2013). It is also worth noting that only a minority of children with an ASD diagnosis have an identifiable genetic syndrome (Siniscalco et al. 2013) and recent studies suggest that the yield of genetic testing is low even when chromosomal microarray analysis is combined with whole exome sequencing, particularly in non-dysmorphic ASD children (Tammimies et al. 2015). Moreover, some genetic abnormalities which increase the risk of developing ASD are also risk factors for other neurodevelopmental or neuroimmune conditions, and are polymorphisms rather than deleterious mutations, being also present in unaffected individuals (Betancur 2011; Sahoo et al. 2011). It would appear that these genes appear to confer vulnerability to a variety of neurodevelopmental disorders (Betancur 2011; Sahoo et al. 2011; Rapoport et al. 2012). Furthermore, a recent heritability estimate stemming from the largest twin study to date yielded a figure as low as 37% (Hallmayer et al. 2011), although another recent study calculated an estimate of heritability between 40 and 60% (Klei et al. 2012).

The concept of ASD as an illness of purely genetic origin has given way to the view that, at the very least, the aetiopathogenesis of ASD involves a highly complex interaction between numerous genes and environmental risk factors (Bushnell 2013; LaSalle 2013). Moreover, it is becoming increasingly apparent that alterations in the epigenetic landscape and dysregulation of epigenetic mechanisms responsible for gene expression also play a major role in the aetiopathogenesis of these disorders (Rangasamy et al. 2013; Flashner et al. 2013; Siniscalco et al. 2013). In a landmark post-mortem microarray study, Voineagu and fellow workers identified 444 genes which were differentially expressed in the cerebral cortex, and two genes which were differentially expressed in the cerebellum, of children with ASD compared with neurotypical age- and sex-matched controls. They reported that the dysregulated patterns of expression of immune and glial gene markers were not associated with any known ASD risk genes, so that immune changes are likely to be either secondary phenomena or the result of environmental factors (Voineagu et al. 2011). In another study, Melnyk and others examined 68 ASD subjects, 40 unaffected siblings and 54 age- and sex-matched controls, and reported oxidative damage to DNA (indexed by the oxidised DNA adduct 8-oxo-deoxyguanosine) and proteins in leukocytes combined with global DNA hypomethylation that was specific to ASD children (Melnyk et al. 2012). The phenomenon of global DNA hypomethylation in the brain as a driver of altered gene expression in ASD children has also been reported (Ladd-Acosta et al. 2014; Nardone et al. 2014). It is also of interest that the latter team reported hypomethylation and consequent upregulation of complement and tumour necrosis factor-alpha (TNF-α) genes, which are involved in the regulation of the neurodevelopmental roles of microglia and synaptic scaling respectively (Nardone et al. 2014).

Further evidence emphasising the importance of epigenetic abnormalities in the pathogenesis of ASD was published by Wong and fellow workers (2014). These authors reported differently methylated DNA regions within 50 monozygotic twin pairs (i.e. 100 individuals) discordant for ASD that correlated with the severity of autistic trait scores, emphasising the importance of epigenetic rather than genetic factors in the pathophysiology and pathogenesis of ASD (Wong et al. 2014). The role of epigenetic dysregulation as an important factor in the pathogenesis of ASD is further supported by evidence of dysregulated microRNA (miRNA) expression in ASD children (Mundalil Vasu et al. 2014; Mellios and Sur 2012). A recent post-mortem study cited evidence of hypomethylated and upregulated miR-142 in the frontal cortex (Brodmann area 10) in children with ASD, which is of interest as this miRNA plays a major role in regulating the neurodevelopmental activities of microglia and maintaining them in a quiescent state (Mor et al. 2015; Vaishnavi et al. 2013; Marrale et al. 2014).

When viewed as a whole, it appears that the aetiology of ASD is multifactorial, involving a highly complex and diverse combination of genetic, epigenetic, environmental and immunological factors (Flashner et al. 2013; Herbert 2010; Roberts et al. 2013). Overall, the conceptualisation of ASD has undergone a paradigm shift, and rather than being viewed as a single illness with a unitary pathogenesis and pathophysiology, it is a clinically heterogeneous syndrome with a complex multifactorial aetiopathogenesis (Zhubi et al. 2014; Voineagu et al. 2011; Betancur 2011; Tordjman et al. 2014; Ruggeri et al. 2014; Georgiades et al. 2013). Ultimately, the pathology in any given child likely has its origins in a dynamic interplay between a broad range of different environmental agents, predisposing genetic factors and complex epigenetic mechanisms as discussed above (Zhubi et al. 2014; Voineagu et al. 2011; Betancur 2011; Tordjman et al. 2014; Ruggeri et al. 2014; Georgiades et al. 2013).

The view of ASD as an illness or illnesses exclusively affecting the brain is also changing. While many ASD children display evidence of activated microglia and astrocytes, which are characteristic of many neuroimmune and neurodegenerative diseases (Morgan et al. 2012; Suzuki et al. 2013; Morgan et al. 2010; Morris and Berk 2015; Morris et al. 2015a), there is also copious evidence of abnormalities in the peripheral immune system. Such evidence includes data demonstrating excessive pro-inflammatory cytokine (PIC) expression, reduced anti-inflammatory cytokine expression, modulated or increased T-cell responses, altered natural killer T-cell responses, activated complement responses, major histocompatibility complex (MHC) class I abnormalities and increased autoantibodies in the periphery as well as in the brain (reviewed in Noriega and Savelkoul 2014; Careaga and Ashwood 2012; Estes and McAllister 2015; Gottfried et al. 2015). The pattern of single nucleotide polymorphisms (SNPs) in immune genes is similar to those seen in several autoimmune diseases such as multiple sclerosis (MS) (Ramos et al. 2012). There is also evidence of abnormally robust pattern recognition receptor activity linked to the presence of SNPs in encoding genes leading to exaggerated immune responses (Enstrom et al. 2010; Mead and Ashwood 2015). It is also noteworthy that genes governing immune and inflammatory responses are upregulated in some children with an ASD diagnosis (Koufaris and Sismani 2015) and that the presence of such abnormally expressed genes can predict the development of ASD in male children with some 83% accuracy (Pramparo et al. 2015). It is also of interest that polymorphisms in cytokine and HLA genes are associated with unusual responses to vaccines (Castiblanco and Anaya 2015). The evidence of immune abnormalities in many, but by no means all, children afforded an ASD diagnosis has led to the proposal of a neuroimmune subtype of ASD (McDougle et al. 2015). Furthermore, several researchers have reported an association between initial inflammatory insults and the subsequent development of chronic immune disturbances in ASD children (McDougle et al. 2015; Gottfried et al. 2015; Siniscalco et al. 2013). One possible explanation for this phenomenon is that an unusually potent and/or prolonged immune response allows for the development of macromolecular or tissue damage leading to the formation of damage-associated molecular patterns (DAMPs) (Lucas et al. 2015). The formation of such DAMPs and the resultant chronic stimulation of pattern recognition receptors (PRRs), leading to the development of an “autotoxic loop” of increasing inflammation and oxidative stress, is considered to play a major role in the maintenance and exacerbation of systemic inflammation, neuro-inflammation and neurodegeneration in a range of autoimmune and neurodegenerative diseases such as systemic lupus erythematosus (SLE), MS and Alzheimer’s disease (AD) (Venegas and Heneka 2017; Land 2015). Frequent or prolonged postnatal infections are an obvious source of inflammatory insults and such events appear to be associated with a significantly increased risk of developing ASD (Abdallah et al. 2012; Hadjkacem et al. 2016). However, other environmental agents putatively associated with an increased risk of developing the ASD phenotype, such as organophosphates, mercury and aluminium, also have the capacity to provoke a prolonged and or exaggerated immune response (Eisenkraft et al. 2013; Kern et al. 2016; Shaw and Tomljenovic 2013). Aluminium salts in adjuvant form functioning as DAMPs activate PRRs and exert profound stimulatory effects on innate immune responses (Powell et al. 2015) and thus could be candidates for the generation of tissue damage and DAMP formation in children with an underlying tendency to produce an exaggerated immune response. There is also evidence of increased aluminium levels in the hair and urine of ASD children compared with unaffected controls (Yasuda and Tsutsui 2013; Mohamed Fel et al. 2015; Blaurock-Busch et al. 2012; Blaurock-Busch et al. 2011), although this not an invariant finding (Fido and Al-Saad 2005; Al-Ayadhi 2005). It should also be noted that aluminium adjuvants are becoming a recognised trigger of autoimmune pathology in genetically susceptible individuals (Morris et al. 2015b).

Intriguingly, chronic or cumulative exposure to aluminium reflected by increased levels in cerebrospinal fluid (CSF) and serum may be one environmental factor in the pathogenesis and pathophysiology of MS, Parkinson’s disease (PD) and AD (Fulgenzi et al. 2014; Exley et al. 2006; Ahmed and Santosh 2010; Yasui et al. 1992; Exley and Vickers 2014; Basun et al. 1991). There is a wealth of research examining the potential association between increased exposure to environmental aluminium and the development of the last of these illnesses. Indeed, a recent meta-analysis involving eight cohort- and case-controlled studies conducted prior to 2015 involving 10,567 participants concluded that increased aluminium exposure increased the risk of developing AD by some 71% (Wang et al. 2016). This seems a noteworthy finding in the light of evidence indicating that AD is also an aetiologically heterogeneous syndrome (Lam et al. 2013; Morris and Berk 2015) as indeed is the case for PD (Klein and Lohmann 2009; Korczyn and Hassin-Baer 2015) and MS (Paz Soldan and Rodriguez 2002). Hence establishing an association between AD and a single environmental factor in a cross-sectional study when a multiplicity of such factors may be involved in different patients is a difficult enterprise. Much of the in vivo evidence examining the mechanisms underpinning the pathological effects of aluminium exposure has been obtained in the area of human and animal research into the pathogenesis of AD. Such evidence includes the induction of oxidative stress, mitochondrial dysfunction, microglial activation and functional dysregulation of microglia (Morris and Berk 2016). This may be highly relevant as many children with ASD also manifest oxidative stress (reviewed in Depino 2013; Rossignol and Frye 2014; Frustaci et al. 2012), mitochondrial dysfunction (reviewed by Goh et al. 2014; Chen et al. 2015; Guevara-Campos et al. 2013) and abnormal microglial activity as discussed above.

In this paper we aim to review the available evidence purporting to establish an association between increased aluminium exposure and an increased risk of developing AD and the evidence aimed at illuminating the potential pathophysiological mechanisms by which aluminium could be an element in the development of the illness in at least some people. The objective of this part of the paper is to inform readers with an interest in the pathogenesis and pathophysiology of ASD who might not be aware of concerns regarding aluminium in the pathogenesis of conditions other than ASD. We also aim to highlight accumulating evidence suggesting that aluminium adjuvants can precipitate serious autoimmune or auto-inflammatory pathology in genetically susceptible people which is a growing area of concern. We will then move on to consider evidence suggesting an association between the increased use of aluminium salt adjuvants and an increased incidence of ASD before moving on to touch briefly on the safety or otherwise of vaccines in people with a predisposition to autoimmunity and a range of polymorphisms in immune genes. This would appear to be appropriate in the light of changes in the conceptualisation of ASD as a syndrome with a multiplicity of potential causes and increasing knowledge regarding the effects of genetic variation in the immune system and the response to vaccines. The remainder of the paper will focus on mechanisms by which increased exposure to aluminium could be an environmental trigger of ASD in at least some children with a range of abnormalities in the performance of their immune systems.

Section 1. Evidence highlighting the neurotoxic properties of aluminium

Evidence of an association between chronic aluminium exposure and the development of AD

The p-block metal aluminium, which is the third most frequently occurring element in the Earth’s crust, occurs naturally in the ore bauxite, various clays and alumino-silicate minerals, and has a preferred oxidation state of +3. Several authors have reported a strong positive correlation between the level of aluminium in drinking water and the incidence of AD throughout the world including the United Kingdom, Canada, Norway and France (Flaten 2001; Kawahara and Kato-Negishi 2011). The most recently reported association was published by Rondeau et al. (2009), who demonstrated that high daily consumption of aluminium in drinking water was associated with a significantly increased risk of developing mild cognitive impairment or AD in a 15-year longitudinal French cohort study involving 1925 recruits (Rondeau et al. 2009).

There is considerable in vitro and in vivo evidence demonstrating that aluminium ions inhibit the dephosphorylation of tau, potentiate the development of neurofibrillary tangles (NFTs), cause the accumulation of amyloid beta protein and accelerate the formation of amyloid plaques (Kawahara 2005; Exley 2005). Despite such evidence, the enthusiasm for aluminium as a factor in the pathogenesis of AD waned largely based on data suggesting that aluminium levels were no higher in the brains of AD patients than in healthy controls, and the failure to detect aluminium in NFTs and amyloid plaques in post-mortem tissue at higher levels in AD than in age- and sex-matched controls (Yumoto et al. 2009). In particular, no evidence of increased brain aluminium levels in AD was found, using flameless atomic absorption spectrophotometry, in the study of Jacobs et al. (1989). Furthermore, high aluminium levels in the cores of amyloid or neuritic (senile) plaques have not been reported in several studies variously employing scanning proton microprobe analysis (Lovell et al. 1993), energy-dispersive X-ray microprobe analysis (Jacobs et al. 1989), electron microprobe analysis (Chafi et al. 1991) or nuclear microscopy using particle-induced X-ray emission, Rutherford backscattering spectrometry and scanning transmission ion microscopy (Landsberg et al. 1992). In contrast, increased plaque core aluminium has been reported in AD using an energy-dispersive X-ray microanalytical system (Edwardson et al. 1986) and a method based on inductively coupled plasma mass spectrometry combined with flow injection (Beauchemin and Kisilevsky 1998). Similarly, the findings in relation to increased aluminium in NFTs are inconsistent, with a positive finding using laser microprobe mass analysis (Good et al. 1992), negative findings using electron microprobe and ion microprobe analyses (Chafi et al. 1991) and an intermediate finding (that is, slight increase) again using laser microprobe mass analysis (Lovell et al. 1993). A histochemical study of AD hippocampal neurones reported evidence of aluminium in nucleoli and in NFTs (Walton 2006).

Notwithstanding the above findings, some recent research studies using more sensitive techniques have detected aluminium in the brains of AD patients within plaques, NFTs and elsewhere at significantly higher levels than in age- and sex-matched unaffected controls (Yumoto et al. 2009; Bouras et al. 1997). Furthermore, a number of studies reporting the effects of aluminium exposure in animals have demonstrated the development of AD and Alzheimer-like pathology in rodents (Al-Olayan et al. 2015; Abd-Elghaffar et al. 2005; Sumathi et al. 2015; Lu et al. 2014; Exley and Vickers 2014; Exley and Esiri 2006). Animal studies have also revealed that aluminium administered orally or via injection significantly decreased reduced glutathione levels and the activities of catalase, superoxide dismutase, glutathione peroxidase and glutathione reductase, and increased the levels of nitric oxide (NO), PICs and lipid peroxidation (Sumathi et al. 2015; Al-Olayan et al. 2015). Moreover, histological examination has revealed apoptosis of hippocampal and cerebral cortical neurones and the presence of NFTs, amyloid plaque deposition, Schwann cell degeneration and nerve fibre demyelination (Abd-Elghaffar et al. 2005).

Knowledge regarding the possible mechanisms by which aluminium exposure could provoke some of the characteristic features underpinning the pathophysiology of AD has also evolved. In a recent paper, Zhao et al. (2014) reported on the ability of physiologically realistic levels of aluminium to provoke the aggregation of Aβ42 monomers into dimeric, oligomeric, and ultimately fibrillary structures. This team of authors also cited decreased expression of triggering receptor expressed in myeloid/microglial cells-2 (TREM2) in microglia subsequent to the upregulation of miR-34a as the mechanism underpinning impaired microglial-mediated clearance of Aβ42 peptides from the brain caused by prolonged exposure to aluminium at nanomolar concentrations (Zhao et al. 2014).

Human in vivo studies have also reported specific aluminium-related abnormalities in the brains of AD patients. The association between prolonged exposure to environmental aluminium and increased levels of phosphorylated tau subspecies in blood lymphocytes has also been reported in a recent study involving 66 retired aluminium workers (Lu et al. 2014). Moreover, it has been demonstrated that ferritin in plasma from AD patients, particularly those with mild AD, contains significantly higher concentrations of aluminium compared with plasma ferritin from age- and sex-matched controls which, given the pivotal role of this protein in the regulation of metal homeostasis, may be a crucial finding; the finding of a higher level in mild AD compared with severe AD may also point to a first phase in which there is an aluminium overload of ferritin, followed by a phase in which ferritin with reduced functional capacity releases aluminium (De Sole et al. 2013). Interestingly, the capacity of aluminium to disrupt the activity of ferritin and transferrin, with the subsequent disruption of iron homeostasis, has been demonstrated in a series of studies implicating aluminium as a potential causative agent in certain types of breast cancer cells as well as in primary invasive breast cancers and ductal carcinoma in situ (Darbre et al. 2013; Darbre et al. 2011; Mannello et al. 2013).

It should also be noted that, until recently, an explanation which could explain the selective effects of AD on various regions of the brain was lacking. However, in a study using electrothermal atomic absorption spectroscopy of the aluminium content of the arterial walls of eight arteries which supply the brain, it was found that aluminium concentration is far higher in the posterior cerebral artery (arteria cerebri posterior), which supplies the hippocampus, in late-stage AD patients than in age- and sex-matched controls (Bhattacharjee et al. 2013). This study is particularly intriguing because, when taken as a whole, the data indicate the presence of biochemical mechanisms in the endothelial cells supplying the cerebral vasculature which enable the binding of aluminium to selected areas such as the hippocampus, known to play a major role in the pathogenesis of the illness (Bhattacharjee et al. 2013).

There is little doubt that the weight of evidence implicating aluminium in the causation of AD in at least some patients is increasing. However, at the current time, despite an analysis using Hill’s causality criteria concluding that aluminium played a causative role in the development of AD (Walton 2014), there is currently no universal consensus on the subject, and it seems reasonable to conclude that there is a correlative link between aluminium and AD but that this association does not currently amount to a causative relationship. There is, however, an accumulating body of evidence suggesting that that aluminium in adjuvant form may provoke systematic and symptomatic autoimmune conditions in genetically susceptible individuals and we will now discuss this phenomenon.

