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Barriers of the Human Organism and Their Achilles’ Heels

  • György BerencsiIIIEmail author
  • Maria Takács
Chapter
  • 570 Downloads

Abstract

The human body is covered by barriers separating it from the external and internal surroundings. The “milieu enterieur” has to be stabilised in spite of the variable external and internal conditions of toxic, osmotic, microbial and climatic environmental circumstances. This first line of barriers is composed of skin and mucous membranes of complicated structures.

A second line of barrier system is present in our organisms. Certain organs have to be separated from the immune system and other parts of the body because of evolutionary reasons (eye-bulb and testicles) because of unique proteins “unknown” for the acquired immune system. The blood-brain barrier (BBB) is providing enhanced safety circumstances for the central nervous system. The second line of barriers is represented by the special properties of the capillary endothelial system.

The maternal-fetal barrier is the most complex. At the maternal fetal interface two individuals of two different haplotypes has to be live 9 months separated by a very complicated dynamic barrier.

The placenta is the organ, which is separating the maternal and fetal tissues. Similar to others the bidirectional transport of gasses, metabolites, cells, proteins, regulatory substances, are transported by active or passive transcellular and intercellular mechanisms.

The fetal immune system develops immunotolerance to all maternal cells and antigens transferred transplacentally. The problem is to mitigate the maternal immune system to tolerate the paternal haplotype of the fetus. In the case of normal pregnancy a complex series of physiological modifications can solve the problem without harmful consequences to the mother and fetus.

The outermost contact cells of trophoblasts express instead of HLA-class Ia and class II antigens non-variable HLA-C, HLA-E, HLA-F and HLA-G antigens. The first consequence of this is reduction of the activity of maternal natural killer cells and maternal dendritic cells;

Progesteron, micro-RNA and mediators influence the development of T effector-cells. The production of soluble HLA-G(5 and 6) and IL-10 supports the differentiation of Th-2 CD4+ helper cells, reducing the ability of maternal cells to kill fetal cells.

Series of receptors and costimulators are expressed by the different lines of semi-allogenic trophoblast cells to bind HLA-G and mitigate maternal immune response;

The maternal immunotolerance is further facilitated by the activation of CD4+CD25brightFoxp3+ regulatory T (TREG) cells.

Infections have to be prevented during pregnancy. The cells of placenta express 10 Toll-like receptors a group of pattern recognition receptors responsible for innate immunity. The interferon level is also higher in the placental tissues than in the somatic fetal or maternal cells.

The complement system is also adapted to the requirements of the pregnancy and fetal damage is inhibited by the production of “assymmetric IgG antibodies” under hormonal and placental-regulation. These modifications prevent the activation of complement, cytotoxic activity, opsonising ability, antigen clearance and precipitating activity of the molecules.

The Achilles’ heels of the different barriers are regularly found by virus infections. Lamina cribrosa of the blood-brain barrier, optical nerve of the eyes, etc. the risk factors of the maternal-fetal barrier has been summarised in Table 1.1.

Keywords

Natural Killer Cell TREG Cell West Nile Virus Trophoblast Cell Human Leukocyte Antigen Class 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

1.1 Introduction

The different barriers of the human body are immunologically unique sites that must promote tolerance to the allogeneic external world, while maintaining host defense against possible harmful influences including pathogens. Mechanistic background of tolerogenesis is present in pregnancy, cancer, oral tolerance and anterior chamber associated immune deviation etc. It contains elements directly capable of promoting tolerogenesis such as T regulatory (T REG ) cells and inhibitory macrophages. The high content of mesenchymal and hematopoietic stem cells provides the possibility of trophic/regenerative potential, which would augment tolerogenic processes by decreasing ongoing inflammation. The application of such autologous cell sources can be used for therapeutic purposes, too. Autoimmune diseases i.e. rheumatoid arthritis can be improved on the basis of the information available (Ichim et al. 2010).

An other function of the barriers is the exchange of gases, liquids, toxic materials in order to stabilise the “milieu enerieur” of the body. Therefore, the barrier functions are asymmetrically bidirectional in the different surfaces of our body.

The most sofisticated unique barrier of the human being is the maternal-fetal interface, which can be considered to be a dynamic border of the infectious and non-infectious components, which have to be separated, but the allogeneic and non-infectious components have to be tolerated. The risk factors affecting the maternal-fetal barriers have been summarised in Table 1.1.
Table 1.1

Different etiologies of recurrent spontaneous abortions (Pandey et al. 2005)

Genetic, hormonal toxic

Immunology and tolerance

Microbiology

Chromosomal (Rubio et al. 2003)

Antipaternal antibodies (APCA) (Orgad et al. 1999)

Infections (Matovina et al. 2004)

Genetic (Takakuwa et al. 2003)

Autoimmune (Wramsby et al. 2000)

High fever (Czeizel et al. 2008)

Anatomical (Stray-Pedersen and Stray-Pedersen 1984)

Alloimmune factors (Eblen et al. 2000)

Prokaryontsa

Endocrinological (Clifford et al. 1994)

Antiidiotypic antibodies (Ab2) (Ito et al. 1999a, b)

Protozoaa

Placental anomalies (Lea et al. 1997)

Blocking antibodies (MLR-Bf) (Adachi et al. 2003)

Maternal-fetal infections with human viruses

Stress factors (Sugiura-Ogasawara et al. 2002)

T-1 pattern of cytokines (Lim et al. 2000)

Pelvic inflammation (Ács et al. 2008)

Smoking and alcohol (Harlap and Shiono 1980)

Natural killer (NK) cells (Faridi and Agrawal 2011)

TLR activation (Riley and Nelson 2010)

Environmental factors (Polifka and Friedman 1991)

Alteration in HLA-G expression (Aldrich et al. 2001)

 

aExceeding the topic of this chapter

1.1.1 Barrier of the Mucosa of Genital Organs

Lentiviruses such as HIV have a daunting challenge in gaining access to a new host predominantly through the barriers of penile, rectal, or vaginal/cervical mucosal tissue after sexual exposure. Multiple mechanisms have evolved to help prevent such infections, including anatomical barriers, innate inhibitors, and adaptive immune responses. For lentiviruses, it appears that in naive or even conventionally vaccinated hosts, typical adaptive immune responses are generally too little and too late to prevent infection (Keele and Estes 2011). The healthy mucous membranes The V1/V2 domain of HIV-1 gp120 mediates binding to integrin α4β7 (α4β7) on CD4+T-cells (Arthos et al. 2008). α4β7 has been termed the gut homing integrin (Wagner et al. 1996). It is upregulated on lymphocytes in Peyer’s patches and mesenteric lymph nodes, and then mediate, with chemokine receptors, the homing of these lymphocytes into gut associated lymphoid tissue (GALT) through interactions with its natural ligands, mucosal addressin cell adhesion molecule (MAdCAM) and vascular cell adhesion molecule (VCAM), which appear on the gut endothelial cells (Bargatze et al. 1995). N-linked glycosylation sites (PNGs) of V1, V2 and V4 domains of viral gp120 remain unglycosylated and surprisingly potentiate the affinity for α4β7 integrin. Therefore only a very small proportion if infecting HIV-1 (A or C subtypes) will be able to infect the mucosal lymphocytes unless an other sexually transmitted infection had not attracted and activated the CD4+ cells in the mucosa of the genital barriers (Nawaz et al. 2011).