The involvement of aluminium adjuvants in the development of autoimmune syndrome induced by adjuvants (ASIA)

Evidence demonstrating the development of chronic autoimmune or auto-inflammatory conditions following environmental exposure to aluminium salts, and indeed other adjuvants, is increasingly becoming a cause for concern (Zafrir et al. 2012; Cerpa-Cruz et al. 2013; Jensen-Jarolim 2015; Willhite et al. 2014). Much of this evidence has been presented in the context of the “autoimmune (auto-inflammatory) syndrome induced by adjuvants” (ASIA), which encompasses a broad spectrum of immune-mediated illnesses triggered by exposure to medical, cosmetic or environmental adjuvants such as aluminium salts, silicon compounds or indoor mould (Agmon-Levin et al. 2009). ASIA is characterised by specific and non-specific manifestations of autoimmune disease such as chronic fatigue, myalgia, arthralgias, neurocognitive impairment, respiratory symptoms, gastrointestinal symptoms, dermatological signs and the development of autoantibodies (Israeli 2012).

Medical conditions considered by some to be part of the syndrome include post-vaccination phenomena, Gulf War syndrome, macrophagic myofasciitis, antiphospholipid syndrome, siliconosis and possibly chronic fatigue syndrome (myalgic encephalomyelitis) and fibromyalgia syndrome (Cruz-Tapias et al. 2013; Vera-Lastra et al. 2013). It is interesting to note that data from animal models suggest that adjuvants may play a role in the development of syndromic autoimmune diseases such as SLE, Sjögren’s syndrome and rheumatoid arthritis in some patients (Cruz-Tapias et al. 2013; Bagavant et al. 2014).

Adjuvants were once thought to pose little or no independent threat as drivers of pathology. Unfortunately, studies of animal models and humans have demonstrated the ability of some of them to induce autoimmunity and immune-mediated diseases (Agmon-Levin et al. 2009; Elkayam et al. 2011). The mechanisms underpinning adjuvant-induced immunotoxicity appear to be somewhat varied, but clearly impinge on both innate and humoral immune responses (Marrack et al. 2009; Kool et al. 2008a; Eisenbarth et al. 2008). It must be stated however that adjuvant exposure per se does not appear to cause problems for the vast majority of people and the development of ASIA seems to depend on genetic predisposition or as yet undetermined environmental co-factors (Perricone et al. 2013; Esposito et al. 2014; Shoenfeld and Agmon-Levin 2011; Soriano et al. 2015).

Several authors have examined patients diagnosed with autoimmune or other immune-mediated illnesses following hepatitis B virus immunisation (Zafrir et al. 2012; Agmon-Levin et al. 2009; Agmon-Levin et al. 2014). The largest such study evaluated the medical records of 93 patients and reported prevalence rates of different manifestations as follows: neurological 67%; general symptoms 60%; musculoskeletal 60%; gastrointestinal 51%; fatigue 42%, ophthalmological 32%; muco-cutaneous 30%; sleep disturbance 19%; psychiatric 16%; and local reactions 11% (Zafrir et al. 2012). Elevated autoantibody titres were also documented in the sera in 80% of the patients. Several vaccine adjuvants have also been implicated in the development of autoimmune diseases which lie outside ASIA, notably ASD which is a subject that we now consider.

Aluminium adjuvants in the pathogenesis of ASD

From the perspective of aluminium adjuvants as a potential contributory factor in the development of ASD (Shaw and Tomljenovic 2013), a recent analysis applying Hill’s criteria for establishing causality reported children living in countries with the highest prevalence of ASD appear to have the greatest exposure to vaccine based aluminium. Perhaps more importantly, the increase in exposure to aluminium adjuvants displayed a significant positive correlation with the increased prevalence of ASD in the USA recorded over the last 20 years (r = 0.92, p < 0.0001). A wider analysis revealed the presence of significant positive correlation between the levels of aluminium in adjuvant form administered to preschool children at around three to four months old and the existing ASD prevalence in seven major Western countries (r = 0.89 to 0.94, p = 0.0018 to 0.0248) (Shaw and Tomljenovic 2013).

Taylor and colleagues, in a meta-analysis of 10 pre-selected predominantly retrospective studies, reported no causal relationship between a range of mercury containing vaccines and a range of neurodevelopmental conditions such as pervasive developmental delay (PDD), attention-deficit hyperactivity disorder (ADHD), autistic disorder and ASD as diagnosed by several different criteria (Taylor et al. 2014).

It is worth noting that the questions asked by the above two groups are different, with the first focusing entirely on autism using current diagnostic criteria while the second used a range of different case definitions of autism and autism-like conditions and also included children with PDD. Indeed, one large study included in the analysis focused entirely on PDD (Smeeth et al. 2004), while another two focused on general neurodevelopmental conditions (Andrews et al. 2004; Verstraeten et al. 2003). It is also fair to say that the conclusions of another study (DeStefano 2007) have been challenged and a re-analysis of the data has revealed a significant association between a first measles, mumps and rubella (MMR) immunisation before the age of 36 months in African-American males and a diagnosis of ASD (Hooker 2014), although it should be noted that this last study has since been retracted. It would appear that the statisticians involved in the meta-analysis by Taylor et al. (2014) viewed PDD, ADHD and ASD as essentially the same condition, or, the interpretation of this and other data is based on the concept of ASD as a discrete disease entity which is being increasingly called into question (Zhubi et al. 2014; Voineagu 2012; Betancur 2011; Tordjman et al. 2014; Ruggeri et al. 2014; Georgiades et al. 2013). However, in spite of these issues those who believe that adjuvants cause “autism” have one question which currently remains unanswered, namely that if aluminium or other adjuvants per se provoke chronic central nervous system and peripheral pathology, why is the prevalence of ASD not far higher than it is now? Given the ubiquity of vaccination one would expect that almost every child would be affected. This fact alone means that adjuvants are highly unlikely to be the main cause of ASD. However, research within the ASIA paradigm and beyond does suggest that aluminium adjuvants, and indeed vaccination per se, can cause serious long-term pathology in people with a certain genetic vulnerability, especially in the case of latent or subclinical auto-immune diseases, and we now move on briefly to detail such evidence.

Section 2. Pathological effects of vaccines in people with a predisposition to autoimmunity

Langer-Gould and colleagues reviewed the medical records of 780 patients with newly diagnosed MS, clinically isolated syndrome (optic neuritis, transverse myelitis, and monofocal or multifocal clinically isolated syndrome) or acute disseminated encephalomyelitis (ADEM) and concluded that vaccines may accelerate or precipitate the transition between subclinical and overt symptomatic autoimmune conditions within the first 30 days post-immunisation, particularly in those aged under 50 years (Langer-Gould et al. 2014). Several other authors have reported an association between the quadrivalent human papilloma vaccine and the development of several autoimmune diseases including Raynaud’s disease, Behçet’s syndrome, type 1 diabetes mellitus and Hashimoto’s syndrome (Arnheim-Dahlstrom et al. 2013; Chao et al. 2012). However, once again it would appear that affected patients displayed signs of subclinical autoimmunity prior to vaccination which may have subsequently triggered active disease (Chao et al. 2012; Arnheim-Dahlstrom et al. 2013). Many research teams reviewing adverse event data have reached similar conclusions (Pellegrino et al. 2015; Petrovsky 2015; Guimaraes et al. 2015). Grimaldi-Bensouda and colleagues found a positive association between a personal and family history of autoimmune diseases and the development of several different autoimmune diseases post-vaccination (Grimaldi-Bensouda et al. 2014). Interestingly, and perhaps reassuringly, a prospective longitudinal case-controlled study examining initially unaffected patients with no evidence of overt or covert autoimmune disease failed to demonstrate any association between vaccination and the development of ADEM or other autoimmune conditions (Scheller et al. 2015). However, as previously noted, there is considerable evidence that vaccines, or more likely vaccine adjuvants, may precipitate specific autoimmune sequelae in genetically or epigenetically vulnerable people (Pellegrino et al. 2015; Petrovsky 2015; Guimaraes et al. 2015). We will now discuss possible mechanisms which may underpin this effect.

Polymorphisms in human leukocyte antigen (HLA) and Toll-like receptor (TLR) and immune response to vaccination

There is a vast body of data demonstrating that immune and inflammatory responses to vaccines such as MMR are heavily influenced by polymorphisms in the HLA region and in genes encoding effector proteins such as cytokines and PRRs which have the capacity to recognise and become activated by conserved pathogen-associated molecular patterns (PAMPs) to produce immune response molecules such as PICs and interferons (Haralambieva et al. 2013; Lucas and Maes 2013). Examples of PRRs include membrane-bound receptors such as TLRs (e.g. TLR-4) and cytosolic receptors such as retinoic acid-inducible gene (RIG)-like receptors (Kumar et al. 2013). Readers interested in examining the evidence purporting to demonstrate an association between HLA polymorphisms and unusual response to the MMR vaccine are referred to an excellent review by Castiblanco and Anaya 2015. Extensive research has also revealed that immune responses to vaccines per se in any given individual are determined by polymorphisms and methylation patterns in the HLA region, cytokine and TLR genes coupled with the composition of the microbiome, the presence of co-infections, and a whole host of environmental variables (review Poland et al. 2013). These observations provide the basis for a mechanism whereby adjuvants could provoke an abnormal response in people with certain polymorphisms and/or methylation patterns in the HLA region, cytokine and TLR genes leading to excessively powerful and/or prolonged immune activity resulting in tissue damage and the generation of DAMPs, such as S100b, with the subsequent development of chronic immune and inflammatory pathology (Lucas and Maes 2013; Lucas et al. 2015). This will be the theme developed in the remainder of this paper. First, however, it is appropriate to consider whether aluminium in environmental or adjuvant form does indeed possess the capacity to generate the range of pathology seen in some children with an ASD diagnosis, which we will now consider.

Section 3. Chronic aluminium exposure and the development of chronic oxidative stress, mitochondrial dysfunction and gliopathology

Aluminium exposure provoking PIC and chemokine production

Aluminium salt-containing adjuvants induce the production of the interleukins (ILs) IL-1β, IL-8 and IL-18 in TLR-stimulated dendritic cells and macrophages (Kuroda et al. 2011; Li et al. 2008; Sharp et al. 2009). There are now considerable, albeit in vitro, data demonstrating that such activation is dependent upon nucleotide-binding oligomerisation domain-like receptor pyrin domain-3 (NLRP3) inflammasome activation (Kool et al. 2008a; Franchi and Nunez 2008). Aluminium salts can activate the NLRP3 inflammasome via a number of different routes. These include destabilisation of phagosomes, acidification of lysosomes and increases in reactive oxygen species (ROS) levels (Kool et al. 2012; Hornung et al. 2008; Sharp et al. 2009). In vivo, aluminium hydroxide appears to induce dendritic cell and T-cell activation at least partly via NLRP3 activation (Kool et al. 2008a; Eisenbarth et al. 2008) although alternative routes such as immunoreceptor tyrosine-based activation motif (ITAM) and interferon response factor 3 (irf3) activation appear to be involved (Kuroda et al. 2011; Marichal et al. 2011). Aluminium adjuvants also provoke an immune response via the generation of DAMPs, notably uric acid and host DNA (outside cell nuclei and mitochondria) (Kool et al. 2012; Kool et al. 2008b). There is a body of evidence demonstrating that uric acid and DNA are released in vivo following aluminium hydroxide injection (Marichal et al. 2011; Kool et al. 2008b). Uric acid is a DAMP synthesised during purine nucleotide catabolism whose concentration increases during cellular stress, such as at the site of injection (Kool et al. 2008b). The functional relevance of uric acid levels in increasing T-cell priming and the instigation of humoral immune responses has been repeatedly demonstrated (Kool et al. 2008b; Munks et al. 2010). Both uric acid and aluminium hydroxide can independently activate the NLRP3 inflammasome, inducing the secretion of IL-1β (Kool et al. 2008a; Franchi and Nunez 2008). Uric acid crystals administered in the form of an adjuvant can also induce complement responses and a T helper type 2 (Th2) cell differentiation pattern (Kool et al. 2011; Shi et al. 2003). Host DNA released into the intracellular space following cellular necrosis also acts as a DAMP. Testimony to the highly immunogenic nature of double-stranded stranded DNA is shown by data demonstrating that it can be used as a substitute for aluminium hydroxide as a vaccine adjuvant (Marichal et al. 2011). Double-stranded cytosolic DNA is sensed by a number of PRRs including TLR-9, leading to the production of PICs via the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) or interferon-beta (IFN-β) via the activation of irf3 (Stetson and Medzhitov 2006; Thompson et al. 2011).

Aluminium exposure and the generation of oxidative stress

Oxidative damage as evidenced by increased lipid peroxidation and depleted anti-oxidant defences induced by prolonged aluminium exposure appears to be focused in the prefrontal cortex, cerebellum, hippocampus and brainstem (Yuan et al. 2012; Kumar et al. 2011). It is also noteworthy that several authors have reported a linear relationship between increased cellular levels of aluminium and concentrations of protein carbonyls and S100 proteins (Mannello et al. 2013; Darbre et al. 2013; Darbre et al. 2011). This is of particular interest as these molecules may function as DAMPs and cause chronic stimulation of PRRs and hence be a source of chronic immune activation as discussed above. Increased levels of lipid peroxidation in the brain with the production of malondialdehyde (MDA), 4-hydroxy-2-trans-nonenal (HNE or 4-hydroxynonenal (4-HNA)) and thiobarbituric acid-reactive substances (TBARS) following oral administration of aluminium chloride is also a common finding in small-animal studies (Newairy et al. 2009; Albendea et al. 2007; Yuan et al. 2012; Lu et al. 2013).

Chronic aluminium exposure also exerts profound detrimental effects on cellular anti-oxidant defences leading to significantly reduced cellular levels of glutathione transferase, glutathione peroxidase, catalase, superoxide dismutase and reduced glutathione (GSH) (Nampoothiri et al. 2015; El-Demerdash 2004; Yousef 2004; Kumar et al. 2011; Newairy et al. 2009). Aluminium ingestion also decreases GSH levels in human blood samples (Khan et al. 2011). Interestingly, aluminium decreases levels of this thiol by inhibiting the activity of NADPH-dependent isocitrate dehydrogenase in mitochondria and malic enzyme and NADPH isocitrate dehydrogenase in the cytosol (Murakami and Yoshino 2004). This is of importance as depleted levels of these enzymes make cells more sensitive to lipid peroxidation and oxidative mitochondrial DNA damage from singlet oxygen species in an environment of chronic oxidative stress (Kim and Park 2003; Lee et al. 2002; Kochevar 2004). In this context the existence of oxidative damage to mitochondrial proteins and DNA following prolonged aluminium exposure was reported by Sharma and colleagues (Sharma et al. 2013). Aluminium ingestion also leads to increased oxidative stress, markers of lipid peroxidation and decreased GSH levels in the epithelial cells lining the small intestine (Orihuela et al. 2005). This depletion of GSH appears to be affected by reduced activity of GSH synthase, GSH reductase and as yet undelineated changes to the plasma membranes resulting in a reduced influx of GSH from the lumen to the mucosa (Orihuela et al. 2005). This aluminium-induced depletion of GSH impairs the activity of calbindin-D9k resulting in decreased transcellular absorption of calcium ions (Orihuela et al. 2005). Given the positive role played by calcium ions in maintaining epithelial barrier integrity (Ma et al. 2000; Schepens et al. 2009), depletion of GSH could well underpin the increases in intestinal inflammation and intestinal barrier permeability caused by prolonged consumption of aluminium (Pineton de Chambrun et al. 2014).

Aluminium exposure and the development of mitochondrial dysfunction

Oxidative stress and subsequent mitochondrial dysfunction constitute the major vehicle underpinning aluminium-induced neurotoxicity (for review see Kumar and Gill 2014). Exposure to aluminium ions leads to a significant decrease in the activity of cytochrome C oxidase, NADH and succinate dehydrogenase, and a subsequent decrease in state 3 (ADP stimulated) and state 4 mitochondrial respiration, which are likely caused by conformational changes in these enzymes as a direct result of aluminium ion binding (Dua et al. 2010; Mohan et al. 2009; Mustafa Rizvi et al. 2014; Kumar et al. 2008). Aluminium also impairs mitochondrial biogenesis by decreasing levels of peroxisome proliferator activated receptor gamma co-activator 1α (PGC-1α) activity, either directly or indirectly as a result of inducing elevated levels of oxidative stress (Sharma et al. 2013). Aluminium ions also display the capacity to bind to the phosphate groups of ATP and ADP and inhibit the phosphorylation of the latter molecule and the dephosphorylation of the former, and this together with the capacity to inhibit a wide range of kinase and phosphatase enzymes can grossly impair energy homeostasis (Kawahara and Kato-Negishi 2011).

Aluminium can also impair mitochondrial function indirectly via mechanisms such as the induction of endoplasmic reticulum (ER) stress (Mustafa Rizvi et al. 2014; Johnson et al. 2005). Aluminium also induces mitochondrial dysfunction by provoking release of calcium ions from intracellular stores, and it is noteworthy that aluminium-induced oxidative damage and disruption of calcium ion homeostasis is similar in pattern to that seen in AD (Johnson et al. 2005; Walton 2012). The functional and physical relationship between the ER and mitochondria is well documented in the context of apoptosis, but perhaps under-discussed in the context of ER stress which is sub-lethal to the cell (Vannuvel et al. 2013). In the latter environment, the unfolded protein response in general, and protein kinase RNA-like ER kinase activity in particular, leads to a state of chronic mitochondrial underperformance rather than cellular death. This is a complex area and readers wishing to delve deeper into such mechanisms are invited to consult the work of Rainbolt et al. 2014.

Calcium dyshomeostasis is equally detrimental to mitochondrial function and of vital importance in the maintenance of neural function by matching mitochondrial energy production to demand (Rueda et al. 2014; Llorente-Folch et al. 2013). In particular, modest elevations of calcium ions in the cytosol following increases in neural activity act as the “gas pedal” (or “accelerator”) to increase energy production and maintain ATP homeostasis, hence impaired calcium homeostasis can have profound adverse effects on neural function, even in the absence of frank apoptosis (Gellerich et al. 2013) The adverse effects of aluminium on calcium homeostasis is likely one mechanism involved in aluminium-induced neuropathology and we now turn to a consideration of other mechanisms whereby aluminium exposure could result in the type of astrocytic and microglial dysfunction seen in many children with a confirmed diagnosis of ASD.

The above effects of aluminium are summarised in Fig. 1.

Aluminium exposure and glial cell activation or dysfunction

Chronic or prolonged exposure to aluminium can induce astrocyte apoptosis with one mechanism thought to involve DNA and chromatin damage, and hence mediated by p53 (Suarez-Fernandez et al. 1999; Johnson et al. 2005). Another route may involve inhibition of mitochondrial function and ATP production, ultimately causing necrosis, which can have profound and prolonged neuro-inflammatory consequences (Lemire and Appanna 2011). Prolonged aluminium exposure can also induce significant metabolic changes in astrocytes, which can compromise function even in the absence of degeneration. Such abnormalities include decreasing the activity of γ-butyrobetainealdehyde dehydrogenase and γ-butyrobetainealdehyde dioxygenase and reduced levels of α-ketoglutarate (AKG), leading to low levels of L-carnitine and subsequently impaired fatty acid beta-oxidation, mitochondrial dysfunction, reduced ATP production and increased lipogenesis (Mailloux et al. 2011; Lemire et al. 2011; Han et al. 2013).