Evidence has been presented, that antigens and cytokine signals in seminal fluid regulate the maternal immune response includes the following components: (1) the TREG cell-inducing cytokine TGFβ and male alloantigens present in seminal fluid; (2) seminal fluid delivery at coitus is sufficient to induce a state of active immune tolerance to paternal alloantigen, even in the absence of conceptus tissue; (3) female dendritic cells can cross-present seminal fluid antigens to activate both CD8+ and CD4+ T cells, and (4) mating events deficient in either sperm or seminal plasma result in diminished CD4+ CD25+ Foxp3+ TREG cell populations at the time of embryo implantation. Ongoing studies indicate that the cytokine environment during priming to male seminal fluid antigens influences the phenotype of responding T cells, and impacts fetal survival in later gestation, too (Robertson et al. 2009).

1.1.2 Oral Tolerance (OT)

Oral tolerance means systemic immunological unresponsiveness to harmless antigens present in the gastrointestinal tract. The secretory IgA and IgM impair or inhibit surface colonisation of microorganisms and dampen penetration of potentially dangerous antigens. The cellular part of OT mainly depends on the development of regulatory T (TREG) cells in mesenteric lymph nodes to which mucosal dendritic cells (DCs) carry exogenous antigens and become conditioned for induction of TREG cells (Brandtzaeg 2010). Tolerance to these antigens may also protect self-proteins that show immunological similarity to the intestinal normal flora. It has been suggested recently, that antigenic mimicry is one of the mechanisms contributing to the extension of OT to intestinal bacteria (bacterial homunkulus) on the basis of similar mimotopes (Kristóf et al. 2009). Cells producing soluble HLA-G antigens were detected in tonsils by immunohistochemistry, suggesting a role of sHLA-G in local control of TFH cell chemotaxis (Morandi et al. 2010).

1.1.3 Organisation of Immune Cells

The gastrointestinal epithelium transports solutes and water between lumen and blood and at the same time forms a barrier between these compartments. This highly selective and regulated barrier permits ions, water, and nutrients to be absorbed, but normally restricts the passage of harmful molecules, bacteria, viruses and other pathogens. Inflammatory processes are accompanied by increased oxidative stress, which in turn can impair the epithelial barrier. Consequently the decrease in transcellular electrical resistance and an increase in paracellular permeability for tracers of different size can be observed (John et al. 2011).

In colonic epithelial cells, hydrogen peroxide caused tyrosine phosphorylation of occludin and dissociation of occludin and ZO-1, leading to decreased transepithelial resistance and increased epithelial permeability (Rao et al. 1997).

Secretory immunity is preferentially stimulated by pathogens and other particulate antigens taken up through thin “M” cells (M) located in the dome epithelium covering inductive mucosa-associated lymphoid tissue. The commensal antigens cause suppression of pro-inflammatory Th2-dependent responses (IgE antibodies), Th1-dependent delayed-type hypersensitivity (DTH), IgG antibodies, and Th17-dependent granulocytic reactions.

Intestinal immune cells are located in three compartments: organised gut-associated lymphoid tissue (GALT), the lamina propria, and the surface epithelium. GALT comprises Peyer’s patches, the appendix, and numerous isolated lymphoid follicles. The B-cell follicles are covered by a specialised epithelium containing membrane (M) cells which, together with intraepithelial dendritic cells (DCs), transport antigens from the gut lumen into the lymphoid tissue (Neutra et al. 2001). Secretory IgA (SIgA) and secretory IgM (SIgM) are dimers and pentamers completed with the pIgR/membrane secretory component (mSC)-mediating epithelial export and rendering them resistant to digestive enzymes.

Plasma cells of B cell origin are differentiated in the lamina propria. In the regional lymph node plasmablasts are produced and transported into secretory glands.

In newborns, secretory IgA (SIgA) is generally undetectable in the mucosa before 10 days of age and SIgM+ PCs often remain predominant up to 1 month. Elevated SIgA probably reduce the risk of allergy before the 2nd year of age, but 70% of the participants continued breast feeding during the study (Kukkonen et al. 2010). Dendritic cells (DCs) of Peyer’s patches express IL-10 mRNA in contrast to DC-s of spleen origin. Cells of mesenterial lymph nodes (MLN) and DCs are inducing α4β7 integrins enabling the homing of T-cells. IgA, with or without bound SC, but not IgG or IgM, bound selectively to murine and human M cells. Fcγμ receptor, FcαRI, and asialoglycoprotein receptor was involved in the process.

Conformational changes following antigen binding modifies the receptor binding capacity. The immune complexes can induce antigen specific immunity or immunotolerance. Beneficial effects of indigenous gut bacteria appear to be mediated largely via pattern recognition receptors (PRRs) expressed by the surface epithelium, particularly Toll-like receptors (TLRs) and similar innate sensors on the plasma membrane (apically or basolaterally) or on endosomal membranes recognise conservative microbe-associated molecular patterns (MAMPs). Polarised epithelial cells have the ability to dampen the proinflammatory effect of PRR-mediated signals coming from the luminal side. In case the microbes were able to damage the epithelial cells, PRR signalling from the basolateral side results in NF-κB activation and release of epithelial defensins to combat the infection (Brandtzaeg 2010).

Secreted immunoglobulins play an integral role in host defense at mucosal surfaces, and recent evidence shows that IgG can participate in antigen sampling from the intestinal lumen. CD23 is a type II integral membrane glycoprotein with a carboxy terminal C-type lectin head that binds its ligand, IgE, in a calcium-dependent manner. It has been shown that human IgE also could facilitate transepithelial antigen sampling. CD23 was expressed constitutively on intestinal epithelial cells (IECs), and food-allergic patients had increased levels of soluble CD23 and food-specific IgE in the stool after challenge. Specific IgE facilitated the uptake of antigen from the apical surface of an epithelial monolayer by rescuing antigen from landing into lysosomes. CD23a functions as a bidirectional transporter of IgE and can capture IgE–antigen complexes and deliver them in an immunologically intact form across the intestinal epithelial barrier (Li et al. 2006a, b).

The role of retinoic acid (RA) in the reciprocal TGF-beta-driven differentiation of T(H)17 and regulatory TREG cells is important also in the control a functional immune system, in particular at the mucosal interface of the intestine (Mucida et al. 2007, 2009).

Antibacterial β defensins are protein antibiotics expressed in the oral mucosa, too (Kesting et al. 2012). Antimicrobial peptides are small, cationic, amphiphilic peptides of 12–50 amino acids with microbicidal activity against both bacteria and fungi. Mammalian defensins are composed of beta-sheet structures which are stabilised by two or three intramolecular disulfide bonds. The mammalian defensins can be subdivided into three main classes according to their structural differences: the alpha-defensins, beta-defensins and the recently described theta-defensins. Beta-defensins have been isolated from both leukocytes and epithelial cells (Schneider et al. 2005). All the genes investigated were expressed significantly more in the oral mucosa than in the skin (β-defensins 1–3 and psoriasin). Defensins were induced in the basal epitelium by bacterial extracts (Guaní-Guerra et al. 2011; Baldassarre et al. 2011).

The instruction of the immune system to be tolerant of self, thereby preventing autoimmunity, is facilitated by the education of T cells in a specialized organ, the thymus, in which self-reactive cells are either eliminated or differentiated into tolerogenic Foxp3(+) regulatory T (TREG) cells. However, it is unknown whether T cells are also educated to be tolerant of foreign antigens, such as those from commensal bacteria, to prevent immunopathology such as inflammatory bowel disease. It has been shown that the contact with commensal microbiota results in the peripheral generation of T REG cells rather than pathogenic effectors. It has been observed that colonic TREG cells used T-cell antigen receptors (TCRs) different from those used by TREG cells in other locations, implying an important role for local antigens in shaping the colonic TREG-cell population. Many of the local antigens seemed to be derived from commensal bacteria, on the basis of the in vitro reactivity of common colon TREG TCRs. These TCRs did not facilitate thymic TREG-cell development, implying that many colonic TREG cells arise instead by means of antigen-driven peripheral TREG-cell development. Microbiota indigenous to the mouse colony examined was required for the generation of colonic TREG cells from otherwise naive T cells. If T cells expressing these TCRs fail to undergo TREG-cell development and instead become effector cells, they have the potential to induce colitis, as evidenced by adoptive transfer studies. These results suggest that the efficient peripheral generation of antigen-specific populations of TREG cells in response to an individual’s microbiota provides important post-thymic education of the immune system to foreign antigens, thereby providing tolerance to commensal microbiota (Lathrop et al. 2011).

1.1.4 Intranasal Inoculation and Oral Tolerance

The Achilles’ heel of oral tolerance is the region of the lamina cribrosa. This place is a contact point between the oral tolerance and blood-brain barrier. Direct exchange of cells and etiological agents can be exchanged in this small region of the two large compartments.

Even stem cells may enter the CNS after intranasal administration. It may provide an extraordinary approach to overcome existing barriers of stem cell delivery for the treatment of many neurological disorders (Jiang et al. 2011a, b). Intranasal inoculation of rabies virus may result in 100% of mouse encephalitis within 9 days following infection, since the sensory nerves penetrating lamina cribrosa transported the virus directly into the brain (Lafay et al. 1991; Klopfleisch et al. 2004; Rosseels et al. 2011).

Coxsackie virus B (CVB) following dissemination, access secondary sites of infection via transmission through an endothelial monolayer such as that of the blood-brain barrier (BBB) and/or venous endothelium. Both polarized epithelial and endothelial cells function to prevent pathogen access to the interstitium, CVBs have developed strategies to subvert these barriers in order to promote their entry (Bozym et al. 2010). Coxsackievirus and adenovirus receptor (CAR) mediates attachment by all six CVB serotypes, but is inaccessible to viruses on the luminal surface due to its localization within intercellular tight junctions. Decay accelerating factor (DAF) is a glycosylphosphatidylinositol (GPI)-anchored membrane protein. It is localized to the apical surface of polarized cells and is accessible to virus in the lumen (Shieh and Bergelson 2002).

Lipid rafts are enriched in a number of signaling molecules including receptor tyrosine kinases, the Src family of nonreceptor tyrosine kinases, small G proteins, and adenylyl cyclases (ACs) and CBA-DAF complex can easily contact lipid rafts because of the absence of cytoplasmic domain of DAF (Parton and Richards 2003). Two tyrosine kinases (Abl and Fyn) are activated by DAF clustering and both are required for CVB entry into polarized epithelial cells (Coyne and Bergelson 2006).

Human brain microvascular endothelial cells (HBMEC), represent an in vitro model of the blood-brain barrier (BBB). CVB-induced clustering of DAF induces an immediate depletion of Ca2 i + stores. the Src family of tyrosine kinases, phospholipase C (PLC), and is mediated specifically by the IP3R isoform 3. Inositol 1,4,5-trisphosphate (IP3), the calpain family of Ca2+-activated proteases plays a role in mediating the trafficking of CVB-containing vesicles within the cell. Interestingly, Cai2+ release is involved in mediating CVB entry into primary human aortic endothelial cells, but is not required for CVB entry into polarized epithelial cells, suggesting that the intracellular signaling molecules hijacked by CVB to facilitate entry are distinct between the endothelium and epithelium.

The integrity of the zona occludens of nasopharingheal and respiratory epithelia may be impaired by rhinovirus and respiratory syncytial virus infections, too. The integrity of tight junctions facilitating bacterial transmigration across polarized airway epithelial cells, similar to the case with replicting rhinoviruses was found to be caused by poly(I:C), i.e. by double stranded RNA. Both stimulated Rac1 activation, reactive oxygen species (ROS) generation, and enhanced Rac1-dependent NADPH oxidase 1 (NOX1) activity, but independent of the stimulation of Toll-like receptor 3 (TLR-3). The NF-κB activation by respiratory syncytial virus (Fink et al. 2008; Yoboua et al. 2010) and IL-8 production of rhinovirus infected cells was also caused by oxidative stress (Biagioli et al. 1999). All of the above mentioned phenomena represent Achilles’ heels of the gastrointestinal system. The adverse effects of the inflammatory mediators on amniotic tight junctions cause severe dysfunction of the amniotic barrier (Kobayashi et al. 2010a, b; Comstock et al. 2011).

1.1.5 The Brest Feeding

Animal experiments revealed recently, that oral feeding of mice with hydrolised whey induced the production of Fox-P3+ TREG cells in the mesenterial lymph nodes of the animals. The transfer of these cells into naive individuals was able to prevent the development of sensitisation and development of skin allergy passively. It is suggested, that this phenomenon is important in the prevention of development of allergic diseases (van Esch et al. 2011). The intestinal commensal bacteria possess similar tolerising effect, too (Lathrop et al. 2011). It has been suggested earlier, that the bacterial mimotopes might play an important role in the tolerogenic effect of commensal bacteria (Kristóf et al. 2009).

In addition to contributing to passive protection, breastfeeding actively stimulates the neonatal immune system of the human offspring, too. Factors including lymphocytes, cytokines, hormones, lactoferrin, and anti-idiotypic antibodies are presumably involved (Corthésy 2007). The neonatal FcRn is also able for the bidirectional transport, but in contrast to rodents, immuncomplexes and not antibodies were shown to be transported from the luminal side of the gut to the dentritic cells of the mucosa for presentation (Yoshida et al. 2004).

Mother’s milk also contains a number of immune cells, cytokines, and growth factors that may exert a significant biological effect in the breast-fed infant’s gut, apparently enhancing in an indirect way even the subsequent health of the individual. The microbe-associated molecular patterns (MAMPs) do not only directly modulate the epithelial barrier function of neonates. Unlike intestinal macrophages, intestinal epithelial cells (IECs) acquire TLR tolerance immediately after birth by exposure to exogenous endotoxin to facilitate microbial colonization and the development of a stable intestinal host–microbe homeostasis (Lotz et al. 2006). Intestinal colonisation of lactobacilli and bifidobacteria is promoted by breast milk because it acts as prebiotics through its large amounts of oligosaccharides (Brandtzaeg 2010). E. coli is a strong inducer of IL-10 secretion being crucial for maintained expression of the Foxp3 transcription factor of TREG cells (Murai et al. 2009).

Intranasal dry powder measles vaccination was also successful (Lin et al. 2011). The virus obviously was dissolved on the surface of cells with CD46+ receptors on the surface of the bronchial mucosa. The transfer of viruses is one of the Achilles’ heels of the OT.