The increased lipogenesis subsequent to aluminium-induced mitochondrial dysfunction via this route is enabled by significant increases in lipogenic enzymes such as acetyl CoA carboxylase (Mailloux et al. 2006). The increase in activity of these enzymes is accompanied by decreases in the activity of key enzymes within the electron transport chain and the tricarboxylic acid (Kreb’s) cycle, such as succinate dehydrogenase and AKG, leading to a significant decrease in the levels of ATP produced by oxidative phosphorylation (Mailloux et al. 2009; Mailloux et al. 2006; Mailloux et al. 2007). The loss of AKG activity in mitochondria and cytosol, likely caused by sequestration of this molecule by antioxidant defences, also results in significant negative consequences for energy generation within the glial cells. Briefly, AKG acts to stabilise hypoxia-inducible factor-1-alpha (HIF-1α) in the cytoplasm and prevents its translocation to the nucleus. However, in a cellular environment of increased aluminium cations and subsequently reduced AKG levels, HIF-1α translocates to the nucleus provoking increases in the transcription of hexokinase, pyruvate kinase, lactate dehydrogenase and glucose-6-phosphate dehydrogenase, with the ultimate effect of switching from energy production by oxidative phosphorylation to the phylogenetically more ancient pathway of energy production via glycolysis (Mailloux and Appanna 2007; Agrawal et al. 2007).

Aluminium also induces significant alterations to glutamate/glutamine recycling within astrocytes leading to increased glutamine to glutamate conversion coupled with increased uptake of glutamate and increased intracellular levels of glutamine (Zielke et al. 1993; Struys-Ponsar et al. 2000). This has the effect of modulating glutamatergic and GABA-ergic neurotransmission, but may also have significant bioenergetic consequences given that increased levels of glutamate within astrocytes act as a further stimulus for increased glycolysis (Albrecht et al. 2010; Bouzier-Sore and Pellerin 2013). These observations are pertinent from the perspective of potentially impaired neurodevelopment as astrocytes play an important role in the development of the brain by regulating processes involved in synaptic transmission, neuronal migration, synaptogenesis and maybe even myelination (reviewed by Molofsky et al. 2012). The weight of evidence also indicates that the activity of these glial cells is of paramount importance in the development and maintenance of neural networks and circuits (Clarke and Barres 2013). Furthermore, there is now considerable evidence indicating that impaired astrocyte function plays a pivotal role in the pathogenesis of neurodevelopmental disorders (Molofsky et al. 2012; Sloan and Barres 2013; Yang et al. 2013).

Aluminium can activate microglia leading to secretion of TNF-α, IL-6 and cytokine-inducible nitric oxide synthase (iNOS or NOS-2) and the development of neuro-inflammatory PICs and ROS (Bondy 2010; Zaky et al. 2013). This is also an important finding as there is now overwhelming evidence demonstrating that microglia play an indispensable role in the development of the brain by regulating processes such as synaptic pruning, synaptic plasticity, synaptogenesis, neuronal development and other vital processes in neurogenesis (Kettenmann et al. 2013). Microglial dysfunction and/or priming provoked by immune challenges, inflammatory events or other changes in the brain which interfere with processes such as synaptic pruning and neural proliferation is now thought to play a major causative role in the development of ASD and other neurodevelopmental disorders such a schizophrenia (Harry and Kraft 2012; Harry 2013; Hoeijmakers et al. 2016; Edmonson et al. 2016). The stepwise development of microglia is regulated by the activity of several genes, and disruption in the expression of these genes can occur as a result of prenatal immune activation or disturbances in the microbiota (Matcovitch-Natan et al. 2016). Aluminium can also provoke microglial activation and dysfunction via several other mechanisms, notably by impairing the function of the multifunctional molecular complex of the adapter protein, DNAX activating protein of 12 kD (DAP12) with TREM2, i.e. DAP12/TREM2, which is expressed on the surface of glial cells (Bhattacharjee et al. 2014; Zhao et al. 2014; Alexandrov et al. 2013).

The DAP12/TREM2 protein complex plays a major role in the regulation of central nervous system homeostasis (Paradowska-Gorycka and Jurkowska 2013; Thrash et al. 2009). TREM2 binds a range of liposaccharides, phospholipids and polyanions with the subsequent activation of DAP12 and an array of downstream kinases cumulating in cellular activation (Poliani et al. 2015; Takahashi et al. 2007). Activation of the DAP12/TREM2 axis has an important role in limiting PICs and other neurotoxins following TLR activation by PAMPs and DAMPs, and promotes the survival and proliferation of microglia and other cells of the myeloid lineage (Poliani et al. 2015; Peng et al. 2013). However, in recent years the bulk of research on the DAP12/TREM2 complex has focused on its role in enabling and regulating microglial phagocytosis (Neumann and Takahashi 2007; Painter et al. 2015). TREM2 acts as a molecular sensor of macromolecular debris and plays an indispensable role in its immunogenically silent clearance, thereby resolving potentially inflammatory reactions and acting as an impediment to the development of neuro-inflammation (Painter et al. 2015; Takahashi et al. 2005; Takahashi et al. 2007; Hsieh et al. 2009).

Microglial phagocytic processes play an essential role in removing damaged or stressed neurons and synaptic structures, apoptotic cells and other cellular debris from the brain, which have the potential of being immunogenic, and thus militate against the development of neuro-inflammation. Hence, this process plays an indispensable role in the maintenance of neural homeostasis (Fu et al. 2014; Jones et al. 2014; Zhao and Lukiw 2013). Unsurprisingly, several research teams have reported that failure of these unceasing microglial phagocytic processes have serious and potentially catastrophic innate-immune, pro-inflammatory and neuropathogenic consequences (Jones et al. 2014; Koenigsknecht-Talboo et al. 2008). Crucially, as previously noted, microglial apoptosis is both regulated and enabled by TREM2 (Zhao and Lukiw 2013; Alexandrov et al. 2013; Jones et al. 2014; Wang et al. 2015). Impairment in the activity and/or expression of TREM2 causes gross impairments of microglial phagocytic activity leading to a broad spectrum of central nervous system pathology including neuro-inflammation, synapatic loss, neuronal loss and exaggerated production of PICs (Wang et al. 2015; Hickman and El Khoury 2014; Jiang et al. 2014).

TREM2 expression in turn is regulated by a number of miRNAs, most notably miR-34a (Zhao et al. 2013; Zhao and Lukiw 2013; Alexandrov et al. 2013). Microglial miR-34a expression is upregulated by activation of the pro-inflammatory transcription factor NF-κB (Zhang et al. 2011; Hickman and El Khoury 2014; Bhattacharjee et al. 2014). Aluminium in adjuvant or environmental form upregulates NF-κB (Pogue et al. 2009; Bondy 2014), and thereby induces a number of NF-κB-sensitive pro-inflammatory miRNAs, notably miR-34a (Fu et al. 2014; Jones et al. 2014; Hickman and El Khoury 2014; Zhang et al. 2013; Zhao and Lukiw 2013), which in turn downregulates TREM2 expression in the membranes of glial cells leading to a profound deficit in their phagocytic capability (Hickman and El Khoury 2014; Zhao et al. 2013; Bhattacharjee et al. 2014).

Upregulation of NF-κB induces the synthesis of other inflammatory miRNAs such as miR-9, miR-125b, miR-146a and miR-155, which are recognised drivers of pathology in several neurodegenerative diseases such as AD (Zhao et al. 2014; Lukiw 2012). While aluminium clearly could provoke chronic pathology in people with a high or prolonged exposure, it should be further emphasised that the likelihood that adjuvant use could be the main cause of ASD in children, or indeed harmful to the vast majority of children with normal immune responses, appears to be vanishingly small. However, the situation in children with an abnormal immune system and a predisposition to autoimmunity may be different, and this will be the final area of discussion in this paper.

The actions of aluminium on astrocytes and microglia are summarised in Fig. 2.
Fig. 1

Summary of the effects of aluminium

Fig. 2

Effects of aluminium on astrocytes and microglia

Section 4. Consequences of aluminium exposure in individuals with abnormal immune responses

Polymorphisms in immune effector genes

Abnormalities in the performance of PPRs are increasingly associated with the development of neurodegenerative and autoimmune conditions (Moraes et al. 2013; Cook et al. 2004; Marshak-Rothstein 2006; Pradhan et al. 2012; Liu et al. 2014). In particular, functional polymorphisms in the genes encoding proteins involved in effecting the immune response following ligation of TLR-4, TLR-7 and TLR-9 increase the susceptibility to and/or severity of a range of neurological, auto-immune, inflammatory and infective illnesses, including SLE, rheumatoid arthritis, asthma, sepsis and hepatitis (Moraes et al. 2013; Dhaouadi et al. 2013; Fichna et al. 2016; Netea et al. 2012). Unsurprisingly, functional polymorphisms in cytokine genes such as those encoding for TNF-α, IL-β, IL-6, IL-10 and IL-4 also increase the susceptibility to develop a range of inflammatory, infective and autoimmune conditions (Morris and Berk 2015).

The presence of these polymorphisms can also heavily influence the severity and ultimate trajectory of these diseases in any given individual (Arfanakis et al. 2013; Tunçbilek 2014; Haukim et al. 2002; Hollegaard and Bidwell 2006). There is also accumulating evidence that functional polymorphisms in genes encoding cytokines and/or their receptors increase the risk of neuro-inflammatory and neurodegenerative pathology such as stroke, AD, and MS (Ottoboni et al. 2013; Bagnoli et al. 2007; Miranda-Hernandez and Baxter 2013; Cui et al. 2012). Functional polymorphisms can also lead to altered structure and function of receptor and effector proteins involved in a broad range of inflammasome responses, and once again such mutations are also involved in the pathogenesis of several autoimmune, neuro-immune and neurodegenerative diseases (Pontillo et al. 2012; Tan et al. 2013; review by Yang and Chiang 2015). In general, “pathological” polymorphisms within nuclear localisation leucine-rich-repeat protein-1 (NLRP1) pathways lead to an exaggerated and/or prolonged inflammatory response (Levandowski et al. 2013).

It is of interest that recent research has revealed a significant association between the cumulative presence of immune gene polymorphisms and increased risk of developing ASD (Ramos et al. 2012). Single nucleotide polymorphisms (SNPs) in immune genes in many children also display a signature pattern which is characteristic of autoimmune diseases such as MS (Jung et al. 2011). Unsurprisingly, polymorphisms in the HLA system, notably HLA-DR4 and HLA-A2, are associated with a significantly increased likelihood of developing the syndrome (Mostafa et al. 2013; Torres et al. 2012). It is also noteworthy that the concomitant presence of abnormally expressed genes governing the regulation and delivery of immune and inflammatory responses can predict the development of ASD with some 83% accuracy (Pramparo et al. 2015).

There is now copious evidence of dysregulated expression of genes regulating the innate and adaptive immune response in children with ASD (Michel et al. 2012; Gupta et al. 2014). There is also some evidence of functional polymorphisms coupled with exaggerated PRR responses in at least some affected children (Bennabi et al. 2015; Enstrom et al. 2010). There is also an accumulating body of research demonstrating that immune responses following activation of TLRs are abnormal in many children who have received a diagnosis of ASD (Mead and Ashwood 2015; Gesundheit et al. 2013; Enstrom et al. 2010). Moreover, several research teams have adduced evidence indicating that the immune response is abnormal in many children with ASD, and in particular that genes governing the regulation and performance of immune and inflammatory responses are upregulated allowing for an excessive and/or prolonged response to an environmental insult (Voineagu and Eapen 2013; Koufaris and Sismani 2015). It is also noteworthy that several researchers have also reported an association between initial inflammatory insults and the subsequent development of chronic immune disturbances in ASD children (Siniscalco 2015; Gottfried et al. 2015; McDougle et al. 2015). This is particularly noteworthy, as prolonged and/or excessive activation of immune and inflammatory pathways leading to oxidative and nitrosative stress can have detrimental consequences for cellular and tissue integrity, which in turn could lead to the chronic activation of immune and inflammatory pathways and ultimately of microglia and astrocytes in the brain as we will now discuss.

Prolonged or excessive immune responses and the production of DAMPs

Oxidative stress activates NFκB and other transcription factors such as activated protein-1 (AP-1), leading to the synthesis and secretion of PICs, various chemokine species by antigen presentation cells, and activation and proliferation of T and B lymphocytes (Morris et al. 2015a; Lucas et al. 2015). Such activation and PIC production leads to the upregulation of iNOS and NADPH oxidase, leading to the production of superoxide, NO and peroxynitrite, and hence further increases in ROS and reactive nitrogen species (RNS) levels (Morris and Maes 2014; Morris et al. 2015a). This bidirectional and self-amplifying relationship between the development of chronic systemic inflammation as evidenced by increased PIC levels and chronic nitro-oxidative stress as evidenced by increased levels of ROS and RNS is often labelled an “autotoxic loop” (Reuter et al. 2010; Ortiz et al. 2013). Excessive levels of ROS and RNS can also lead to the oxidative and nitrosative modification of lipids, proteins and DNA, leading to misfolded, and consequently immunogenic, proteins, oxidative modification of DNA and lipid peroxidation of cell membranes, together with the production of highly reactive ketones and aldehydes (Lucas et al. 2015). The net result of these processes is the indirect and direct formation of DAMPs capable of activating pathogen-sensing receptors on the cell surface, and in the cytoplasm of immune cells (Hwang 2013; Ortiz et al. 2013).

In summary, the presence of the immune abnormalities discussed allows for an abnormally excessive or prolonged inflammatory response following exposure to aluminium adjuvants, leading to the production of DAMPs and subsequent chronic immune activation in genetically susceptible children. It is noteworthy that several authors have reported the presence of DAMPs such as protein carbonyls, MDA and high-mobility group box-1 (HMGB1) protein in at least some children afforded a diagnosis of ASD, and such DAMPs could play a major role in initiating and maintaining a state of immune activation and inflammation seen in many children with an ASD diagnosis (Babinska et al. 2014; Emanuele et al. 2010; Frank et al. 2016; Napoli et al. 2013).

Chronic engagement of TLRs by DAMPs leads to the development of a positive feedback loop, whereby increasing tissue damage caused by elevated PICs, ROS and RNS perpetuates and escalates pro-inflammatory responses, leading to a state of chronic inflammation nitro-oxidative stress, mitochondrial dysfunction and glial cell activation (Drexler and Foxwell 2010; Piccinini and Midwood 2010; Goh and Midwood 2012; Morris and Berk 2015). Unsurprisingly, chronic engagement of TLRs, nucleotide-binding oligomerisation domain (NOD)-like receptors and RIG-like receptors is implicated in the pathogenesis and pathophysiology of SLE, rheumatoid arthritis and MS (review (Drexler and Foxwell 2010; Piccinini and Midwood 2010; Goh and Midwood 2012)). Pertinently, the presence of DAMPs can also lead to the chronic activation of the inflammasome (Anders and Schaefer 2014) which is also implicated in the development of neuro-inflammation and abnormal central nervous system signalling characteristic of neurodegenerative and neurodevelopmental disorders (Tan et al. 2013; Singhal et al. 2014). It is also of interest that a recent study has reported the presence of activated inflammasome complexes in at least some children afforded a diagnosis of ASD (Saresella et al. 2016) There is now overwhelming evidence that prolonged and/or chronic activation of peripheral immune and inflammatory pathways provokes the development of chronic neuro-inflammtion and/or microglial priming and a brief explanation of this process will constitute the final subsection of this paper.

Systemic immune activation primed microglia and chronic neuro-inflammation

There is ample evidence demonstrating that chronic immune system activation and systemic inflammation can lead to the development of chronic neuro-inflammation (Perry and Holmes 2014; Cunningham 2013). Communication of inflammatory signals to the brain is mediated by PICs via a number of routes, including innervation of the vagus nerve, carrier-enabled transport across the blood-brain barrier (BBB), activation of endothelial cells within the BBB and perivascular macrophages, and finally via transport through circumventricular organs devoid of a functional BBB (Morris and Maes 2012, 2014). The transduced inflammatory signals may lead to the development of chronic neuro-inflammation via the activation of microglia if of sufficient intensity and/or duration or lead to the development of “primed” microglia (Perry and Holmes 2014; Su and Federoff 2014). Microglial priming involves the upregulation of a range of surface receptors such as MHC class II, CD11b and CD11c integrins, co-stimulatory molecule CD86 and TLR-4 (Su and Federoff 2014).

Following the upregulation of these receptors, such microglia become exquisitely sensitive to subsequent inflammatory stimuli, leading to an exaggerated production of neurotoxic molecules that may exacerbate the pre-existing pathology and may even accelerate the progression of existing neuro-inflammatory or neurodegenerative diseases (Ferrari and Tarelli 2011; Lunnon et al. 2011). Activated microglia exert their neurotoxic effects by releasing PICs, such as TNF-α, IL-1β, IL-6, and IFN-γ, and free radicals including superoxide, NO and peroxynitrite, as well as inflammatory molecules such as prostaglandin E2. Moreover, TNF-α, IL-1β and IFN-γ can act as secondary sources of RNS and other inflammatory molecules by acting as potent inducers of iNOS and via their capacity to upregulate cyclooxygenase-2 (COX-2) with the resultant production of prostaglandin E2 (Morris et al. 2015b; Perry et al. 2010). The concept of microglial priming could change the frame of reference from a consideration of a single inoculation containing aluminium adjuvant to a cumulative effect caused by a vaccination schedule in which successive immune insults over a short period could provoke chronic pathology either directly, by provoking microglial activity, or more indirectly by provoking macromolecular damage which could eventually reach a threshold capable of provoking chronic pathology. It should be noted that there is an accumulating body of evidence, albeit from animal studies, that successive and frequent postnatal immune and inflammatory insults play a pivotal role in the advent of microglial priming and the genesis of neurodevelopmental disorders (Ibi and Yamada 2015; Nagai 2013). There is also emerging data implicating the development of microglial priming as a major factor in the development of several if not all neurodegenerative diseases (Bhattacharya et al. 2016; Zhao et al. 2014; Shastri et al. 2013; Hoeijmakers et al. 2016).


Evidence of the neurotoxicity of aluminium cations (Al3+) includes: an association between chronic aluminium exposure and the development of AD; the involvement of aluminium adjuvants in the development of ASIA; and epidemiological evidence pointing to an association between the use of aluminium adjuvants and ASD. There is good evidence to suggest that immunisation may accelerate or precipitate the transition between subclinical and overt symptomatic autoimmune conditions within the first 30 days post-immunisation, particularly in those younger than 50 years of age. The immune response to immunisation may be influenced by variations in HLA, TLR and cytokine genes. Moreover, aluminium exposure is associated with the production of pro-inflammatory cytokines and chemokines and with the development of chronic oxidative stress, mitochondrial dysfunction and glial activation or dysfunction; these changes in turn are associated with ASD.

Conclusions and Future Directions

Aluminium has no known beneficial physiological action in the human body and some genetic polymorphisms predispose to a greater susceptibility to its adverse effects. Therefore, a strong case can be made for avoiding unnecessary exposure to environmental sources of aluminium salts, especially on the part of children, pregnant mothers and women of child-bearing age who may become pregnant. Such avoidance need not lead to hardship or inconvenience; aluminium cookware may be replaced by safer alternatives, while aluminium-containing antiperspirants, potentially implicated in the rise of cases of breast cancer particularly affecting the upper outer quadrant of the mammary gland, may be replaced by non-aluminium versions. The use of aluminium salts in medical products is a more contentious issue. While antacids are available which do not contain aluminium salts, the avoidance of immunisations which do not contain aluminium salts as adjuvants has wider political and financial implications. It would seem prudent to try to find an alternative to aluminium adjuvants as soon as possible and phase out their use.



The authors wish to thank Victoria Storey for her help in constructing the figures.

Compliance with ethical standards

Conflicts of Interest

The authors declare that they have no conflict of interest.