1.2 The Blood-Brain Barrier (BBB)

The blood-brain barrier (BBB), comprised of the endothelial cells lining the cerebral vasculature, regulates the paracellular and transcellular passage of molecules and solutes between the cerebral vessels and the brain neuropils. The site of barrier function is at the level of the endothelium, astrocytes are known to induce and maintain permeability properties of the BBB. Another potential role of astrocytes is in the actual regulation of water transport across the BBB, mainly because of the highly polarized localization of aquaporin-4 (AQP4) in the perivascular endfeet of astrocytes (Quick and Cipolla 2005). During the telencephalon morphogenesis the immature astroglia cells play a role in the early establishment of the distribution pattern of the neural microvessels and in their growth and maturation. Astrocytes are well known to establish close anatomical and functional relationships with the adult brain microvessels and to induce the expression and maintenance of the blood-brain barrier (BBB) phenotype of the brain endothelial cells (Virgintino et al. 1998). One pathologic condition that may involve AQP4 and edema formation is eclampsia. Eclampsia is a serious complication of pregnancy due to its neurological complications, including headaches, nausea, vomiting, and seizures (Mas and Lamy 1998). Eclampsia seems to be similar to hypertensive encephalopathy in which an acute rise in blood pressure causes forced dilation of the cerebral arteries and arterioles, decreased cerebrovascular resistance, and increased pressure on the microcirculation, resulting in disruption of the BBB and vasogenic edema (Engelter et al. 2000).

Pregnancy has been shown to up-regulate aquaporin expression in other organs such as the uterus. Rat experiments suggested that pregnancy and the postpartum state upregulated AQP4 protein located around the intraparenchymal blood vessels, a consequence that could promote edema formation when blood pressure is acutely and excessively elevated, as during eclampsia (Quick and Cipolla 2005).

Some enterovirus 71 (EV71) antigens were shown to induce cross-reactivity to human cerebra. The infection led to a persistent viremia and a transient increase in BBB permeability, but only low levels of virus could be detected in the mice brain. The brain binding partner of EV71 induced IgG was not identified. The increase of BBB permeability after EV71 infection could result in the entrance and localization of the IgG into brain tissues. The increase of BBB permeability in neonatal mice under EV71 infection and the entry of brain cross-reactive IgG were supposed to play a role in the development of subsequent clinical symptoms (Jia et al. 2010).

Transcellular migration of neutrophil granulocytes forms an additional Achilles’ heel of the blood-brain barrier, since both cells and bacteria were shown to penetrate the plexus chorioideus capillary vessels and epithelium in the presence of intact zona occludens (Wewer et al. 2011).

In utero the blood-brain barrier (BBB) is not yet developed, therefore the transplacental antibodies are able to react with fetal neurones, too. The newborns of mothers suffering from SLE may have learning and memory disturbances (Cohen-Solal and Diamond 2011).

1.3 The Human Skin Is Homing More T-Cells Than the Blood and Lymphoid Organs

1.3.1 T Cells from Normal Human Skin

T cells from normal human skin using both established and novel methods were tested. Skin resident T cells expressed high levels of cutaneous lymphocyte antigen positive (CLA+), CCR4, and CCR6, and a subset expressed CCR8 and CXCR6 chemokine receptors. Skin T cells had a remarkably diverse TCR repertoire and were mostly Th1 memory effector cells with smaller subsets of central memory, Th2, and functional T regulatory cells (Clark et al. 2006a, b).

Exposure to parasites in the skin coincides closely with vaccine failure. Malaria naïve subjects, (which excludes bloodstage immunosuppressive effects) live-parasite immunization transiting unmodified skin is inefficient. Immunity diminishes after unmodified skin-parasite interactions and is significantly less robust generated via skin exposure (Guilbride et al. 2010). Subcutaneous antigen delivery bypasses plenty of TREG cells present within the cutis. This is the reason, why mosquito bites result in tolerance (i.e. impairment of immune response, but mitigation of the clinical symptoms in children).

The presence of protein antibiotics (β defensin 1–4) were identified in the human skin, too (Ali et al. 2001).

Proteoglycane recognition proteins 1–4 are coded for by the genes Pglyrp 1–4. Their products are recognising bacterial peptidoglycans, and function in antibacterial immunity. These can protect mice against experimental colitis, and arthritis (Saha et al. 2009, 2010) and are able to modulate the development of experimental atopic dermatitis. It has been shown, that Pglyrp3 and Pglyrp4 products limit over-activation of Th17 cells by promoting accumulation of TREG cells at the site of chronic inflammation, which protects the skin from exaggerated inflammatory response to cell activators and allergens. By contrast, Pglyrp1 protein has an opposite pro-inflammatory effect in the skin (Park et al. 2011).

1.3.2 Dendritic Cells, Skin and Mucosal Barriers

Langerhans cells have been discovered in 1868 (Langerhans 1868). Three fractions of DCs in the human peripheral blood using a panel of mAbs have been characterised. One of them has the capacity to become LCs. Blood DC fractions (subsets) are different not only in their maturational stages, but also in their lineage or differentiation pathways (Ito et al. 1999a, b). Langerhans-like cells have been identified already among salmonid lymphoid cells (Lovy et al. 2011). LCs as scattered starry cells in the basal and supra-basal of epidermis layers. In the subcutaneous lymph-nodes, LCs could be demonstrated already from the 4th month of foetal life. LCs were suggested to be of neural crest origin, similar to the melanocytes (Muretto 2008). Langerhans cells utilize CD1a and langerin to efficiently present nonpeptide antigens to T cells (Hunger et al. 2004).

Dendritic cell (DC) subsets in mucosal tissues are thought to transmit HIV-1 to T cells through C-type lectins. In mucosal tissues, DC subsets can be distinguished by their expression of C-type lectins. HIV can interact concomitantly with non-LC dendritic cells in two separate and distinct ways: a CD4- and CCR5-dependent infection pathway and a CD4- and CCR5-independent capture pathway mediated by DC-SIGN, a C-type lectin molecule. Langerhans cells (LCs) specifically express Langerin and DCs express DC-SIGN (de Witte et al. 2007).

LCs reside in the epidermis of the skin and in most mucosal epithelia, such as the ectocervix, vagina and foreskin, whereas DC-SIGN+ DCs reside in the subepithelium (Veazey et al. 2005; Veazey and Lackner 2005). Thus, LCs are the first DC subset to encounter HIV-1 (Kawamura et al. 2005). LCs are resistant to this subversion and do not efficiently transmit virus to T cells, unless a C-type lectin is inhibited by a C-type lectin inhibitor mannane (de Witte et al. 2007).

Langerin (CD207) is a C-type lectin expressed in human exclusively by Langerhans cells (LCs). Langerin is a type II transmembrane protein that contains one calciumdependent carbohydrate recognition domain with a short cytoplasmic tail with a proline rich motif. Langerin forms a trimer on the cell surface and upon crosslinking with either a cell-bound or a soluble ligand. Langerin is inducing the formation of Birbeck granules: Organelles, consisting of pentalamellar and zippered membranes that can be visualized using electron microscopy. The Birbeck organelles have only been found in LCs. The function of Birbeck granules is not known yet (Geijtenbeek et al. 2000; de Witte et al. 2008).

Human primary LCs were shown to be capable of capturing measles virus (MV) through the C-type lectin Langerin. Both immature and mature LCs presented MV-derived antigens in the context of HLA class II to MV-specific CD4+ T cells. Immature LCs were not susceptible to productive infection by MV and did not present endogenous viral antigens in the context of HLA class I. In contrast, mature LCs could be infected by MV and presented de novo synthesized viral antigens to MV-specific CD8+ T cells. Immune activation of LCs seems a prerequisite for MV infection of LCs and subsequent CD8+ T-cell priming via the endogenous antigen presentation pathway (de Jong and Geijtenbeek 2010; van der Vlist et al. 2011).