  1. Abdallah MW, Hougaard DM, Norgaard-Pedersen B, Grove J, Bonefeld-Jorgensen EC, Mortensen EL (2012) Infections during pregnancy and after birth, and the risk of autism spectrum disorders: a register-based study utilizing a Danish historic birth cohort. Turk psikiyatri dergisi = Turkish J Psychiatry 23(4):229–235Google Scholar
  2. Abd-Elghaffar S, El-Sokkary GH, Sharkawy AA (2005) Aluminum-induced neurotoxicity and oxidative damage in rabbits: protective effect of melatonin. Neuro Endocrinol Lett 26(5):609–616PubMedGoogle Scholar
  3. Agmon-Levin N, Paz Z, Israeli E, Shoenfeld Y (2009) Vaccines and autoimmunity. Nat Rev Rheumatol 5(11):648–652. doi: 10.1038/nrrheum.2009.196 PubMedCrossRefGoogle Scholar
  4. Agmon-Levin N, Zafrir Y, Kivity S, Balofsky A, Amital H, Shoenfeld Y (2014) Chronic fatigue syndrome and fibromyalgia following immunization with the hepatitis B vaccine: another angle of the 'autoimmune (auto-inflammatory) syndrome induced by adjuvants' (ASIA). Immunol Res 60(2–3):376–383. doi: 10.1007/s12026-014-8604-2 PubMedCrossRefGoogle Scholar
  5. Agrawal A, Guttapalli A, Narayan S, Albert TJ, Shapiro IM, Risbud MV (2007) Normoxic stabilization of HIF-1alpha drives glycolytic metabolism and regulates aggrecan gene expression in nucleus pulposus cells of the rat intervertebral disk. Am J Physiol Cell Physiol 293(2):C621–C631. doi: 10.1152/ajpcell.00538.2006 PubMedCrossRefGoogle Scholar
  6. Ahmed SS, Santosh W (2010) Metallomic profiling and linkage map analysis of early Parkinson's disease: a new insight to aluminum marker for the possible diagnosis. PLoS One 5(6):e11252. doi: 10.1371/journal.pone.0011252 PubMedPubMedCentralCrossRefGoogle Scholar
  7. Al-Ayadhi LY (2005) Heavy metals and trace elements in hair samples of autistic children in central Saudi Arabia. Neurosci (Riyadh, Saudi Arabia) 10(3):213–218Google Scholar
  8. Albendea CD, Gomez-Trullen EM, Fuentes-Broto L, Miana-Mena FJ, Millan-Plano S, Reyes-Gonzales MC, Martinez-Ballarin E, Garcia JJ (2007) Melatonin reduces lipid and protein oxidative damage in synaptosomes due to aluminium. J Trace Elements Med Biol: Organ of the Society for Minerals and Trace Elements (GMS) 21(4):261–268. doi: 10.1016/j.jtemb.2007.04.002 CrossRefGoogle Scholar
  9. Albrecht J, Sidoryk-Wegrzynowicz M, Zielinska M, Aschner M (2010) Roles of glutamine in neurotransmission. Neuron Glia Biol 6(4):263–276. doi: 10.1017/s1740925x11000093 PubMedCrossRefGoogle Scholar
  10. Alexandrov PN, Zhao Y, Jones BM, Bhattacharjee S, Lukiw WJ (2013) Expression of the phagocytosis-essential protein TREM2 is down-regulated by an aluminum-induced miRNA-34a in a murine microglial cell line. J Inorg Biochem 128:267–269. doi: 10.1016/j.jinorgbio.2013.05.010 PubMedCrossRefGoogle Scholar
  11. Al-Olayan EM, El-Khadragy MF, Abdel Moneim AE (2015) The protective properties of melatonin against aluminium-induced neuronal injury. Int J Exp Pathol 96(3):196–202. doi: 10.1111/iep.12122 PubMedPubMedCentralCrossRefGoogle Scholar
  12. Anders HJ, Schaefer L (2014) Beyond tissue injury-damage-associated molecular patterns, toll-like receptors, and inflammasomes also drive regeneration and fibrosis. J Am Soc Nephrol: JASN 25(7):1387–1400. doi: 10.1681/asn.2014010117 PubMedPubMedCentralCrossRefGoogle Scholar
  13. Andrews N, Miller E, Grant A, Stowe J, Osborne V, Taylor B (2004) Thimerosal exposure in infants and developmental disorders: a retrospective cohort study in the United kingdom does not support a causal association. Pediatrics 114(3):584–591. doi: 10.1542/peds.2003-1177-L PubMedCrossRefGoogle Scholar
  14. Arfanakis K, Fleischman DA, Grisot G, Barth CM, Varentsova A, Morris MC, Barnes LL, Bennett DA (2013) Systemic Inflammation in Non-Demented Elderly Human Subjects: Brain Microstructure and Cognition. PLoS One 8(8):e73107. doi: 10.1371/journal.pone.0073107 PubMedPubMedCentralCrossRefGoogle Scholar
  15. Arnheim-Dahlstrom L, Pasternak B, Svanstrom H, Sparen P, Hviid A (2013) Autoimmune, neurological, and venous thromboembolic adverse events after immunisation of adolescent girls with quadrivalent human papillomavirus vaccine in Denmark and Sweden: cohort study. BMJ 347:f5906. doi: 10.1136/bmj.f5906 PubMedPubMedCentralCrossRefGoogle Scholar
  16. van Assen S, Elkayam O, Agmon-Levin N, Cervera R, Doran MF, Dougados M, Emery P, Geborek P, Ioannidis JP, Jayne DR, Kallenberg CG, Muller-Ladner U, Shoenfeld Y, Stojanovich L, Valesini G, Wulffraat NM, Bijl M (2011) Vaccination in adult patients with auto-immune inflammatory rheumatic diseases: a systematic literature review for the European League Against Rheumatism evidence-based recommendations for vaccination in adult patients with auto-immune inflammatory rheumatic diseases. Autoimmun Rev 10(6):341–352. doi: 10.1016/j.autrev.2010.12.003 PubMedCrossRefGoogle Scholar
  17. Babinska K, Bucova M, Durmanova V, Lakatosova S, Janosikova D, Bakos J, Hlavata A, Ostatnikova D (2014) Increased plasma levels of the high mobility group box 1 protein (HMGB1) are associated with a higher score of gastrointestinal dysfunction in individuals with autism. Physiol Res 63(Suppl 4):S613–S618PubMedGoogle Scholar
  18. Bagavant H, Nandula SR, Kaplonek P, Rybakowska PD, Deshmukh US (2014) Alum, an Aluminum Based Adjuvant, Induces Sjögren’s Syndrome-like Disorder in Mice. Clin Exp Rheumatol 32(2):251–255PubMedPubMedCentralGoogle Scholar
  19. Bagnoli S, Cellini E, Tedde A, Nacmias B, Piacentini S, Bessi V, Bracco L, Sorbi S (2007) Association of IL10 promoter polymorphism in Italian Alzheimer's disease. Neurosci Lett 418(3):262–265. doi: 10.1016/j.neulet.2007.03.030 PubMedCrossRefGoogle Scholar
  20. Basun H, Forssell LG, Wetterberg L, Winblad B (1991) Metals and trace elements in plasma and cerebrospinal fluid in normal aging and Alzheimer's disease. J Neural Transm Park Dis Dement Sect 3(4):231–258PubMedGoogle Scholar
  21. Beauchemin D, Kisilevsky R (1998) A method based on ICP-MS for the analysis of Alzheimer's amyloid plaques. Anal Chem 70(5):1026–1029PubMedCrossRefGoogle Scholar
  22. Bennabi M, Delorme R, Oliveira J, Fortier C, Lajnef M, Boukouaci W, Feugeas J-P, Marzais F, Gaman A, Charron D, Ghaleh B, Krishnamoorthy R, Leboyer M, Tamouza R (2015) Dectin-1 Polymorphism: A Genetic Disease Specifier in Autism Spectrum Disorders? PLoS One 10(9):e0137339. doi: 10.1371/journal.pone.0137339 PubMedPubMedCentralCrossRefGoogle Scholar
  23. Betancur C (2011) Etiological heterogeneity in autism spectrum disorders: more than 100 genetic and genomic disorders and still counting. Brain Res 1380:42–77. doi: 10.1016/j.brainres.2010.11.078 PubMedCrossRefGoogle Scholar
  24. Bhattacharjee S, Zhao Y, Hill JM, Culicchia F, Kruck TPA, Percy ME, Pogue AI, Walton JR, Lukiw WJ (2013) Selective accumulation of aluminum in cerebral arteries in Alzheimer's disease (AD). J Inorg Biochem 126:35–37. doi: 10.1016/j.jinorgbio.2013.05.007 PubMedPubMedCentralCrossRefGoogle Scholar
  25. Bhattacharjee S, Zhao Y, Lukiw WJ (2014) Deficits in the miRNA-34a-regulated endogenous TREM2 phagocytosis sensor-receptor in Alzheimer's disease (AD); an update. Front Aging Neurosci 6:116. doi: 10.3389/fnagi.2014.00116 PubMedPubMedCentralGoogle Scholar
  26. Bhattacharya A, Derecki NC, Lovenberg TW, Drevets WC (2016) Role of neuro-immunological factors in the pathophysiology of mood disorders. Psychopharmacology 233(9):1623–1636. doi: 10.1007/s00213-016-4214-0 PubMedCrossRefGoogle Scholar
  27. Blaurock-Busch E, Amin OR, Rabah T (2011) Heavy metals and trace elements in hair and urine of a sample of arab children with autistic spectrum disorder. Maedica 6(4):247–257PubMedPubMedCentralGoogle Scholar
  28. Blaurock-Busch E, Amin OR, Dessoki HH, Rabah T (2012) Toxic Metals and Essential Elements in Hair and Severity of Symptoms among Children with Autism. Maedica 7(1):38–48PubMedPubMedCentralGoogle Scholar
  29. Bondy SC (2010) The neurotoxicity of environmental aluminum is still an issue. Neurotoxicology 31(5):575–581. doi: 10.1016/j.neuro.2010.05.009 PubMedPubMedCentralCrossRefGoogle Scholar
  30. Bondy SC (2014) Prolonged exposure to low levels of aluminum leads to changes associated with brain aging and neurodegeneration. Toxicology 315:1–7. doi: 10.1016/j.tox.2013.10.008 PubMedCrossRefGoogle Scholar
  31. Bouras C, Giannakopoulos P, Good PF, Hsu A, Hof PR, Perl DP (1997) A Laser Microprobe Mass Analysis of Brain Aluminum and Iron in Dementia pugilistica: Comparison with Alzheimer's Disease. Eur Neurol 38(1):53–58PubMedCrossRefGoogle Scholar
  32. Bouzier-Sore A-K, Pellerin L (2013) Unraveling the complex metabolic nature of astrocytes. Front Cell Neurosci 7. doi: 10.3389/fncel.2013.00179
  33. Bushnell PJ (2013) Special issue: Environmental influences and emerging mechanisms in the etiology of autism. Neurotoxicol Teratol 36:1–2. doi: 10.1016/ PubMedCrossRefGoogle Scholar
  34. Careaga M, Ashwood P (2012) Autism spectrum disorders: from immunity to behavior. Methods Mol Biol 934:219–240. doi: 10.1007/978-1-62703-071-7_12 PubMedCrossRefGoogle Scholar
  35. Castiblanco J, Anaya J-M (2015) Genetics and Vaccines in the Era of Personalized Medicine. Current Genomics 16(1):47–59. doi: 10.2174/1389202916666141223220551 PubMedPubMedCentralCrossRefGoogle Scholar
  36. Cerpa-Cruz S, Paredes-Casillas P, Landeros Navarro E, Bernard-Medina AG, Martinez-Bonilla G, Gutierrez-Urena S (2013) Adverse events following immunization with vaccines containing adjuvants. Immunol Res 56(2–3):299–303. doi: 10.1007/s12026-013-8400-4 PubMedCrossRefGoogle Scholar
  37. Chafi AH, Hauw JJ, Rancurel G, Berry JP, Galle C (1991) Absence of aluminium in Alzheimer's disease brain tissue: electron microprobe and ion microprobe studies. Neurosci Lett 123(1):61–64PubMedCrossRefGoogle Scholar
  38. Chao C, Klein NP, Velicer CM, Sy LS, Slezak JM, Takhar H, Ackerson B, Cheetham TC, Hansen J, Deosaransingh K, Emery M, Liaw KL, Jacobsen SJ (2012) Surveillance of autoimmune conditions following routine use of quadrivalent human papillomavirus vaccine. J Intern Med 271(2):193–203. doi: 10.1111/j.1365-2796.2011.02467.x PubMedCrossRefGoogle Scholar
  39. Chen S, Li Z, He Y, Zhang F, Li H, Liao Y, Wei Z, Wan G, Xiang X, Hu M, Xia K, Chen X, Tang J (2015) Elevated mitochondrial DNA copy number in peripheral blood cells is associated with childhood autism. BMC Psychi 15:50. doi: 10.1186/s12888-015-0432-y CrossRefGoogle Scholar
  40. Clarke LE, Barres BA (2013) Emerging roles of astrocytes in neural circuit development. Nat Rev Neurosci 14(5):311–321. doi: 10.1038/nrn3484 PubMedPubMedCentralCrossRefGoogle Scholar
  41. Cook DN, Pisetsky DS, Schwartz DA (2004) Toll-like receptors in the pathogenesis of human disease. Nat Immunol 5(10):975–979PubMedCrossRefGoogle Scholar
  42. Cruz-Tapias P, Agmon-Levin N, Israeli E, Anaya JM, Shoenfeld Y (2013) Autoimmune (auto-inflammatory) syndrome induced by adjuvants (ASIA)--animal models as a proof of concept. Current Med Chem 20(32):4030–4036CrossRefGoogle Scholar
  43. Cui G, Wang H, Li R, Zhang L, Li Z, Wang Y, Hui R, Ding H, Wang DW (2012) Polymorphism of tumor necrosis factor alpha (TNF-alpha) gene promoter, circulating TNF-alpha level, and cardiovascular risk factor for ischemic stroke. J Neuroinflammation 9:235. doi: 10.1186/1742-2094-9-235 PubMedPubMedCentralCrossRefGoogle Scholar
  44. Cunningham C (2013) Microglia and neurodegeneration: the role of systemic inflammation. Glia 61:71–90PubMedCrossRefGoogle Scholar
  45. Darbre PD, Pugazhendhi D, Mannello F (2011) Aluminium and human breast diseases. J Inorg Biochem 105(11):1484–1488. doi: 10.1016/j.jinorgbio.2011.07.017 PubMedCrossRefGoogle Scholar
  46. Darbre PD, Mannello F, Exley C (2013) Aluminium and breast cancer: Sources of exposure, tissue measurements and mechanisms of toxicological actions on breast biology. J Inorg Biochem 128:257–261. doi: 10.1016/j.jinorgbio.2013.07.005 PubMedCrossRefGoogle Scholar
  47. De Sole P, Rossi C, Chiarpotto M, Ciasca G, Bocca B, Alimonti A, Bizzarro A, Rossi C, Masullo C (2013) Possible relationship between Al/ferritin complex and Alzheimer's disease. Clin Biochem 46(1–2):89–93. doi: 10.1016/j.clinbiochem.2012.10.023 PubMedCrossRefGoogle Scholar
  48. Depino AM (2013) Peripheral and central inflammation in autism spectrum disorders. Mol Cell Neurosci 53:69–76. doi: 10.1016/j.mcn.2012.10.003 PubMedCrossRefGoogle Scholar
  49. DeStefano F (2007) Vaccines and autism: evidence does not support a causal association. Clin Pharmacol Ther 82(6):756–759. doi: 10.1038/sj.clpt.6100407 PubMedCrossRefGoogle Scholar
  50. Dhaouadi T, Sfar I, Haouami Y, Abdelmoula L, Turki S, Hassine L (2013) Polymorphisms of Toll-like receptor-4 and CD14 in systemic lupus erythematosus and rheumatoid arthritis. Biomark Res 1:20PubMedPubMedCentralCrossRefGoogle Scholar
  51. Drexler SK, Foxwell BM (2010) The role of toll-like receptors in chronic inflammation. Int J Biochem Cell Biol 42(4):506–518. doi: 10.1016/j.biocel.2009.10.009 PubMedCrossRefGoogle Scholar
  52. Dua R, Sunkaria A, Kumar V, Gill KD (2010) Impaired mitochondrial energy metabolism and kinetic properties of cytochrome oxidase following acute aluminium phosphide exposure in rat liver. Food Chem Toxicol 48(1):53–60. doi: 10.1016/j.fct.2009.09.014 PubMedCrossRefGoogle Scholar
  53. Edmonson CA, Ziats MN, Rennert OM (2016) A Non-inflammatory Role for Microglia in Autism Spectrum Disorders. Front Neurol 7:9. doi: 10.3389/fneur.2016.00009 PubMedPubMedCentralCrossRefGoogle Scholar
  54. Edwardson JA, Klinowski J, Oakley AE, Perry RH, Candy JM (1986) Aluminosilicates and the ageing brain: implications for the pathogenesis of Alzheimer's disease. CIBA Found Symp 121:160–179PubMedGoogle Scholar
  55. Eisenbarth SC, Colegio OR, O'Connor W, Sutterwala FS, Flavell RA (2008) Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature 453(7198):1122–1126. doi: 10.1038/nature06939 PubMedPubMedCentralCrossRefGoogle Scholar
  56. Eisenkraft A, Falk A, Finkelstein A (2013) The role of glutamate and the immune system in organophosphate-induced CNS damage. Neurotox Res 24(2):265–279. doi: 10.1007/s12640-013-9388-1 PubMedCrossRefGoogle Scholar
  57. El-Demerdash FM (2004) Antioxidant effect of vitamin E and selenium on lipid peroxidation, enzyme activities and biochemical parameters in rats exposed to aluminium. J Trace Elem Med Biol 18(1):113–121. doi: 10.1016/j.jtemb.2004.04.001 PubMedCrossRefGoogle Scholar
  58. Emanuele E, Boso M, Brondino N, Pietra S, Barale F, Ucelli di Nemi S, Politi P (2010) Increased serum levels of high mobility group box 1 protein in patients with autistic disorder. Prog Neuro-Psychopharmacol Biol Psychiatry 34(4):681–683. doi: 10.1016/j.pnpbp.2010.03.020 CrossRefGoogle Scholar
  59. Enstrom AM, Onore CE, Van de Water JA, Ashwood P (2010) Differential monocyte responses to TLR ligands in children with autism spectrum disorders. Brain Behav Immun 24(1):64–71. doi: 10.1016/j.bbi.2009.08.001 PubMedCrossRefGoogle Scholar
  60. Esposito S, Prada E, Mastrolia MV, Tarantino G, Codeca C, Rigante D (2014) Autoimmune/inflammatory syndrome induced by adjuvants (ASIA): clues and pitfalls in the pediatric background. Immunol Res 60(2–3):366–375. doi: 10.1007/s12026-014-8586-0 PubMedCrossRefGoogle Scholar
  61. Estes ML, McAllister AK (2015) Immune mediators in the brain and peripheral tissues in autism spectrum disorder. Nat Rev Neurosci 16(8):469–486. doi: 10.1038/nrn3978 PubMedCrossRefGoogle Scholar
  62. Exley C (2005) The aluminium-amyloid cascade hypothesis and Alzheimer's disease. Subcell Biochem 38:225–234PubMedCrossRefGoogle Scholar
  63. Exley C, Esiri MM (2006) Severe cerebral congophilic angiopathy coincident with increased brain aluminium in a resident of Camelford, Cornwall, UK. J Neurol Neurosurg Psychiatry 77(7):877–879. doi: 10.1136/jnnp.2005.086553 PubMedPubMedCentralCrossRefGoogle Scholar
  64. Exley C, Vickers T (2014) Elevated brain aluminium and early onset Alzheimer's disease in an individual occupationally exposed to aluminium: a case report. J Med Case Rep 8(1):41PubMedPubMedCentralCrossRefGoogle Scholar
  65. Exley C, Mamutse G, Korchazhkina O, Pye E, Strekopytov S, Polwart A, Hawkins C (2006) Elevated urinary excretion of aluminium and iron in multiple sclerosis. Mult Scler 12(5):533–540PubMedCrossRefGoogle Scholar
  66. Ferrari C, Tarelli R (2011) Parkinson's disease and systemic inflammation. Parkinsons Dis 2011:436813PubMedPubMedCentralGoogle Scholar
  67. Fichna M, Zurawek M, Fichna P, Januszkiewicz-Lewandowska D, Ruchala M, Nowak J (2016) Polymorphisms of the Toll-Like Receptor-3 Gene in Autoimmune Adrenal Failure and Type 1 Diabetes in Polish Patients. Arch Immunol Ther Exp 64(1):83–87. doi: 10.1007/s00005-015-0360-z CrossRefGoogle Scholar
  68. Fido A, Al-Saad S (2005) Toxic trace elements in the hair of children with autism. Autism 9(3):290–298. doi: 10.1177/1362361305053255 PubMedCrossRefGoogle Scholar
  69. Flashner BM, Russo ME, Boileau JE, Leong DW, Gallicano GI (2013) Epigenetic factors and autism spectrum disorders. NeuroMolecular Med 15(2):339–350. doi: 10.1007/s12017-013-8222-5 PubMedCrossRefGoogle Scholar
  70. Flaten TP (2001) Aluminium as a risk factor in Alzheimer's disease, with emphasis on drinking water. Brain Res Bull 55(2):187–196PubMedCrossRefGoogle Scholar
  71. Franchi L, Nunez G (2008) The Nlrp3 inflammasome is critical for aluminium hydroxide-mediated IL-1beta secretion but dispensable for adjuvant activity. Eur J Immunol 38(8):2085–2089. doi: 10.1002/eji.200838549 PubMedPubMedCentralCrossRefGoogle Scholar
  72. Frank MG, Weber MD, Fonken LK, Hershman SA, Watkins LR, Maier SF (2016) The redox state of the alarmin HMGB1 is a pivotal factor in neuroinflammatory and microglial priming: A role for the NLRP3 inflammasome. Brain Behav Immun 55:215–224. doi: 10.1016/j.bbi.2015.10.009 PubMedCrossRefGoogle Scholar
  73. Frustaci A, Neri M, Cesario A, Adams J, Domenici E, Dalla Bernardina B (2012) Oxidative stress-related biomarkers in autism: systematic review and meta-analyses. Free Radic Biol Med 52:2128–2141PubMedCrossRefGoogle Scholar
  74. Fu R, Shen Q, Xu P, Luo JJ, Tang Y (2014) Phagocytosis of microglia in the central nervous system diseases. Mol Neurobiol 49(3):1422–1434. doi: 10.1007/s12035-013-8620-6 PubMedPubMedCentralCrossRefGoogle Scholar