Direct or competitive inhibition of Langerin function and inhibition of the Langerint expression was shown to facilitate HIV-1 replication in LCs (de Jong and Geijtenbeek 2010). The inhibition of Toll like receptors had no influence on the restricting function of Langerin i.e. HIV replication in dendritic cells (Ogawa et al. 2009).

Complement also can influence the adaptive immune response by modulating DC function and thus regulating antigen specific T cell responses. C1q was shown to activate dendritic cells (Götherström et al. 2005; Csomor et al. 2007; Fazekasova et al. 2009). Murine bone marrow dendritic cells (BMDCs) are important local source of complement and can react to activated complement products (C3a, C5a) through specific receptors (C3aR, C5aR) expressed on DCs, which leads to cell activation and functional modulation.

Monocyte derived CD1a+CD14, dermal CD1a+DC-SIGN+, Langerhans CD1a+ Langerin+, myeloid CD1c+CD19, plamacytoid CD45RA+CD123+ express many of the components of the classical and alternative and terminal pathways of complement.

Human DCs have receptors C3aR and C5aR known to recognise the biologically active peptides C3a and C5a. Membrane receptor proteins inducing immune adhesion CR3, CR4 CRIg and bind C3b and metabolites iC3b and C3d. The human DC surface is characterised by membrane bound regulators of complement activation, which are also known to participate in intracellular signalling (CD46, CD55, CD59). These findings suggest, that the complement system can influence both the antigen presentation and autoimmune illnesses (Li et al. 2011) in addition to the many other circumstances discussed above.

1.4 The Blood-Retinal Barrier and Sympathetic Ophtalmia

Interstitial retinoidbinding proteins, are capable of eliciting uveitis. Another recent histochemical investigation suggests that sympathetic ophtalmia (SO) is mediated by delayed T-cell hypersensitivity directed at surface membrane antigens shared by photoreceptors, retinal pigment epithelial cells, and choroidal melanocytes (Chaithanyaa et al. 2011). The eye which has suffered penetrating injury, has to be enucleated within 2 weeks in order to prevent sensitisation. The absence of lymphatics within the eye may play an important role in the pathogenesis of SO. Intraocular antigens circulate to the blood and spleen following penetrating injury, bypassing local lymph nodes, which may result in the induction of blocking antibodies or suppressor cells in spleen. Bacterial or other microbial contamination may potentiate sensitisation (Chaithanyaa et al. 2011).

The barrier can be penetrated by therapeutic methotrexate, methylpredenisolone, mycophenolate mofetil, cyclosporine and infliximab. The therapy using anti-tumor necrosis factor (anti-TNFα), but not daclizumab (monoclonal antibody specific for the receptor of interleukin 2) therefore only the first group can achieve prolonged remission of the patient (Gupta et al. 2011).

This disease indicates, that the fetal thymus and immune system did not met these antigens during the embryonic development. The transbarrier metabolism, however, was found to be very active. In diabetic retinopathy 27 cytokines and chemokines were found in the vitreous fluid. The development of both central retinal vein occlusion and rethinopathy seemed to be associated with increased concentrations of inflammatory cytokines IL-10, IL-13, platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). The screening was performed using a microbead-array system by the authors (Suzuki et al. 2011).

Expression and organization of a well-developed tight junction (TJ) complex in the inner retinal capillaries contributes to the formation of the internal blood-retinal barrier (iBRB). Transport of molecules across the vascular endothelium may occur by transcellular pathways, including specific transporters or by paracellular transport, which includes transport across the junctional complex, across a broken junctional complex, or across a large gap caused by cell death or cell division. Oncotic pressure and hydrostatic pressure drive both fluid and solute transport.

A three-pore model of transport – namely, transcellular transport through vesicles, broken TJs, and large pores, also termed leaky junctions have been developed. Bovine retinal endothelial cell (BREC) monolayer was used for the tests seeded onto a TUNEL assay kit. The fluorescent solutes were carboxytetramethylrhodamine (TAMRA of a Stokes diameter of 1.3 nm), 70-kDa TRITC-dextran (of 11 nm) and low density lipoproteid (Dil-LDL of 22 nm). The results support the existence of an indirect pathway by which iBRB permeability is increased through the upregulation of retinal VEGF in response to hyperglycemia (Lopez-Quintero et al. 2011).

Examinations using human “Angiogenesis Antibody Array” for retinal pigment endothelial (RPE) cells showed high production of interleukin-8 (IL-8) and monocyte chemotactic protein-I (MCP-I). Stimulation of RPE cells (mediated by Toll-like receptor 3) with the dsRNA analogue poly(I:C) enhanced the secretion of IL-8 and MCP-I, as well as the expression of junctional adhesion molecule-I (Jam-I) and intracellular adhesion molecule-I (ICAM-I), and promoted the adhesion of monocytes to these cells. In contrast, stimulation with the CpG-DNA motif (mediated by Toll-like receptor) only enhanced the secretion of IL-8 and enhanced phagocytosis in RPE cells. These results may indicate that TLR 3 and 9 play a distinct role in the inflammatory response that clears viruses from the retina (Ebihara et al. 2007).

1.4.1 Virus Infections of the Eye Bulb, Lens and Retinal Epithelium

Rubellavirus and human hervesvirus 2 (HHSV-2) were identified in the lens aspirate of newborns suffering from connatal cataract (Shyamala et al. 2008). Herpes simplex virus 1 and varicella-zoster virus encephalitides were followed by acute retinal necrosis after some delay. The delay, however may last sometimes for decates (Klein and Lefebvre 2007; Vandercam et al. 2008). The way of HSV-1 to retinal cell layers were mediated by nectin-1 receptor being the major determinant of HHSV-1 entry into retinal pigment epithelial (RPE) cells. In addition, nectin-1 can influence cell to-cell spread of the virions involving membrane fusion. This is probably the mechanism helping the virus to enter the inner eye (Tiwari et al. 2008). Human cytomegalovirus (HCMV) produced in epithelial cells preferentially fuses with the plasma membrane of retinal pigmented epithelial cells, whereas fibroblast-derived virus mostly enters by receptor-mediated endocytosis (Wang et al. 2007). Human cytomegalovirus retinitis of patients suffering from HIV-1 disease occurs frequently, too (Geng et al. 2011). Eyes of AIDS patients with a clinical history of HCMV retinitis were tested positive for HCMV, but also for JC papillomavirus and HIV-1 provirus (Eberwein et al. 2005). Multifocal choroiditis is the most common ocular manifestation associated with West-Nile Virus (WNV) infection, with a typically benign clinical course. Less frequent ocular lesions, including optic neuritis and occlusive vasculitis, frequently induce persistent and likely permanent visual deficit (Chan et al. 2006).

1.4.2 The Effect of Pregnancy and Diabetes on the Blood-Retinal Barrier

Normal pregnancy was characterized by an activation of circulating leukocytes as part of a generalized immune response. This leukocyte activation is marked by up-regulation in the expression of different adhesion molecules such as CD11a,b/CD18, CD54 (ICAM-1) and CD49d as well as integrins and selectins present on the surface of circulating leukocytes. These activated leukocytes have the increased potential to bind to the endothelium of blood vessels via interactions with ICAM-1 and VCAM-1 molecules. One of the essential pathologic events in the development of diabetic retinopathy is activated during pregnancy and could therefore be at least partially responsible for its progression in the gestation period. Patients suffering form proliferative diabetic retinopathy (PDR) possessed increased vitreous concentrations of interleukin-1beta (IL-1beta), IL-6, soluble IL-2 receptor (sIL-2R) and IL-8 were found. Their sera contained elevated levels of tumor necrosis factor-alpha (TNF-alpha), IL-6, IL-8 and sIL-2R (Kaštelan et al. 2010). The cytokine changes during pregnancy and possible influence on retinopathy are summarised in Table 1.2.
Table 1.2

Cytokine changes during pregnancy and possible influence on retinopathy (Kaštelan et al. 2010)

TNF-α

Increased mediator of endothelial dysfunction in preeclampsia

IL-1α

Increased in serum

IL-1β

No change in serum concentration but elevated vitreous level

IL-4

Reduced in serum

IL-6

Increased serum and vitreous levels; pro-inflammatory cytokines breakdown of blood-retinal barrier and mediator of endothelial dysfunction in preeclampsia, highest level at labour;

IL-8

Angiogenic and fibrovascular proliferative effect (ocular neovascularisation)

sIL-2R

Increased vitreous concentration

IL-10

Increased in serum

VEGF

Increased in serum

EGF

Increased in serum

ICAM-1

Increased on the membrane of endothelial cells; Increased leukocyte adhesion;

VCAM-1

Increased on the membrane of endothelial cells; Increased leukocyte adhesion;

E-selectin

Increased on the membrane of leukocytes; Increased leukocyte adhesion; Occl.

P-selectin

Increased on the membrane of leukocytes; Increased leukocyte adhesion; Occl.

PDR proliferative diabetic retinopathy, TNF tumor necrosis factor, IL interleukin, VEGF vascular endothelial growth factor, EGF epidermal growth factor, ICAM intercellular adhesion molecule, VCAM vascular cell adhesion molecule, Occl capillary occlusion

Preeclampsia is a well recognized risk factor for the progression and deterioration of diabetic retinopathy during pregnancy. It is associated with increased systemic vascular resistance, enhanced platelet aggregation, activation of the coagulation system and endothelial cell dysfunction as part of a general inflammatory reaction. Analysis of PCT and IL-6 concentrations in serum allows to identify women that are more likely to deliver newborns with symptoms of severe infection. In cases of severe infection, the usefulness of procalcitonin (PCT) measurement surpasses any currently used methods (Camacho et al. 2010).

1.5 Blood Testicle Barrier (BTB)

The assymmetric nature of the blood-testicle barrier has been discovered first (Berencsi and Kereszti 1976), when Scarlet Red and p-Dimethylamino-azobenzene dissolved in paraffin oil has been injected into rabbit testicles. p-Dimethylamino-azobenzene caused no significant changes in the macromolecular fractions of the blood, while scarlet Red injected into the testicles caused a significant increase of the total lipids in the second week after the exposition. Similar effect could not be observed when Scarlet Red was introduced by any other route.

The difference in the protein content of human seminiferous fluid and blood was detected first by Koskimies et al. (1973) detecting the existence of a barrier.

Very different immunological environments are represented by the testis, where sperm develop, and by the epididymis, where sperm mature and are stored. In comparison with the elaborate blood-testis barrier, the tight junctions of the epididymis are much less effective. Unlike the seminiferous epithelium, immune cells are commonly observed within the epithelium, and may even be found within the lumen, of the epididymis (Le Tortorec and Dejucq-Rainsford 2010; Hedger 2011). The function of the blood-testis barrier formed by Sertoli cells protects autoimmunogenic haploid germ cells from the attack by the autoimmune system. In mice infertility was caused by induction of experimental autoimmune orchitis (EAO) and by the surgical placement of testes, epididymides and vasa deferentia (TEV) into the abdominal cavity or subcutaneous space from a syngeneic donor (Terayama et al. 2011).

Traumatic spinal cord injury (SCI) was shown to impair tight junctional integrity within the seminiferous epithelium. Three days after post-SCI, decreased expression of the tight junction protein occludin was observed. High expression of the proinflammatory cytokine interleukin-1 beta was detected indicating inflammation. CD68+ immune cell infiltrate and mast cells were also detected within the seminiferous epithelium of both acute and chronic SCI groups but not in controls. The integrity of the BTB was measured by gadopentate dimeglumine (Gd) injected intravenously. The results indicate that the BTB remains compromised and testis immune cell infiltration persists for months after the initial injury (Dulin et al. 2011).

Drug transporters i.e. efflux pumps such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are localized at the blood-testis barrier (BTB), where they protect the testis from drugs and xenobiotics that are detrimental to spermatogenesis. At the same time, efflux pumps might also preclude entry of non-hormonal contraceptives to the testis. In more recent studies, P-gp function was correlated with BTB integrity as summarised in a recent review (Mruk et al. 2011).

Virus infection of testicles. HCMV was detected in male germ cells, both in sperm samples and in testis organotypic culture. The virus may infect immature germ cells which develop to mature HCMV-carrying spermatozoa. A considerable decrease in the number of immature germ cells indicates that HCMV produces a direct gametotoxic effect and can contribute to male infertility (Naumenko et al. 2011).

Endogeneous retrovirus 9 (HERV-9) was found to carry the TP63 locus only recently in evolution and is unique to humans and great apes (Hominidae). A corresponding p63 protein is the sole p63 species in healthy human testis, and is strongly expressed in spermatogenic precursors but not in mature spermatozoa (Beyer et al. 2011).

Extremely seldom the West Nile virus (WNV) was found to replicate in endotelial cells of teticles (Armah et al. 2007). Both testicle and epididimal cells were found to be susceptible to HIV-1 (Roulet et al. 2006).

Orchitic SARS testes displayed widespread germ cell destruction, few or no spermatozoon in the seminiferous tubule, thickened basement membrane, and leukocyte infiltration. The numbers of CD3+ T lymphocytes and CD68+ macrophages increased significantly in the interstitial tissue compared with the control group (P < 0.05). Severe acute respiratory syndrome (SARS) viral genomic sequences were not detected in the cells. The inflammation was the result of a possible immune response (Xu et al. 2006). Papillomaviruses were shown to replicate in both Leydig cells and Sertoli cells of human testicles (Martorell et al. 2005). Mumps Paramyxovirus attacks the testicular glands, leading to parenchymal inflammation, separation of seminiferous tubules and perivascular interstitial lymphocyte infiltration. This infection was the most frequent cause of orchitis sometimes resulting sterility before the introduction of vaccination (Masarani et al. 2006). Mumps virus was isolated from the semen 14 days after onset of parotitis and mumps RNA was detected in semen for up to 40 days using RT-PCR (Jalal et al. 2004).

1.6 Unique Features of the Maternal-Fetal Barrier

Maternal-fetal barrier represents an initial contact point for genital pathogens and, therefore, has specialized innate and adaptive immune attributes. This same tissue, however, must simultaneously tolerate the growing pregnancy, allowing allogenic fetally derived placental cells to reside in direct apposition with immunocompetent maternal lymphocytes. CD56brightCD16dim natural killer (NK)-like cells (decidual NK cells) and CD3+ T cells comprise the two major subsets of decidual lymphocytes. The fetomaternal barrier has to be capable to prevent penetration of harmful substances and infectious agents, but in the same time without injuries caused to the semiallogenic fetal tissues. This dynamic role is fulfilled by many different functions and mechanisms. The clonal deletion mechanism of B-cell tolerance has been shown first in mice (Nossal and Pike 1975).