  75. Fulgenzi A, Vietti D, Ferrero ME (2014) Aluminium Involvement in Neurotoxicity. Biomed Res Int 2014:758323. doi: 10.1155/2014/758323 PubMedPubMedCentralGoogle Scholar
  76. Gellerich FN, Gizatullina Z, Gainutdinov T, Muth K, Seppet E, Orynbayeva Z, Vielhaber S (2013) The control of brain mitochondrial energization by cytosolic calcium: The mitochondrial gas pedal. IUBMB Life 65(3):180–190. doi: 10.1002/iub.1131 PubMedCrossRefGoogle Scholar
  77. Georgiades S, Szatmari P, Boyle M (2013) Importance of studying heterogeneity in autism. Neuropsychiatry 3(2):123–125. doi: 10.2217/npy.13.8 CrossRefGoogle Scholar
  78. Gesundheit B, Rosenzweig JP, Naor D, Lerer B, Zachor DA, Prochazka V, Melamed M, Kristt DA, Steinberg A, Shulman C, Hwang P, Koren G, Walfisch A, Passweg JR, Snowden JA, Tamouza R, Leboyer M, Farge-Bancel D, Ashwood P (2013) Immunological and autoimmune considerations of Autism Spectrum Disorders. J Autoimmun 44:1–7. doi: 10.1016/j.jaut.2013.05.005 PubMedCrossRefGoogle Scholar
  79. Goh FG, Midwood KS (2012) Intrinsic danger: activation of Toll-like receptors in rheumatoid arthritis. Rheumatology (Oxford) 51(1):7–23. doi: 10.1093/rheumatology/ker257 CrossRefGoogle Scholar
  80. Goh S, Dong Z, Zhang Y, DiMauro S, Peterson BS (2014) Mitochondrial dysfunction as a neurobiological subtype of autism spectrum disorder: Evidence from brain imaging. JAMA Psychiatry 71(6):665–671. doi: 10.1001/jamapsychiatry.2014.179 PubMedPubMedCentralCrossRefGoogle Scholar
  81. Good PF, Perl DP, Bierer LM, Schmeidler J (1992) Selective accumulation of aluminum and iron in the neurofibrillary tangles of Alzheimer's disease: a laser microprobe (LAMMA) study. Ann Neurol 31(3):286–292PubMedCrossRefGoogle Scholar
  82. Gottfried C, Bambini-Junior V, Francis F, Riesgo R, Savino W (2015) The Impact of Neuroimmune Alterations in Autism Spectrum Disorder. Front Psychiatry 6:121. doi: 10.3389/fpsyt.2015.00121 PubMedPubMedCentralCrossRefGoogle Scholar
  83. Grether JK, Rosen NJ, Smith KS, Croen LA (2009) Investigation of shifts in autism reporting in the California Department of Developmental Services. J Autism Dev Disord 39(10):1412–1419. doi: 10.1007/s10803-009-0754-z PubMedCrossRefGoogle Scholar
  84. Grimaldi-Bensouda L, Guillemot D, Godeau B, Benichou J, Lebrun-Frenay C, Papeix C, Labauge P, Berquin P, Penfornis A, Benhamou PY, Nicolino M, Simon A, Viallard JF, Costedoat-Chalumeau N, Courcoux MF, Pondarre C, Hilliquin P, Chatelus E, Foltz V, Guillaume S, Rossignol M, Abenhaim L (2014) Autoimmune disorders and quadrivalent human papillomavirus vaccination of young female subjects. J Intern Med 275(4):398–408. doi: 10.1111/joim.12155 PubMedCrossRefGoogle Scholar
  85. Guevara-Campos J, Gonzalez-Guevara L, Puig-Alcaraz C, Cauli O (2013) Autism spectrum disorders associated to a deficiency of the enzymes of the mitochondrial respiratory chain. Metab Brain Dis 28(4):605–612. doi: 10.1007/s11011-013-9419-x PubMedCrossRefGoogle Scholar
  86. Guimaraes LE, Baker B, Perricone C, Shoenfeld Y (2015) Vaccines, adjuvants and autoimmunity. Pharmacol Res 100:190–209. doi: 10.1016/j.phrs.2015.08.003 PubMedCrossRefGoogle Scholar
  87. Gupta S, Ellis SE, Ashar FN, Moes A, Bader JS, Zhan J, West AB, Arking DE (2014) Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism. Nat Commun 5. doi: 10.1038/ncomms6748
  88. Hadjkacem I, Ayadi H, Turki M, Yaich S, Khemekhem K, Walha A, Cherif L, Moalla Y, Ghribi F (2016) Prenatal, perinatal and postnatal factors associated with autism spectrum disorder. J Pediatr 92(6):595–601. doi: 10.1016/j.jped.2016.01.012 CrossRefGoogle Scholar
  89. Hallmayer J, Cleveland S, Torres A et al (2011) GEnetic heritability and shared environmental factors among twin pairs with autism. Arch Gen Psychiatry 68(11):1095–1102. doi: 10.1001/archgenpsychiatry.2011.76 PubMedPubMedCentralCrossRefGoogle Scholar
  90. Han S, Lemire J, Appanna VP, Auger C, Castonguay Z, Appanna VD (2013) How aluminum, an intracellular ROS generator promotes hepatic and neurological diseases: the metabolic tale. Cell Biol Toxicol 29(2):75–84. doi: 10.1007/s10565-013-9239-0 PubMedCrossRefGoogle Scholar
  91. Haralambieva IH, Ovsyannikova IG, Pankratz VS, Kennedy RB, Jacobson RM, Poland GA (2013) The genetic basis for interindividual immune response variation to measles vaccine: new understanding and new vaccine approaches. Exp Rev Vacc 12(1):57–70. doi: 10.1586/erv.12.134 CrossRefGoogle Scholar
  92. Harry GJ (2013) Microglia during development and aging. Pharmacol Ther 139(3):313–326. doi: 10.1016/j.pharmthera.2013.04.013 PubMedPubMedCentralCrossRefGoogle Scholar
  93. Harry GJ, Kraft AD (2012) Microglia in the developing brain: a potential target with lifetime effects. Neurotoxicology 33(2):191–206. doi: 10.1016/j.neuro.2012.01.012 PubMedPubMedCentralCrossRefGoogle Scholar
  94. Haukim N, Bidwell JL, Smith AJP, Keen LJ, Gallagher G, Kimberly R, Huizinga T, McDermott MF, Oksenberg J, McNicholl J, Pociot F, Hardt C, Dalfonso S (2002) Cytokine gene polymorphism in human disease: on-line databases, Supplement 2. Genes Immun 3(6):313–330PubMedCrossRefGoogle Scholar
  95. Herbert MR (2010) Contributions of the environment and environmentally vulnerable physiology to autism spectrum disorders. Curr Opin Neurol 23(2):103–110. doi: 10.1097/WCO.0b013e328336a01f PubMedCrossRefGoogle Scholar
  96. Hertz-Picciotto I (2009) Commentary: Diagnostic change and the increased prevalence of autism. Int J Epidemiol 38(5):1239–1241. doi: 10.1093/ije/dyp258 PubMedPubMedCentralCrossRefGoogle Scholar
  97. Hickman SE, El Khoury J (2014) TREM2 and the neuroimmunology of Alzheimer's disease. Biochem Pharmacol 88(4):495–498. doi: 10.1016/j.bcp.2013.11.021 PubMedCrossRefGoogle Scholar
  98. Hoeijmakers L, Heinen Y, van Dam A-M, Lucassen PJ, Korosi A (2016) Microglial Priming and Alzheimer’s Disease: A Possible Role for (Early) Immune Challenges and Epigenetics? Front Hum Neurosci 10:398. doi: 10.3389/fnhum.2016.00398 PubMedPubMedCentralCrossRefGoogle Scholar
  99. Hollegaard MV, Bidwell JL (2006) Cytokine gene polymorphism in human disease: on-line databases, Supplement 3. Genes Immun 7(4):269–276PubMedCrossRefGoogle Scholar
  100. Hooker BS (2014) Measles-mumps-rubella vaccination timing and autism among young african american boys: a reanalysis of CDC data. Transl Neurodegener 3(1):1–6. doi: 10.1186/2047-9158-3-16 CrossRefGoogle Scholar
  101. Hornung V, Bauernfeind F, Halle A, Samstad EO, Kono H, Rock KL, Fitzgerald KA, Latz E (2008) Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol 9(8):847–856. doi: 10.1038/ni.1631 PubMedPubMedCentralCrossRefGoogle Scholar
  102. Hsieh CL, Koike M, Spusta SC, Niemi EC, Yenari M, Nakamura MC, Seaman WE (2009) A role for TREM2 ligands in the phagocytosis of apoptotic neuronal cells by microglia. J Neurochem 109(4):1144–1156. doi: 10.1111/j.1471-4159.2009.06042.x PubMedPubMedCentralCrossRefGoogle Scholar
  103. Hwang O (2013) Role of oxidative stress in Parkinson's disease. Exp Neurobiol 22:11–17PubMedPubMedCentralCrossRefGoogle Scholar
  104. Ibi D, Yamada K (2015) Therapeutic Targets for Neurodevelopmental Disorders Emerging from Animal Models with Perinatal Immune Activation. Int J Mol Sci 16(12):28218–28229. doi: 10.3390/ijms161226092 PubMedPubMedCentralCrossRefGoogle Scholar
  105. Israeli E (2012) Gulf War syndrome as a part of the autoimmune (autoinflammatory) syndrome induced by adjuvant (ASIA). Lupus 21(2):190–194. doi: 10.1177/0961203311429552 PubMedCrossRefGoogle Scholar
  106. Jacobs RW, Duong T, Jones RE, Trapp GA, Scheibel AB (1989) A reexamination of aluminum in Alzheimer's disease: analysis by energy dispersive X-ray microprobe and flameless atomic absorption spectrophotometry. Can J Neurol Sci 16:498–503PubMedCrossRefGoogle Scholar
  107. Jensen-Jarolim E (2015) Aluminium in Allergies and Allergen immunotherapy. World Aller Org J 8(1):7. doi: 10.1186/s40413-015-0060-5 Google Scholar
  108. Jiang T, Tan L, Zhu XC, Zhang QQ, Cao L, Tan MS, Gu LZ, Wang HF, Ding ZZ, Zhang YD, Yu JT (2014) Upregulation of TREM2 ameliorates neuropathology and rescues spatial cognitive impairment in a transgenic mouse model of Alzheimer's disease. Neuropsychopharmacology 39(13):2949–2962. doi: 10.1038/npp.2014.164 PubMedPubMedCentralCrossRefGoogle Scholar
  109. Johnson VJ, Kim S-H, Sharma RP (2005) Aluminum-Maltolate Induces Apoptosis and Necrosis in Neuro-2a Cells: Potential Role for p53 Signaling. Toxicol Sci 83(2):329–339. doi: 10.1093/toxsci/kfi028 PubMedCrossRefGoogle Scholar
  110. Jones BM, Bhattacharjee S, Dua P, Hill JM, Zhao Y, Lukiw WJ (2014) Regulating amyloidogenesis through the natural triggering receptor expressed in myeloid/microglial cells 2 (TREM2). Front Cell Neurosci 8:94. doi: 10.3389/fncel.2014.00094 PubMedPubMedCentralGoogle Scholar
  111. Jung JY, Kohane IS, Wall DP (2011) Identification of autoimmune gene signatures in autism. Transl Psychiatry 1:e63. doi: 10.1038/tp.2011.62 PubMedPubMedCentralCrossRefGoogle Scholar
  112. Kawahara M (2005) Effects of aluminum on the nervous system and its possible link with neurodegenerative diseases. J Alzheimer's Dis: JAD 8(2):171–182 discussion 209-115PubMedCrossRefGoogle Scholar
  113. Kawahara M, Kato-Negishi M (2011) Link between Aluminum and the Pathogenesis of Alzheimer's Disease: The Integration of the Aluminum and Amyloid Cascade Hypotheses. Int J Alzheimers Dis 2011:276393. doi: 10.4061/2011/276393 PubMedPubMedCentralGoogle Scholar
  114. Kern JK, Geier DA, Sykes LK, Haley BE, Geier MR (2016) The relationship between mercury and autism: A comprehensive review and discussion. J Trace Elem Med Biol 37:8–24. doi: 10.1016/j.jtemb.2016.06.002 PubMedCrossRefGoogle Scholar
  115. Kettenmann H, Kirchhoff F, Verkhratsky A (2013) Microglia: new roles for the synaptic stripper. Neuron 77(1):10–18. doi: 10.1016/j.neuron.2012.12.023 PubMedCrossRefGoogle Scholar
  116. Khan H, Khan MF, Jan SU, Ullah N (2011) Effect of aluminium metal on glutathione (GSH) level in plasma and cytosolic fraction of human blood. Pak J Pharm Sci 24(1):13–18PubMedGoogle Scholar
  117. Kim SY, Park JW (2003) Cellular defense against singlet oxygen-induced oxidative damage by cytosolic NADP+−dependent isocitrate dehydrogenase. Free Radic Res 37(3):309–316PubMedCrossRefGoogle Scholar
  118. Kim YS, Leventhal BL, Koh YJ, Fombonne E, Laska E, Lim EC, Cheon KA, Kim SJ, Kim YK, Lee H, Song DH, Grinker RR (2011) Prevalence of autism spectrum disorders in a total population sample. Am J Psychiatry 168(9):904–912. doi: 10.1176/appi.ajp.2011.10101532 PubMedCrossRefGoogle Scholar
  119. King M, Bearman P (2009) Diagnostic change and the increased prevalence of autism. Int J Epidemiol 38(5):1224–1234. doi: 10.1093/ije/dyp261 PubMedPubMedCentralCrossRefGoogle Scholar
  120. Klei L, Sanders SJ, Murtha MT, Hus V, Lowe JK, Willsey AJ, Moreno-De-Luca D, Yu TW, Fombonne E, Geschwind D, Grice DE, Ledbetter DH, Lord C, Mane SM, Martin CL, Martin DM, Morrow EM, Walsh CA, Melhem NM, Chaste P, Sutcliffe JS, State MW, Cook EH Jr, Roeder K, Devlin B (2012) Common genetic variants, acting additively, are a major source of risk for autism. Molecular Autism 3(1):9. doi: 10.1186/2040-2392-3-9 PubMedPubMedCentralCrossRefGoogle Scholar
  121. Klein C, Lohmann K (2009) Parkinson disease(s): Is “Parkin disease” a distinct clinical entity? Neurology 72(2):106–107. doi: 10.1212/01.wnl.0000333666.65522.8d PubMedCrossRefGoogle Scholar
  122. Kochevar IE (2004) Singlet oxygen signaling: from intimate to global. Sci STKE 2004 (221):pe7. doi: 10.1126/stke.2212004pe7
  123. Koenigsknecht-Talboo J, Meyer-Luehmann M, Parsadanian M, Garcia-Alloza M, Finn MB, Hyman BT, Bacskai BJ, Holtzman DM (2008) Rapid microglial response around amyloid pathology after systemic anti-Abeta antibody administration in PDAPP mice. J Neurosci 28(52):14156–14164. doi: 10.1523/jneurosci.4147-08.2008 PubMedPubMedCentralCrossRefGoogle Scholar
  124. Kool M, Petrilli V, De Smedt T, Rolaz A, Hammad H, van Nimwegen M (2008a) Cutting edge: alum adjuvant stimulates inflammatory dendritic cells through activation of the NALP3 inflammasome. J Immunol 181:3755–3759PubMedCrossRefGoogle Scholar
  125. Kool M, Soullie T, van Nimwegen M, Willart MA, Muskens F, Jung S, Hoogsteden HC, Hammad H, Lambrecht BN (2008b) Alum adjuvant boosts adaptive immunity by inducing uric acid and activating inflammatory dendritic cells. J Exp Med 205(4):869–882. doi: 10.1084/jem.20071087 PubMedPubMedCentralCrossRefGoogle Scholar
  126. Kool M, Willart MA, van Nimwegen M, Bergen I, Pouliot P, Virchow JC, Rogers N, Osorio F, Reise Sousa C, Hammad H, Lambrecht BN (2011) An unexpected role for uric acid as an inducer of T helper 2 cell immunity to inhaled antigens and inflammatory mediator of allergic asthma. Immunity 34(4):527–540. doi: 10.1016/j.immuni.2011.03.015 PubMedCrossRefGoogle Scholar
  127. Kool M, Fierens K, Lambrecht BN (2012) Alum adjuvant: some of the tricks of the oldest adjuvant. J Med Microbiol 61(Pt 7):927–934. doi: 10.1099/jmm.0.038943-0 PubMedCrossRefGoogle Scholar
  128. Korczyn AD, Hassin-Baer S (2015) Can the disease course in Parkinson’s disease be slowed? BMC Med 13:295. doi: 10.1186/s12916-015-0534-x PubMedPubMedCentralCrossRefGoogle Scholar
  129. Koufaris C, Sismani C (2015) Modulation of the genome and epigenome of individuals susceptible to autism by environmental risk factors. Int J Mol Sci 16(4):8699–8718. doi: 10.3390/ijms16048699 PubMedPubMedCentralCrossRefGoogle Scholar
  130. Kumar V, Gill KD (2014) Oxidative stress and mitochondrial dysfunction in aluminium neurotoxicity and its amelioration: A review. Neurotoxicology 41:154–166. doi: 10.1016/j.neuro.2014.02.004 PubMedCrossRefGoogle Scholar
  131. Kumar V, Bal A, Gill KD (2008) Impairment of mitochondrial energy metabolism in different regions of rat brain following chronic exposure to aluminium. Brain Res 1232:94–103. doi: 10.1016/j.brainres.2008.07.028 PubMedCrossRefGoogle Scholar
  132. Kumar A, Prakash A, Dogra S (2011) Neuroprotective effect of carvedilol against aluminium induced toxicity: possible behavioral and biochemical alterations in rats. Pharmacol Rep 63(4):915–923PubMedCrossRefGoogle Scholar
  133. Kumar S, Ingle H, Prasad DV, Kumar H (2013) Recognition of bacterial infection by innate immune sensors. Crit Rev Microbiol 39(3):229–246. doi: 10.3109/1040841x.2012.706249 PubMedCrossRefGoogle Scholar
  134. Kuroda E, Ishii KJ, Uematsu S, Ohata K, Coban C, Akira S, Aritake K, Urade Y, Morimoto Y (2011) Silica crystals and aluminum salts regulate the production of prostaglandin in macrophages via NALP3 inflammasome-independent mechanisms. Immunity 34(4):514–526. doi: 10.1016/j.immuni.2011.03.019 PubMedCrossRefGoogle Scholar
  135. Ladd-Acosta C, Hansen KD, Briem E, Fallin MD, Kaufmann WE, Feinberg AP (2014) Common DNA methylation alterations in multiple brain regions in autism. Mol Psychiatry 19(8):862–871. doi: 10.1038/mp.2013.114 PubMedCrossRefGoogle Scholar
  136. Lam B, Masellis M, Freedman M, Stuss DT, Black SE (2013) Clinical, imaging, and pathological heterogeneity of the Alzheimer's disease syndrome. Alzheimers Res Ther 5(1):1. doi: 10.1186/alzrt155 PubMedPubMedCentralCrossRefGoogle Scholar
  137. Land WG (2015) The role of damage-associated molecular patterns in human diseases: part i - promoting inflammation and immunity. Sultan Qaboos Univ Med J 15(1):e9–e21PubMedPubMedCentralGoogle Scholar
  138. Landsberg JP, McDonald B, Watt F (1992) Absence of aluminium in neuritic plaque cores in Alzheimer's disease. Nature 360:65–68PubMedCrossRefGoogle Scholar
  139. Langer-Gould A, Qian L, Tartof SY, Brara SM, Jacobsen SJ, Beaber BE, Sy LS, Chao C, Hechter R, Tseng HF (2014) Vaccines and the risk of multiple sclerosis and other central nervous system demyelinating diseases. JAMA Neurol 71(12):1506–1513. doi: 10.1001/jamaneurol.2014.2633 PubMedCrossRefGoogle Scholar
  140. LaSalle JM (2013) Epigenomic strategies at the interface of genetic and environmental risk factors for autism. J Hum Genet 58(7):396–401. doi: 10.1038/jhg.2013.49 PubMedPubMedCentralCrossRefGoogle Scholar
  141. Lee SM, Koh HJ, Park DC, Song BJ, Huh TL, Park JW (2002) Cytosolic NADP(+)-dependent isocitrate dehydrogenase status modulates oxidative damage to cells. Free Radic Biol Med 32(11):1185–1196PubMedCrossRefGoogle Scholar
  142. Lemire J, Appanna VD (2011) Aluminum toxicity and astrocyte dysfunction: a metabolic link to neurological disorders. J Inorg Biochem 105(11):1513–1517. doi: 10.1016/j.jinorgbio.2011.07.001 PubMedCrossRefGoogle Scholar
  143. Lemire J, Mailloux R, Darwich R, Auger C, Appanna VD (2011) The disruption of L-carnitine metabolism by aluminum toxicity and oxidative stress promotes dyslipidemia in human astrocytic and hepatic cells. Toxicol Lett 203(3):219–226. doi: 10.1016/j.toxlet.2011.03.019 PubMedCrossRefGoogle Scholar
  144. Levandowski CB, Mailloux CM, Ferrara TM, Gowan K, Ben S, Jin Y, McFann KK, Holland PJ, Fain PR, Dinarello CA, Spritz RA (2013) NLRP1 haplotypes associated with vitiligo and autoimmunity increase interleukin-1beta processing via the NLRP1 inflammasome. Proc Natl Acad Sci 110(8):2952–2956. doi: 10.1073/pnas.1222808110 PubMedPubMedCentralCrossRefGoogle Scholar
  145. Li H, Willingham SB, Ting JP, Re F (2008) Cutting edge: inflammasome activation by alum and alum's adjuvant effect are mediated by NLRP3. J Immunol 181(1):17–21PubMedPubMedCentralCrossRefGoogle Scholar
  146. Liu Y, Yin H, Zhao M, Lu Q (2014) TLR2 and TLR4 in autoimmune diseases: a comprehensive review. Clin Rev Allergy Immunol 47(2):136–147. doi: 10.1007/s12016-013-8402-y PubMedCrossRefGoogle Scholar
  147. Llorente-Folch I, Rueda CB, Amigo I, del Arco A, Saheki T, Pardo B, Satrustegui J (2013) Calcium-regulation of mitochondrial respiration maintains ATP homeostasis and requires ARALAR/AGC1-malate aspartate shuttle in intact cortical neurons. J Neurosci 33 (35):13957-13971, 13971a. doi: 10.1523/jneurosci.0929-13.2013
  148. Lovell MA, Ehmann WD, Markesbery WR (1993) Laser microprobe analysis of brain aluminum in Alzheimer's disease. Ann Neurol 33(1):36–42PubMedCrossRefGoogle Scholar
  149. Lu H, Hu J, Li J, Pang W, Hu Y, Yang H, Li W, Huang C, Zhang M, Jiang Y (2013) Optimal dose of zinc supplementation for preventing aluminum-induced neurotoxicity in rats. Neural Regen Res 8(29):2754–2762. doi: 10.3969/j.issn.1673-5374.2013.29.007 PubMedPubMedCentralGoogle Scholar