Peptide antibiotics are present in the vernix caseosa and in the skin of the healthy newborn infant, indicating effective innate immune protection already during fetal and neonatal life (Marchini et al. 2002). Beta-defensins have been isolated from both leukocytes and epithelial cells (Schneider et al. 2005). Human antimicrobial proteins, β-defensins are also expressed at the human chorioamniotic barrier (Polettini et al. 2011).

In chorioamnionitis, intra-amniotic infections render the amniotic fluid an adverse environment for the foetus and increase the risk of foetal mortality and morbidity. It is still unclear how infection crosses the amniotic barrier, which is made up of tight junctions (TJs). Amniotic TJs were disrupted by single applications of interleukin (IL)-1β, IL-6, tumour necrosis factor-α (TNF-α) and prostaglandin E2.

In organ cultures of amniotic membrane these inflammatory mediators decreased the claudin-3 and claudin-4 levels at the apical junction at different times. Artificial injection of IL-6 into the amniotic cavity concurrently induced the disruption of amniotic TJs by decreasing the claudin-3 and claudin-4 levels at the apical junction resulting in the dysfunction of the amniotic barrier. The injection of TNF-α weakened the amniotic barrier by inducing apoptosis of the amniotic epithelial cells, with no decrease in claudin-3 and claudin-4 at the apical junction. The administration of the amniotic fluid of pregnant mice with bacterial lipopolysaccharide caused dysfunction of the amniotic barrier and disruption of TJs, involving the decrease of claudin-3 and claudin-4 levels at the apical junction and apoptosis in the amniotic epithelium (Kobayashi et al. 2010a, b).

1.7 Immunomodulation of the Maternal Immune System in Order to Tolerate Fetal Tissues

In humans placental trophoblast cells encounter the maternal immune system in two main areas – the villous trophoblast cells interact with the maternal blood and the extravillous trophoblast cells interact with the uterine tissue. In humans, the syncytiotrophoblast is therefore in contact with the systemic but not the uterine immune components of the mother. The syncytiotrophoblast expresses no MHC antigens on its surface, which is consistent with the concept that the placenta is immunologically neutral. Indeed, it has been difficult to demonstrate any systemic maternal T- or B-cell responses to trophoblast cells (as opposed to fetal cells that cross into the maternal circulation) during human pregnancy. The outermost layer of the human placenta is devoid of classical class I human leukocyte antigens (HLA-A, HLA-B, and HLA-C) and class II proteins (HLA-DR, HLA-DQ, and HLA-DP). Although this prevents recognition by maternal T lymphocytes, the lack of class I molecules leaves these cells susceptible to attack by natural killer (NK) cells. HLA-C is the only HLA molecule expressed by trophoblast cells that shows any appreciable polymorphism.

There are qualitative differences in all systemic T- and B-cell responses in pregnancy because of the altered clinical course of autoimmune diseases and viral infections during pregnancy. For example, the symptoms of rheumatoid arthritis (which is TH1-cell mediated) improve during pregnancy, whereas those of systemic lupus erythematosus (which is TH2-cell mediated) worsen and this is presumably caused by the bias away from TH1-towards TH2-cell responses.

The second area of contact is between invasive extravillous trophoblast (EVT) cells and immune cells in the decidua. In contrast to the syncytiotrophoblast, extravillous trophoblast cells express an unusual combination of HLA-C, HLA-G, HLA-E and HLA-F molecules (Shobu et al. 2006). Extravillous trophoblast cells have an extraordinarily high proliferating capacity and their telomerase activity is substantially higher than that of somatic cells. Survivin, a protein that promotes proliferation and inhibits apoptosis, is overexpressed in trophoblast cells.

Insulin-like growth factor (IGF) stimulates proliferation of trophoblast cells through the MAPK pathway and survival via activation of the PI3K pathway by binding to its receptor IGF1R. The fetal form of insulin receptor itself (IRA) reacts also with insulin-like growth factor 2 (IGF-2) participating in the regulation of trophoblast proliferation. In contrast to cancer cells trophoblasts follow an organized pattern of differentiation from proliferation to invasion without distant metastasis (Marco et al. 2009). To promote invasion the epithelial trophoblasts differentiate and mesenchymal transition occurs, which results in loss of cell-to-cell contact inhibition and the loss of cell polarity. Cells secrete proteases required for the spread in the decidua. The expressed HSP27 is corresponding to the matrix protease MMP-2 (Soundararajan and Rao 2004; Holtan et al. 2009, 2011; Ma et al. 2010).

Trophoblast cells, however, directly in contact with the maternal tissues express the class I molecule HLA-G, which may be involved in protecting the trophoblast from recognition by NK cells. HLA-G is sufficient to protect otherwise susceptible target cells from lysis by activated NK1 and NK2 cell lines and clones that are specific for distinct groups of HLA-C alleles. HLA-E, -F, and -G, have restricted expression, few variants, and appear rarely to be immunostimulatory (Carosella et al. 2003). One class Ia antigen, HLA-C, and the three class Ib antigens are differentially expressed by trophoblast cell subpopulations. HLA-G5 and HLA-G6 are the soluble isoforms of the antigen (Sargent et al. 2006). HLA-G5 is a homodimer without β2-microglobulin (β2m). The results suggest that the β2m-free structure has selective functional advantages for trophoblast cells, perhaps in evading immune recognition (Apps et al. 2007; Kuroki and Maenaka 2007; Morales et al. 2007). The cell migration from the fetus to the mother is a well known phenomenon during pregnancy (Dawe et al. 2007). It is hypothesised, that the HLA-G allels on the surface of the fetal cells might play a role in the long term survival of microchimeric cells in the maternal organisms.

A systematic sequencing study of HLA-G alleles was done obtaining the complete genomic sequence of 16 different HLA-G alleles: nine alleles were intron and exon confirmatory sequences, four were exon confirmatory and new intron described sequences, and three were new alleles Human leukocyte antigen-G allele polymorphisms have evolved following three different evolutionary lineages based on the alterations of intron sequences (Cervera et al. 2010, 2011). In Brasil 28 different HLA-G haplotypes were identified (Castelli et al. 2011). HLA-G polymorphisms may be associated with HPV infection and squamous intraepithelial lesions (SIL), consequently representing a profile of predisposition to cervical cancer and miscarriage (Moreau et al. 2008; Simões et al. 2009).

It has been suggested recently, that HLA-G is expressed also by stem cells other than hematopoetic origin (Selmani et al. 2008, 2009). The panleukocyte marker CD45 is missing from the mesenchymal stem cells (MSC). HLA class I antigens were found to be expressed, but only to a low level in MSC. HLA class II antigens were not expressed at all. (Castelli et al. 2009). MSCs, through HLA-G5, affect innate immunity by inhibiting both NK cell-mediated cytolysis and interferon-γ secretion (Selmani et al. 2008).

The regulation of HLA-G expression. Progesterone was shown to play role in uterine homing of NK cells and in upregulating HLA-G gene expression. At high concentrations, progesterone is a potent inducer of Th2-type cytokines as well as of leukemia inhibitory factor (LIF) and macrophage-colony stimulating factor (M-CSF) production by T cells. A protein called progesterone-induced blocking factor (PIBF) have been cloned (Polgár et al. 2003). PIBF an inducer of Th2-dominant cytokine production mediates the immunological effects of progesterone. PIBF binds to a novel type of the IL-4 receptor and signals via the Jak/STAT pathway, to induce a number of genes, that not only affect the immune response, but might also play a role in trophoblast invasiveness (Szekeres-Bartho et al. 2009).