  150. Lu X, Liang R, Jia Z, Wang H, Pan B, Zhang Q, Niu Q (2014) Cognitive disorders and tau-protein expression among retired aluminum smelting workers. J Occup Environ Med 56(2):155–160. doi: 10.1097/jom.0000000000000100 PubMedCrossRefGoogle Scholar
  151. Lucas K, Maes M (2013) Role of the Toll Like receptor (TLR) radical cycle in chronic inflammation: possible treatments targeting the TLR4 pathway. Mol Neurobiol 48:190–204PubMedCrossRefGoogle Scholar
  152. Lucas K, Morris G, Anderson G, Maes M (2015) The toll-like receptor radical cycle pathway: a new drug target in immune-related chronic fatigue. CNS Neurol Disord Drug Targets 14(7):838–854PubMedCrossRefGoogle Scholar
  153. Lukiw WJ (2012) NF-kappaB-regulated, proinflammatory miRNAs in Alzheimer's disease. Alzheimers Res Ther 4(6):47. doi: 10.1186/alzrt150 PubMedPubMedCentralCrossRefGoogle Scholar
  154. Lunnon K, Teeling J, Tutt A, Cragg M, Glennie M, Perry V (2011) Systemic inflammation modulates Fc receptor expression on microglia during chronic neurodegeneration. J Immunol 186:7215–7224PubMedCrossRefGoogle Scholar
  155. Ma TY, Tran D, Hoa N, Nguyen D, Merryfield M, Tarnawski A (2000) Mechanism of extracellular calcium regulation of intestinal epithelial tight junction permeability: role of cytoskeletal involvement. Microsc Res Tech 51(2):156–168. doi: 10.1002/1097-0029(20001015)51:2<156::aid-jemt7>;2-j PubMedCrossRefGoogle Scholar
  156. Mailloux RJ, Appanna VD (2007) Aluminum toxicity triggers the nuclear translocation of HIF-1alpha and promotes anaerobiosis in hepatocytes. Toxicol in Vitro 21(1):16–24. doi: 10.1016/j.tiv.2006.07.013 PubMedCrossRefGoogle Scholar
  157. Mailloux RJ, Hamel R, Appanna VD (2006) Aluminum toxicity elicits a dysfunctional TCA cycle and succinate accumulation in hepatocytes. J Biochem Mol Toxicol 20(4):198–208. doi: 10.1002/jbt.20137 PubMedCrossRefGoogle Scholar
  158. Mailloux R, Lemire J, Appanna V (2007) Aluminum-induced mitochondrial dysfunction leads to lipid accumulation in human hepatocytes: a link to obesity. Cell Physiol Biochem 20(5):627–638. doi: 10.1159/000107546 PubMedCrossRefGoogle Scholar
  159. Mailloux RJ, Puiseux-Dao S, Appanna VD (2009) Alpha-ketoglutarate abrogates the nuclear localization of HIF-1alpha in aluminum-exposed hepatocytes. Biochimie 91(3):408–415. doi: 10.1016/j.biochi.2008.10.014 PubMedCrossRefGoogle Scholar
  160. Mailloux RJ, Lemire J, Appanna VD (2011) Hepatic response to aluminum toxicity: dyslipidemia and liver diseases. Exp Cell Res 317(16):2231–2238. doi: 10.1016/j.yexcr.2011.07.009 PubMedCrossRefGoogle Scholar
  161. Mannello F, Ligi D, Canale M (2013) Aluminium, carbonyls and cytokines in human nipple aspirate fluids: Possible relationship between inflammation, oxidative stress and breast cancer microenvironment. J Inorg Biochem 128:250–256. doi: 10.1016/j.jinorgbio.2013.07.003 PubMedCrossRefGoogle Scholar
  162. Marichal T, Ohata K, Bedoret D, Mesnil C, Sabatel C, Kobiyama K, Lekeux P, Coban C, Akira S, Ishii KJ, Bureau F, Desmet CJ (2011) DNA released from dying host cells mediates aluminum adjuvant activity. Nat Med 17(8):996–1002. doi: 10.1038/nm.2403 PubMedCrossRefGoogle Scholar
  163. Marrack P, McKee AS, Munks MW (2009) Towards an understanding of the adjuvant action of aluminium. Nat Rev Immunol 9(4):287–293. doi: 10.1038/nri2510 PubMedPubMedCentralCrossRefGoogle Scholar
  164. Marrale M, Albanese NN, Cali F, Romano V (2014) Assessing the impact of copy number variants on miRNA genes in autism by Monte Carlo simulation. PLoS One 9(3):e90947. doi: 10.1371/journal.pone.0090947 PubMedPubMedCentralCrossRefGoogle Scholar
  165. Marshak-Rothstein A (2006) Toll-like receptors in systemic autoimmune disease. Nat Rev Immunol 6(11):823–835PubMedCrossRefGoogle Scholar
  166. Matcovitch-Natan O, Winter DR, Giladi A, Vargas Aguilar S, Spinrad A, Sarrazin S, Ben-Yehuda H, David E, Zelada González F, Perrin P, Keren-Shaul H, Gury M, Lara-Astaiso D, Thaiss CA, Cohen M, Bahar Halpern K, Baruch K, Deczkowska A, Lorenzo-Vivas E, Itzkovitz S, Elinav E, Sieweke MH, Schwartz M, Amit I (2016) Microglia development follows a stepwise program to regulate brain homeostasis. Science 353(6301):aad8670. doi:  10.1126/science.aad8670
  167. McDougle CJ, Landino SM, Vahabzadeh A, O'Rourke J, Zurcher NR, Finger BC, Palumbo ML, Helt J, Mullett JE, Hooker JM, Carlezon WA Jr (2015) Toward an immune-mediated subtype of autism spectrum disorder. Brain Res 1617:72–92. doi: 10.1016/j.brainres.2014.09.048 PubMedCrossRefGoogle Scholar
  168. Mead J, Ashwood P (2015) Evidence supporting an altered immune response in ASD. Immunol Lett 163(1):49–55. doi: 10.1016/j.imlet.2014.11.006 PubMedCrossRefGoogle Scholar
  169. Mellios N, Sur M (2012) The Emerging Role of microRNAs in Schizophrenia and Autism Spectrum Disorders. Front Psychiatry 3:39. doi: 10.3389/fpsyt.2012.00039 PubMedPubMedCentralCrossRefGoogle Scholar
  170. Melnyk S, Fuchs G, Schulz E, Lopez M, Kahler S, Fussell J (2012) Metabolic imbalance associated with methylation dysregulation and oxidative damage in children with autism. J Autism Dev Disord 42:367–377PubMedPubMedCentralCrossRefGoogle Scholar
  171. Michel M, Schmidt MJ, Mirnics K (2012) Immune system gene dysregulation in autism and schizophrenia. Developl Neurobiol 72(10):1277–1287. doi: 10.1002/dneu.22044 CrossRefGoogle Scholar
  172. Miranda-Hernandez S, Baxter A (2013) Role of toll-like receptors in multiple sclerosis. Am J Clin Exp Immunol 2:75–93PubMedPubMedCentralGoogle Scholar
  173. Mohamed Fel B, Zaky EA, El-Sayed AB, Elhossieny RM, Zahra SS, Salah Eldin W, Youssef WY, Khaled RA, Youssef AM (2015) Assessment of Hair Aluminum, Lead, and Mercury in a Sample of Autistic Egyptian Children: Environmental Risk Factors of Heavy Metals in Autism. Behav Neurol 2015:545674. doi: 10.1155/2015/545674 PubMedGoogle Scholar
  174. Mohan N, Alleyne T, Adogwa A (2009) The effects of ingested aluminium on brain cytochrome oxidase activity. West Indian Med J 58(5):422–427PubMedGoogle Scholar
  175. Molofsky AV, Krenick R, Ullian E, H-h T, Deneen B, Richardson WD, Barres BA, Rowitch DH (2012) Astrocytes and disease: a neurodevelopmental perspective. Genes Dev 26(9):891–907. doi: 10.1101/gad.188326.112 PubMedPubMedCentralCrossRefGoogle Scholar
  176. Mor M, Nardone S, Sams DS, Elliott E (2015) Hypomethylation of miR-142 promoter and upregulation of microRNAs that target the oxytocin receptor gene in the autism prefrontal cortex. Molecular Autism 6:46. doi: 10.1186/s13229-015-0040-1 PubMedPubMedCentralCrossRefGoogle Scholar
  177. Moraes CF, Benedet AL, Souza VC, Lins TC, Camargos EF, Naves JO, Brito CJ, Cordova C, Pereira RW, Nobrega OT (2013) Cytokine gene polymorphisms and Alzheimer's disease in Brazil. Neuroimmunomodulation 20(5):239–246. doi: 10.1159/000350368 PubMedCrossRefGoogle Scholar
  178. Morgan J, Chana G, Pardo C, Achim C, Semendeferi K, Buckwalter J (2010) Microglial activation and increased microglial density observed in the dorsolateral prefrontal cortex in autism. Biol Psychiatry 68:368–376PubMedCrossRefGoogle Scholar
  179. Morgan JT, Chana G, Abramson I, Semendeferi K, Courchesne E, Everall IP (2012) Abnormal microglial-neuronal spatial organization in the dorsolateral prefrontal cortex in autism. Brain Res 1456:72–81. doi: 10.1016/j.brainres.2012.03.036 PubMedCrossRefGoogle Scholar
  180. Morris G, Berk M (2015) The many roads to mitochondrial dysfunction in neuroimmune and neuropsychiatric disorders. BMC Med 13(1):68PubMedPubMedCentralCrossRefGoogle Scholar
  181. Morris G, Berk M (2016) The Putative Use of Lithium in Alzheimer's Disease. Curr Alzheimer Res 13(8):853–861PubMedCrossRefGoogle Scholar
  182. Morris G, Maes M (2012) A neuro-immune model of myalgic encephalomyelitis/chronic fatigue syndrome. Metab Brain Dis 28:523–540. doi: 10.1007/s11011-012-9324-8
  183. Morris G, Maes M (2014) Oxidative and nitrosative stress and immune-inflammatory pathways in patients with Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS). Curr Neuropharmacol 12:168–185PubMedPubMedCentralCrossRefGoogle Scholar
  184. Morris G, Berk M, Galecki P, Walder K, Maes M (2015a) The Neuro-Immune Pathophysiology of Central and Peripheral Fatigue in Systemic Immune-Inflammatory and Neuro-Immune Diseases. Mol Neurobiol 53(2):1195–1219. doi: 10.1007/s12035-015-9090-9 PubMedCrossRefGoogle Scholar
  185. Morris G, Berk M, Walder K, Maes M (2015b) Central pathways causing fatigue in neuro-inflammatory and autoimmune illnesses. BMC Med 13(1):28PubMedPubMedCentralCrossRefGoogle Scholar
  186. Mostafa GA, Shehab AA, Al-Ayadhi LY (2013) The link between some alleles on human leukocyte antigen system and autism in children. J Neuroimmunol 255(1–2):70–74. doi: 10.1016/j.jneuroim.2012.10.002 PubMedCrossRefGoogle Scholar
  187. Mundalil Vasu M, Anitha A, Thanseem I, Suzuki K, Yamada K, Takahashi T, Wakuda T, Iwata K, Tsujii M, Sugiyama T, Mori N (2014) Serum microRNA profiles in children with autism. Molecular Autism 5:40. doi: 10.1186/2040-2392-5-40 PubMedPubMedCentralCrossRefGoogle Scholar
  188. Munks MW, McKee AS, Macleod MK, Powell RL, Degen JL, Reisdorph NA, Kappler JW, Marrack P (2010) Aluminum adjuvants elicit fibrin-dependent extracellular traps in vivo. Blood 116(24):5191–5199. doi: 10.1182/blood-2010-03-275529 PubMedPubMedCentralCrossRefGoogle Scholar
  189. Murakami K, Yoshino M (2004) Aluminum decreases the glutathione regeneration by the inhibition of NADP-isocitrate dehydrogenase in mitochondria. J Cell Biochem 93(6):1267–1271. doi: 10.1002/jcb.20261 PubMedCrossRefGoogle Scholar
  190. Mustafa Rizvi SH, Parveen A, Verma AK, Ahmad I, Arshad M, Mahdi AA (2014) Aluminium induced endoplasmic reticulum stress mediated cell death in SH-SY5Y neuroblastoma cell line is independent of p53. PLoS One 9(5):e98409. doi: 10.1371/journal.pone.0098409 PubMedPubMedCentralCrossRefGoogle Scholar
  191. Nagai T (2013) Perinatal innate immune activation and neuropsychological development. Nihon Shinkei Seishin Yakurigaku Zasshi 33(4):149–154PubMedGoogle Scholar
  192. Nampoothiri M, John J, Kumar N, Mudgal J, Nampurath GK, Chamallamudi MR (2015) Modulatory role of simvastatin against aluminium chloride-induced behavioural and biochemical changes in rats. Behav Neurol 2015:210169. doi: 10.1155/2015/210169 PubMedPubMedCentralCrossRefGoogle Scholar
  193. Napoli E, Wong S, Giulivi C (2013) Evidence of reactive oxygen species-mediated damage to mitochondrial DNA in children with typical autism. Molecular Autism 4(1):1–8. doi: 10.1186/2040-2392-4-2 CrossRefGoogle Scholar
  194. Nardone S, Sharan Sams D, Reuveni E, Getselter D, Oron O, Karpuj M, Elliott E (2014) DNA methylation analysis of the autistic brain reveals multiple dysregulated biological pathways. Transl Psychiatry 4:e433. doi: 10.1038/tp.2014.70 PubMedPubMedCentralCrossRefGoogle Scholar
  195. Netea MG, Wijmenga C, O'Neill LAJ (2012) Genetic variation in Toll-like receptors and disease susceptibility. Nat Immunol 13(6):535–542PubMedCrossRefGoogle Scholar
  196. Neumann H, Takahashi K (2007) Essential role of the microglial triggering receptor expressed on myeloid cells-2 (TREM2) for central nervous tissue immune homeostasis. J Neuroimmunol 184(1–2):92–99. doi: 10.1016/j.jneuroim.2006.11.032 PubMedCrossRefGoogle Scholar
  197. Newairy AS, Salama AF, Hussien HM, Yousef MI (2009) Propolis alleviates aluminium-induced lipid peroxidation and biochemical parameters in male rats. Food Chem Toxicol 47(6):1093–1098PubMedCrossRefGoogle Scholar
  198. Noriega DB, Savelkoul HF (2014) Immune dysregulation in autism spectrum disorder. Eur J Pediatr 173(1):33–43. doi: 10.1007/s00431-013-2183-4 PubMedCrossRefGoogle Scholar
  199. Orihuela D, Meichtry V, Pizarro M (2005) Aluminium-induced impairment of transcellular calcium absorption in the small intestine: calcium uptake and glutathione influence. J Inorg Biochem 99(9):1879–1886. doi: 10.1016/j.jinorgbio.2005.07.003 PubMedCrossRefGoogle Scholar
  200. Ortiz G, Pacheco-Moises F, Bitzer-Quintero O, Ramirez-Anguiano A, Flores-Alvarado L, Ramirez-Ramirez V (2013) Immunology and oxidative stress in multiple sclerosis: clinical and basic approach. Clin Dev Immunol 2013:708659PubMedPubMedCentralCrossRefGoogle Scholar
  201. Ottoboni L, Frohlich IY, Lee M, Healy BC, Keenan BT, Xia Z, Chitnis T, Guttmann CR, Khoury SJ, Weiner HL, Hafler DA, De Jager PL (2013) Clinical relevance and functional consequences of the TNFRSF1A multiple sclerosis locus. Neurology 81(22):1891–1899. doi: 10.1212/01.wnl.0000436612.66328.8a PubMedPubMedCentralCrossRefGoogle Scholar
  202. Painter MM, Atagi Y, Liu CC, Rademakers R, Xu H, Fryer JD, Bu G (2015) TREM2 in CNS homeostasis and neurodegenerative disease. Mol Neurodegener 10:43. doi: 10.1186/s13024-015-0040-9 PubMedPubMedCentralCrossRefGoogle Scholar
  203. Paradowska-Gorycka A, Jurkowska M (2013) Structure, expression pattern and biological activity of molecular complex TREM-2/DAP12. Hum Immunol 74(6):730–737. doi: 10.1016/j.humimm.2013.02.003 PubMedCrossRefGoogle Scholar
  204. Paz Soldan MM, Rodriguez M (2002) Heterogeneity of Pathogenesis in Multiple Sclerosis: Implications for Promotion of Remyelination. Journal of Infectious Diseases 186 (Supplement 2):S248-S253. doi: 10.1086/344283
  205. Pellegrino P, Clementi E, Radice S (2015) On vaccine's adjuvants and autoimmunity: Current evidence and future perspectives. Autoimmun Rev 14(10):880–888. doi: 10.1016/j.autrev.2015.05.014 PubMedCrossRefGoogle Scholar
  206. Pelly L, Vardy C, Fernandez B, Newhook LA, Chafe R (2015) Incidence and cohort prevalence for autism spectrum disorders in the Avalon Peninsula, Newfoundland and Labrador. CMAJ Open 3(3):E276–E280. doi: 10.9778/cmajo.20140056 PubMedPubMedCentralCrossRefGoogle Scholar
  207. Peng Q, Long CL, Malhotra S, Humphrey MB (2013) A physical interaction between the adaptor proteins DOK3 and DAP12 is required to inhibit lipopolysaccharide signaling in macrophages. Sci Signal 6(289):ra72. doi: 10.1126/scisignal.2003801 PubMedPubMedCentralCrossRefGoogle Scholar
  208. Perricone C, Colafrancesco S, Mazor RD, Soriano A, Agmon-Levin N, Shoenfeld Y (2013) Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) 2013: Unveiling the pathogenic, clinical and diagnostic aspects. J Autoimmun 47:1–16. doi: 10.1016/j.jaut.2013.10.004 PubMedCrossRefGoogle Scholar
  209. Perry V, Holmes C (2014) Microglial priming in neurodegenerative disease. Nat Rev Neurol 10:217–224PubMedCrossRefGoogle Scholar
  210. Perry V, Nicoll J, Holmes C (2010) Microglia in neurodegenerative disease. Nat Rev Neurol 6:193–201PubMedCrossRefGoogle Scholar
  211. Petrovsky N (2015) Comparative Safety of Vaccine Adjuvants: A Summary of Current Evidence and Future Needs. Drug Saf 38(11):1059–1074. doi: 10.1007/s40264-015-0350-4 PubMedPubMedCentralCrossRefGoogle Scholar
  212. Piccinini AM, Midwood KS (2010) DAMPening inflammation by modulating TLR signalling. Mediat Inflamm 2010. doi: 10.1155/2010/672395
  213. Pineton de Chambrun G, Body-Malapel M, Frey-Wagner I, Djouina M, Deknuydt F, Atrott K, Esquerre N, Altare F, Neut C, Arrieta MC, Kanneganti TD, Rogler G, Colombel JF, Cortot A, Desreumaux P, Vignal C (2014) Aluminum enhances inflammation and decreases mucosal healing in experimental colitis in mice. Mucosal Immunol 7(3):589–601. doi: 10.1038/mi.2013.78 PubMedCrossRefGoogle Scholar
  214. Pogue AI, Li YY, Cui JG, Zhao Y, Kruck TP, Percy ME, Tarr MA, Lukiw WJ (2009) Characterization of an NF-kappaB-regulated, miRNA-146a-mediated down-regulation of complement factor H (CFH) in metal-sulfate-stressed human brain cells. J Inorg Biochem 103(11):1591–1595. doi: 10.1016/j.jinorgbio.2009.05.012 PubMedCrossRefGoogle Scholar
  215. Poland GA, Kennedy RB, McKinney BA, Ovsyannikova IG, Lambert ND, Jacobson RM, Oberg AL (2013) Vaccinomics, adversomics, and the immune response network theory: Individualized vaccinology in the 21st century. Semin Immunol 25(2):89–103. doi: 10.1016/j.smim.2013.04.007 PubMedPubMedCentralCrossRefGoogle Scholar
  216. Poliani PL, Wang Y, Fontana E, Robinette ML, Yamanishi Y, Gilfillan S, Colonna M (2015) TREM2 sustains microglial expansion during aging and response to demyelination. J Clin Invest 125(5):2161–2170. doi: 10.1172/jci77983 PubMedPubMedCentralCrossRefGoogle Scholar
  217. Pontillo A, Girardelli M, Kamada AJ, Pancotto JA, Donadi EA, Crovella S, Sandrin-Garcia P (2012) Polimorphisms in inflammasome genes are involved in the predisposition to systemic lupus erythematosus. Autoimmunity 45(4):271–278. doi: 10.3109/08916934.2011.637532 PubMedCrossRefGoogle Scholar
  218. Powell BS, Andrianov AK, Fusco PC (2015) Polyionic vaccine adjuvants: another look at aluminum salts and polyelectrolytes. Clin Exper Vacc Res 4(1):23–45. doi: 10.7774/cevr.2015.4.1.23 CrossRefGoogle Scholar
  219. Pradhan VD, Das S, Surve P, Ghosh K (2012) Toll-like receptors in autoimmunity with special reference to systemic lupus erythematosus. Indian J Human Gene 18(2):155–160. doi: 10.4103/0971-6866.100750 CrossRefGoogle Scholar
  220. Pramparo T, Pierce K, Lombardo MV, Carter Barnes C, Marinero S, Ahrens-Barbeau C, Murray SS, Lopez L, Xu R, Courchesne E (2015) Prediction of autism by translation and immune/inflammation coexpressed genes in toddlers from pediatric community practices. JAMA Psychiatry 72(4):386–394. doi: 10.1001/jamapsychiatry.2014.3008 PubMedCrossRefGoogle Scholar
  221. Rainbolt TK, Saunders JM, Wiseman RL (2014) Stress-responsive regulation of mitochondria through the ER unfolded protein response. Trends Endocrinol Metab 25(10):528–537. doi: 10.1016/j.tem.2014.06.007 PubMedCrossRefGoogle Scholar
  222. Ramos PS, Sajuthi S, Langefeld CD, Walker SJ (2012) Immune function genes CD99L2, JARID2 and TPO show association with autism spectrum disorder. Molecular Autism 3:4–4. doi: 10.1186/2040-2392-3-4 PubMedPubMedCentralCrossRefGoogle Scholar
  223. Rangasamy S, D'Mello SR, Narayanan V (2013) Epigenetics, autism spectrum, and neurodevelopmental disorders. Neurotherapeutics 10(4):742–756. doi: 10.1007/s13311-013-0227-0 PubMedPubMedCentralCrossRefGoogle Scholar
  224. Rapoport JL, Giedd JN, Gogtay N (2012) Neurodevelopmental model of schizophrenia: update 2012. Mol Psychiatry 17(12):1228–1238. doi: 10.1038/mp.2012.23 PubMedPubMedCentralCrossRefGoogle Scholar
  225. Reuter S, Gupta S, Chaturvedi M, Aggarwal B (2010) Oxidative stress, inflammation, and cancer: how are they linked? Free Radic Biol Med 49:1603–1616PubMedPubMedCentralCrossRefGoogle Scholar
  226. Roberts AL, Lyall K, Hart JE, Laden F, Just AC, Bobb JF, Koenen KC, Ascherio A, Weisskopf MG (2013) Perinatal air pollutant exposures and autism spectrum disorder in the children of Nurses' Health Study II participants. Environ Health Perspect 121(8):978–984. doi: 10.1289/ehp.1206187 PubMedPubMedCentralGoogle Scholar
  227. Rondeau V, Jacqmin-Gadda H, Commenges D, Helmer C, Dartigues J-F (2009) Aluminum and silica in drinking water and the risk of Alzheimer's disease or cognitive decline: findings from 15-year follow-up of the PAQUID cohort. Am J Epidemiol 169(4):489–496. doi: 10.1093/aje/kwn348 PubMedCrossRefGoogle Scholar
  228. Rossignol D, Frye R (2014) Evidence linking oxidative stress, mitochondrial dysfunction, and inflammation in the brain of individuals with autism. Front Physiol 5:150PubMedPubMedCentralCrossRefGoogle Scholar
  229. Rueda CB, Llorente-Folch I, Amigo I, Contreras L, Gonzalez-Sanchez P, Martinez-Valero P, Juaristi I, Pardo B, del Arco A, Satrustegui J (2014) Ca(2+) regulation of mitochondrial function in neurons. Biochim Biophys Acta 1837(10):1617–1624. doi: 10.1016/j.bbabio.2014.04.010 PubMedCrossRefGoogle Scholar
  230. Ruggeri B, Sarkans U, Schumann G, Persico AM (2014) Biomarkers in autism spectrum disorder: the old and the new. Psychopharmacology 231(6):1201–1216. doi: 10.1007/s00213-013-3290-7 PubMedCrossRefGoogle Scholar
  231. Rutter M (2005) Incidence of autism spectrum disorders: changes over time and their meaning. Acta Paediatr 94(1):2–15PubMedCrossRefGoogle Scholar
  232. Sahoo T, Theisen A, Rosenfeld JA, Lamb AN, Ravnan JB, Schultz RA, Torchia BS, Neill N, Casci I, Bejjani BA, Shaffer LG (2011) Copy number variants of schizophrenia susceptibility loci are associated with a spectrum of speech and developmental delays and behavior problems. Gene Med 13(10):868–880. doi: 10.1097/GIM.0b013e3182217a06 CrossRefGoogle Scholar
  233. Saresella M, Piancone F, Marventano I, Zoppis M, Hernis A, Zanette M, Trabattoni D, Chiappedi M, Ghezzo A, Canevini MP, la Rosa F, Esposito S, Clerici M (2016) Multiple inflammasome complexes are activated in autistic spectrum disorders. Brain Behav Immun 57:125–133. doi: 10.1016/j.bbi.2016.03.009 PubMedCrossRefGoogle Scholar
  234. Scheller NM, Svanstrom H, Pasternak B, Arnheim-Dahlstrom L, Sundstrom K, Fink K, Hviid A (2015) Quadrivalent HPV vaccination and risk of multiple sclerosis and other demyelinating diseases of the central nervous system. JAMA 313(1):54–61. doi: 10.1001/jama.2014.16946 PubMedCrossRefGoogle Scholar
  235. Schepens MA, Schonewille AJ, Vink C, van Schothorst EM, Kramer E, Hendriks T, Brummer RJ, Keijer J, van der Meer R, Bovee-Oudenhoven IM (2009) Supplemental calcium attenuates the colitis-related increase in diarrhea, intestinal permeability, and extracellular matrix breakdown in HLA-B27 transgenic rats. J Nutr 139(8):1525–1533. doi: 10.3945/jn.109.105205 PubMedCrossRefGoogle Scholar
  236. Sharma DR, Sunkaria A, Wani WY, Sharma RK, Kandimalla RJL, Bal A, Gill KD (2013) Aluminium induced oxidative stress results in decreased mitochondrial biogenesis via modulation of PGC-1α expression. Toxicol Appl Pharmacol 273(2):365–380. doi: 10.1016/j.taap.2013.09.012 PubMedCrossRefGoogle Scholar
  237. Sharp FA, Ruane D, Claass B, Creagh E, Harris J, Malyala P, Singh M, O'Hagan DT, Petrilli V, Tschopp J, O'Neill LA, Lavelle EC (2009) Uptake of particulate vaccine adjuvants by dendritic cells activates the NALP3 inflammasome. Proc Natl Acad Sci U S A 106(3):870–875. doi: 10.1073/pnas.0804897106 PubMedPubMedCentralCrossRefGoogle Scholar
  238. Shastri A, Bonifati DM, Kishore U (2013) Innate Immunity and Neuroinflammation. Mediat Inflamm 2013:342931. doi: 10.1155/2013/342931 CrossRefGoogle Scholar
  239. Shaw CA, Tomljenovic L (2013) Aluminum in the central nervous system (CNS): toxicity in humans and animals, vaccine adjuvants, and autoimmunity. Immunol Res 56(2–3):304–316. doi: 10.1007/s12026-013-8403-1 PubMedCrossRefGoogle Scholar
  240. Shi Y, Evans JE, Rock KL (2003) Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 425(6957):516–521. doi: 10.1038/nature01991 PubMedCrossRefGoogle Scholar
  241. Shoenfeld Y, Agmon-Levin N (2011) 'ASIA' - autoimmune/inflammatory syndrome induced by adjuvants. J Autoimmun 36(1):4–8. doi: 10.1016/j.jaut.2010.07.003 PubMedCrossRefGoogle Scholar
  242. Singhal G, Jaehne EJ, Corrigan F, Toben C, Baune BT (2014) Inflammasomes in neuroinflammation and changes in brain function: a focused review. Front Neurosci 8(315). doi: 10.3389/fnins.2014.00315
  243. Siniscalco D (2015) Commentary: The Impact of Neuroimmune Alterations in Autism Spectrum Disorder. Front Psychiatry 6:145. doi: 10.3389/fpsyt.2015.00145 PubMedPubMedCentralCrossRefGoogle Scholar
  244. Siniscalco D, Cirillo A, Bradstreet JJ, Antonucci N (2013) Epigenetic Findings in Autism: New Perspectives for Therapy. Int J Environ Res Public Health 10(9):4261–4273. doi: 10.3390/ijerph10094261 PubMedPubMedCentralCrossRefGoogle Scholar
  245. Sloan SA, Barres BA (2013) Glia as primary drivers of neuropathology in TDP-43 proteinopathies. Proc Natl Acad Sci U S A 110(12):4439–4440. doi: 10.1073/pnas.1301608110 PubMedPubMedCentralCrossRefGoogle Scholar
  246. Smeeth L, Cook C, Fombonne E, Heavey L, Rodrigues LC, Smith PG, Hall AJ (2004) MMR vaccination and pervasive developmental disorders: a case-control study. Lancet 364(9438):963–969. doi: 10.1016/s0140-6736(04)17020-7 PubMedCrossRefGoogle Scholar
  247. Soriano A, Nesher G, Shoenfeld Y (2015) Predicting post-vaccination autoimmunity: who might be at risk? Pharmacol Res 92:18–22. doi: 10.1016/j.phrs.2014.08.002 PubMedCrossRefGoogle Scholar
  248. Stetson DB, Medzhitov R (2006) Recognition of cytosolic DNA activates an IRF3-dependent innate immune response. Immunity 24(1):93–103. doi: 10.1016/j.immuni.2005.12.003 PubMedCrossRefGoogle Scholar
  249. Struys-Ponsar C, Guillard O, van den Bosch de Aguilar P (2000) Effects of aluminum exposure on glutamate metabolism: a possible explanation for its toxicity. Exp Neurol 163(1):157–164. doi: 10.1006/exnr.2000.7355 PubMedCrossRefGoogle Scholar
  250. Su X, Federoff H (2014) Immune responses in Parkinson's disease: interplay between central and peripheral immune systems. Biomed Res Int 2014:275178PubMedPubMedCentralGoogle Scholar
  251. Suarez-Fernandez MB, Soldado AB, Sanz-Medel A, Vega JA, Novelli A, Fernandez-Sanchez MT (1999) Aluminum-induced degeneration of astrocytes occurs via apoptosis and results in neuronal death. Brain Res 835(2):125–136PubMedCrossRefGoogle Scholar
  252. Sumathi T, Shobana C, Thangarajeswari M, Usha R (2015) Protective effect of L-Theanine against aluminium induced neurotoxicity in cerebral cortex, hippocampus and cerebellum of rat brain - histopathological, and biochemical approach. Drug Chem Toxicol 38(1):22–31. doi: 10.3109/01480545.2014.900068 PubMedCrossRefGoogle Scholar
  253. Suzuki K, Sugihara G, Ouchi Y, Nakamura K, Futatsubashi M, Takebayashi K, Yoshihara Y, Omata K, Matsumoto K, Tsuchiya KJ, Iwata Y, Tsujii M, Sugiyama T, Mori N (2013) Microglial activation in young adults with autism spectrum disorder. JAMA Psychiatry 70(1):49–58. doi: 10.1001/jamapsychiatry.2013.272 PubMedCrossRefGoogle Scholar
  254. Takahashi K, Rochford CD, Neumann H (2005) Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J Exp Med 201(4):647–657. doi: 10.1084/jem.20041611 PubMedPubMedCentralCrossRefGoogle Scholar
  255. Takahashi K, Prinz M, Stagi M, Chechneva O, Neumann H (2007) TREM2-transduced myeloid precursors mediate nervous tissue debris clearance and facilitate recovery in an animal model of multiple sclerosis. PLoS Med 4(4):e124. doi: 10.1371/journal.pmed.0040124 PubMedPubMedCentralCrossRefGoogle Scholar
  256. Tammimies K, Marshall CR, Walker S, Kaur G, Thiruvahindrapuram B, Lionel AC, Yuen RK, Uddin M, Roberts W, Weksberg R, Woodbury-Smith M, Zwaigenbaum L, Anagnostou E, Wang Z, Wei J, Howe JL, Gazzellone MJ, Lau L, Sung WW, Whitten K, Vardy C, Crosbie V, Tsang B, D'Abate L, Tong WW, Luscombe S, Doyle T, Carter MT, Szatmari P, Stuckless S, Merico D, Stavropoulos DJ, Scherer SW, Fernandez BA (2015) Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder. JAMA 314(9):895–903. doi: 10.1001/jama.2015.10078 PubMedCrossRefGoogle Scholar
  257. Tan MS, Yu JT, Jiang T, Zhu XC, Wang HF, Zhang W, Wang YL, Jiang W, Tan L (2013) NLRP3 polymorphisms are associated with late-onset Alzheimer's disease in Han Chinese. J Neuroimmunol 265(1–2):91–95. doi: 10.1016/j.jneuroim.2013.10.002 PubMedCrossRefGoogle Scholar
  258. Taylor LE, Swerdfeger AL, Eslick GD (2014) Vaccines are not associated with autism: An evidence-based meta-analysis of case-control and cohort studies. Vaccine 32(29):3623–3629. doi: 10.1016/j.vaccine.2014.04.085 PubMedCrossRefGoogle Scholar
  259. Thompson MR, Kaminski JJ, Kurt-Jones EA, Fitzgerald KA (2011) Pattern Recognition Receptors and the Innate Immune Response to Viral Infection. Viruses 3(6):920–940. doi: 10.3390/v3060920 PubMedPubMedCentralCrossRefGoogle Scholar
  260. Thrash JC, Torbett BE, Carson MJ (2009) Developmental regulation of TREM2 and DAP12 expression in the murine CNS: implications for Nasu-Hakola disease. Neurochem Res 34(1):38–45. doi: 10.1007/s11064-008-9657-1 PubMedCrossRefGoogle Scholar
  261. Tordjman S, Somogyi E, Coulon N, Kermarrec S, Cohen D, Bronsard G, Bonnot O, Weismann-Arcache C, Botbol M, Lauth B, Ginchat V, Roubertoux P, Barburoth M, Kovess V, Geoffray MM, Xavier J (2014) Gene x Environment interactions in autism spectrum disorders: role of epigenetic mechanisms. Front Psychiatry 5:53. doi: 10.3389/fpsyt.2014.00053 PubMedPubMedCentralCrossRefGoogle Scholar
  262. Torres AR, Westover JB, Rosenspire AJ (2012) HLA Immune Function Genes in Autism. Autism Res Treat 2012:959073. doi: 10.1155/2012/959073 PubMedPubMedCentralGoogle Scholar
  263. Tunçbilek S (2014) Relationship between cytokine gene polymorphisms and chronic hepatitis B virus infection. World J Gastroenterol 20(20):6226–6235. doi: 10.3748/wjg.v20.i20.6226 PubMedPubMedCentralCrossRefGoogle Scholar
  264. Vaishnavi V, Manikandan M, Tiwary BK, Munirajan AK (2013) Insights on the functional impact of microRNAs present in autism-associated copy number variants. PLoS One 8(2):e56781. doi: 10.1371/journal.pone.0056781 PubMedPubMedCentralCrossRefGoogle Scholar
  265. Vannuvel K, Renard P, Raes M, Arnould T (2013) Functional and morphological impact of ER stress on mitochondria. J Cell Physiol 228(9):1802–1818. doi: 10.1002/jcp.24360 PubMedCrossRefGoogle Scholar
  266. Venegas C, Heneka MT (2017) Danger-associated molecular patterns in Alzheimer’s disease. J Leukoc Biol 101(1):87–98. doi: 10.1189/jlb.3MR0416-204R PubMedCrossRefGoogle Scholar
  267. Vera-Lastra O, Medina G, Cruz-Dominguez M, Jara L, Shoenfeld Y (2013) Autoimmune/inflammatory syndrome induced by adjuvants (Shoenfeld's syndrome): clinical and immunological spectrum. Expert Rev Clin Immunol 9:361–373PubMedCrossRefGoogle Scholar
  268. Verstraeten T, Davis RL, DeStefano F, Lieu TA, Rhodes PH, Black SB, Shinefield H, Chen RT (2003) Safety of thimerosal-containing vaccines: a two-phased study of computerized health maintenance organization databases. Pediatrics 112(5):1039–1048PubMedGoogle Scholar
  269. Voineagu I (2012) Gene expression studies in autism: moving from the genome to the transcriptome and beyond. Neurobiol Dis 45(1):69–75. doi: 10.1016/j.nbd.2011.07.017 PubMedCrossRefGoogle Scholar
  270. Voineagu I, Eapen V (2013) Converging Pathways in Autism Spectrum Disorders: Interplay Between Synaptic Dysfunction and Immune Responses. Front Hum Neurosci 7:738. doi: 10.3389/fnhum.2013.00738 PubMedPubMedCentralCrossRefGoogle Scholar
  271. Voineagu I, Wang X, Johnston P, Lowe J, Tian Y, Horvath S (2011) Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature 474:380–384PubMedPubMedCentralCrossRefGoogle Scholar
  272. Walton JR (2006) Aluminum in hippocampal neurons from humans with Alzheimer's disease. Neurotoxicology 27(3):385–394PubMedCrossRefGoogle Scholar
  273. Walton JR (2012) Aluminum disruption of calcium homeostasis and signal transduction resembles change that occurs in aging and Alzheimer's disease. J Alzheimers Dis 29(2):255–273. doi: 10.3233/jad-2011-111712 PubMedGoogle Scholar
  274. Walton JR (2014) Chronic aluminum intake causes Alzheimer's disease: applying Sir Austin Bradford Hill's causality criteria. J Alzheimers Dis 40(4):765–838. doi: 10.3233/jad-132204 PubMedGoogle Scholar
  275. Wang Y, Cella M, Mallinson K, Ulrich JD, Young KL, Robinette ML, Gilfillan S, Krishnan GM, Sudhakar S, Zinselmeyer BH, Holtzman DM, Cirrito JR, Colonna M (2015) TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model. Cell 160(6):1061–1071. doi: 10.1016/j.cell.2015.01.049 PubMedPubMedCentralCrossRefGoogle Scholar
  276. Wang Z, Wei X, Yang J, Suo J, Chen J, Liu X, Zhao X (2016) Chronic exposure to aluminum and risk of Alzheimer's disease: A meta-analysis. Neurosci Lett 610:200–206. doi: 10.1016/j.neulet.2015.11.014 PubMedCrossRefGoogle Scholar
  277. Willhite CC, Karyakina NA, Yokel RA, Yenugadhati N, Wisniewski TM, Arnold IM, Momoli F, Krewski D (2014) Systematic review of potential health risks posed by pharmaceutical, occupational and consumer exposures to metallic and nanoscale aluminum, aluminum oxides, aluminum hydroxide and its soluble salts. Crit Rev Toxicol 44(Suppl 4):1–80. doi: 10.3109/10408444.2014.934439 PubMedPubMedCentralCrossRefGoogle Scholar
  278. Wong C, Meaburn E, Ronald A, Price T, Jeffries A, Schalkwyk L (2014) Methylomic analysis of monozygotic twins discordant for autism spectrum disorder and related behavioural traits. Mol Psychiatry 19:495–503PubMedCrossRefGoogle Scholar
  279. Yang CA, Chiang BL (2015) Inflammasomes and human autoimmunity: A comprehensive review. J Autoimmun 61:1–8. doi: 10.1016/j.jaut.2015.05.001 PubMedCrossRefGoogle Scholar
  280. Yang Y, Higashimori H, Morel L (2013) Developmental maturation of astrocytes and pathogenesis of neurodevelopmental disorders. J Neurodev Disord 5(1):22. doi: 10.1186/1866-1955-5-22 PubMedPubMedCentralCrossRefGoogle Scholar
  281. Yasuda H, Tsutsui T (2013) Assessment of infantile mineral imbalances in autism spectrum disorders (ASDs). Int J Environ Res Public Health 10(11):6027–6043. doi: 10.3390/ijerph10116027 PubMedPubMedCentralCrossRefGoogle Scholar
  282. Yasui M, Kihira T, Ota K (1992) Calcium, magnesium and aluminum concentrations in Parkinson's disease. Neurotoxicology 13(3):593–600PubMedGoogle Scholar
  283. Yousef MI (2004) Aluminium-induced changes in hemato-biochemical parameters, lipid peroxidation and enzyme activities of male rabbits: protective role of ascorbic acid. Toxicology 199(1):47–57. doi: 10.1016/j.tox.2004.02.014 PubMedCrossRefGoogle Scholar
  284. Yuan CY, Lee YJ, Hsu GS (2012) Aluminum overload increases oxidative stress in four functional brain areas of neonatal rats. J Biomed Sci 19:51. doi: 10.1186/1423-0127-19-51 PubMedPubMedCentralCrossRefGoogle Scholar
  285. Yumoto S, Kakimi S, Ohsaki A, Ishikawa A (2009) Demonstration of aluminum in amyloid fibers in the cores of senile plaques in the brains of patients with Alzheimer’s disease. J Inorg Biochem 103(11):1579–1584. doi: 10.1016/j.jinorgbio.2009.07.023 PubMedCrossRefGoogle Scholar
  286. Zafrir Y, Agmon-Levin N, Paz Z, Shilton T, Shoenfeld Y (2012) Autoimmunity following hepatitis B vaccine as part of the spectrum of 'Autoimmune (Auto-inflammatory) Syndrome induced by Adjuvants' (ASIA): analysis of 93 cases. Lupus 21(2):146–152. doi: 10.1177/0961203311429318 PubMedCrossRefGoogle Scholar
  287. Zaky A, Mohammad B, Moftah M, Kandeel K, Bassiouny A (2013) Apurinic/apyrimidinic endonuclease 1 is a key modulator of aluminum-induced neuroinflammation. BMC Neurosci 14(1):26PubMedPubMedCentralCrossRefGoogle Scholar
  288. Zhang YW, Thompson R, Zhang H, Xu H (2011) APP processing in Alzheimer's disease. Mol Brain 4:3. doi: 10.1186/1756-6606-4-3 PubMedPubMedCentralCrossRefGoogle Scholar
  289. Zhang Y, Yamamoto T, Hisatome I, Li Y, Cheng W, Sun N, Cai B, Huang T, Zhu Y, Li Z, Jing X, Zhou R, Cheng J (2013) Uric acid induces oxidative stress and growth inhibition by activating adenosine monophosphate-activated protein kinase and extracellular signal-regulated kinase signal pathways in pancreatic β cells. Mol Cell Endocrinol 375(1–2):89–96. doi: 10.1016/j.mce.2013.04.027 PubMedCrossRefGoogle Scholar
  290. Zhao Y, Lukiw WJ (2013) TREM2 signaling, miRNA-34a and the extinction of phagocytosis. Front Cell Neurosci 7:131. doi: 10.3389/fncel.2013.00131 PubMedPubMedCentralGoogle Scholar
  291. Zhao Y, Bhattacharjee S, Jones BM, Dua P, Alexandrov PN, Hill JM, Lukiw WJ (2013) Regulation of TREM2 expression by an NF-small ka, CyrillicB-sensitive miRNA-34a. Neuroreport 24(6):318–323. doi: 10.1097/WNR.0b013e32835fb6b0 PubMedPubMedCentralCrossRefGoogle Scholar
  292. Zhao Y, Bhattacharjee S, Jones BM, Hill J, Dua P, Lukiw WJ (2014) Regulation of neurotropic signaling by the inducible, NF-kB-sensitive miRNA-125b in Alzheimer’s disease (AD) and in primary human neuronal-glial (HNG) cells. Mol Neurobiol 50(1):97–106. doi: 10.1007/s12035-013-8595-3 PubMedCrossRefGoogle Scholar
  293. Zhubi A, Cook EH, Guidotti A, Grayson DR (2014) Epigenetic mechanisms in autism spectrum disorder. Int Rev Neurobiol 115:203–244. doi: 10.1016/b978-0-12-801311-3.00006-8 PubMedCrossRefGoogle Scholar
  294. Zielke HR, Jackson MJ, Tildon JT, Max SR (1993) A glutamatergic mechanism for aluminum toxicity in astrocytes. Mol Chem Neuropathol 19(3):219–233PubMedCrossRefGoogle Scholar

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Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Authors and Affiliations

  • Gerwyn Morris
    • 1
  • Basant K. Puri
    • 2
    Email author
  • Richard E. Frye
    • 3
  1. 1.Tir Na NogLlanelliUK
  2. 2.Department of MedicineImperial College London, Hammersmith HospitalLondonUK
  3. 3.College of Medicine, Department of PediatricsUniversity of Arkansas for Medical Sciences, Arkansas Children’s Hospital Research InstituteLittle RockUSA

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