Soluble HLA-Gs (sHLA-G) was shown to mitigate the maternal immune response directed to the fetus by downregulating expression of CCR2, CXCR3 and CXCR5 in CD4+ T cells; CXCR3 in CD8+ T cells; CXCR3 in Th1 clones; CXCR3 in TCR Vd2c9 T cells, but upregulated CXCR4 expression in TCR Vd2c9 T cells. sHLA-G inhibited in vitro chemotaxis of CD4+ T cells towards CCL2, CCL8, XCL10 and CXCL11; CD8+ T cells towards CXCL10 and CXCL11; Th1 clones towards CXCL10; and TCR Vd2c9 T cells towards CXCL10 and CXCL11. Phosphorylation of Stat5, p70 s6k, β-arrestin and SHP2 was also modulated by sHLA-G treatment (Morandi et al. 2010).

It has been reported that microRNAs (miRNA) may have allele-specific targeting for the 3′ untranslated region (3′ UTR) of the HLA-G locus. On the basis of an in silico analysis it was supposed, that several miRNAs might have also role in the regulation of HLA-G expression (Castelli et al. 2009, 2010). In a tissue culture system the overexpression of miR-152 reduced the expression of HLA-G therefore the cells of cytotrophoblast origin became less resistant to NK-cell lysis (Zhu et al. 2010). The ras-responsive element 1 (RREB-1) was shown to bind to the promoter of HLA-G being probably a repressor of the gene. Human cytomegalovirus (HCMV)-carrier cells and HIV-1 infection can derepress the HLA-G expression (Flajollet et al. 2009; Moreau et al. 2009; Donadi et al. 2011). HLA G1-G2, and G5-7 allels are expressed in myeloid and plasmacytoid dendritic cells present in the cord-blood circulation (Román et al. 2009). Human leukocyte antigen (HLA)-G has direct inhibitory effects on natural killer cells (NK), dendritic cells (DC), T cells and can induce tolerant regulatory cells. The expression of HLA-G has been correlated with the tolerance of the fetus, the acceptance of organ transplants, and the immune escape of tumor cells of virus-infected cells.

Aberrant and/or virus infection dependent induction of HLA-G expression has been postulated as one of the initiating steps in the development of malignancies. The plasma concentration of soluble HLA-G can be used as surrogate marker for certain viruses (Yan 2011), for hepatitis B virus (HBV) infection (Shi et al. 2011), HCV infection (Weng et al. 2011). The induction of HLA-G by Epstein-Barr virus (EBV) was found to be dependent also on the culture conditions of the cells (Gazit et al. 2007). The mechanism of the release of the soluble plasma HLA-G protein was clarified in the case of HCMV, since the virus-coded US-10 protein facilitated the release of the HLA-G antigen from the membranes of infected cells (Zheng et al. 2009; Park et al. 2010).

The 14 bp insertion/deletion “indel” haplotype polymorphism of HLA-G-3 was suggested to be a marker for genetic susceptibility to hepatocellular carcinoma (HCC) in Chinese populations (Jiang et al. 2011a, b). The HLA-G 14 bp insertion/deletion polymorphism is a putative susceptibility factor also for active human cytomegalovirus infection in children (Weng et al. 2009).

Cell surface HLA-G expression was markedly induced in influenza A/H1N1v-infected and seasonal influenza A/H1N1-infected patients, and increased TREG count was observed only in A/H1N1v-infected patients. Given its immune-suppressive property, elevated cell surface HLA-G expression may help to explain the virus escaping from host immune control (LeBouder et al. 2009; Chen et al. 2011). Chronic hepatitis B virus infection was also stimulating HLA-G synthesis (Souto et al. 2011). Rabies virus avoids inducing neuronal cell death, but also ‘protective’ T cells that migrate into the infected nervous system are killed by apoptosis or inactivated, as a result of the overexpression of immunosubversive molecules such as FasL, HLA-E, HLA-G and B7-H1 (Mégret et al. 2007; Lafon 2008).

Especially in Epstein-Barr virus (EBV)-negative classical Hodgkin’s lymphoma (cHL), the neoplastic Hodgkin-Reed-Sternberg (HRS) cells have lost protein expression of major histocompatibility complex (MHC) class I, enabling escape from cytotoxic T lymphocyte (CTL) responses. Induction of HLA-G protein expression in HRS cells contributes to the modulation of immune responses observed in classical Hodgkin’s lymphoma (Diepstra et al. 2008). Membrane linked HLA-G molecules were expressed in a significant number of benign and premalignant oral lesions, but it was not correlated with human papillomavirus (HPV) infection or oral cancer (Fregonezi et al. 2010).

The soluble HLA-G5 and G6 drive transforming growth factor-β1 (TGF-β1) production of myelomonocytic cells. High doses of both significantly decreased interleukin (IL)-10 and dramatically increased TGF-β1 production. Differential effectiveness between the isoforms was demonstrated in dose-response studies, as was differential binding to inhibitory immunoglobulin-like transcript (ILT) receptors for HLA-G, ILT2 and ILT4.ILT2 and ILT4 in receptor-blocking studies.

How are adverse maternal T-cell responses to paternally expressed HLA-C molecules or other unidentified trophoblast-cell antigens avoided?

Each cell type express a specific surface receptor for human leukocyte antigen (HLA)-G (an MHC class Ib protein that is expressed on extravillous trophoblasts), LILRB1 on CD14+ macrophages and KIR2DL4 on CD56+NK cells (Li et al. 2009).

Another possible mechanism to explain the lack of uterine T-cell activation in normal pregnancies depends on the high-avidity binding of HLA-G to leukocyte immunoglobulin-like receptors (LILRs) expressed by myelomonocytic cells. Increased expression of LILRB1 is associated with the induction of a ‘tolerogenic’ population of DCs, which, in a transplantation setting, results in tolerance. HLA-G-induced tolerance was due to decreased MHC class II peptide presentation by the tolerogenic DCs. Unlike blood NK cells, all uterine NK cells express high levels of the C-type lectin family member CD94–NKG2A, which binds to HLA-E resulting in inhibition of NK-cell cytotoxicity (Lopez-Botet et al. 2000).

The receptors on NK cells that recognize HLA-G have been also identified (Pazmany et al. 1996; Bainbridge et al. 2000a, b). Decidual natural killer (NK) cells play key developmental roles at the feto-maternal interface. Individual differences in NK-cell interactions are dependent on the combinations of variable killer immunoglobulin-like receptor (KIR) and HLA class-I gene products (Faridi and Agrawal 2011). A physiologic condition associated with a shift in NK homeostasis toward a noncytolytic phenotype is normal human pregnancy, where expansion of weakly cytotoxic CD56brightCD16dim/ NK cells occurs. CD56bright NK cells may represent predecessors to CD16+ mature NK cells and can be seen both in the peripheral blood of pregnant women and enriched at the fetomaternal interface (Moffett-King 2002).

HLA-C is the only known polymorphic MHC or MHC-like molecule that is expressed by trophoblast cells and is the dominant ligand for the members of the KIR family of receptors that have two immunoglobulin-like domains (KIR2D). These might be activating (KIR2DS) or inhibitory (KIR2DL) receptors. KIR haplotypes comprise two groups, A and B. The main difference between them is that there are more activating receptors in the B haplotype. In any pregnancy, the maternal KIR genotype could be AA (no activating KIR) or AB/BB (presence of one to five activating KIRs). The HLA-C ligands for KIRs on trophoblast cells can belong to two groups, HLA-C1 and HLA-C2, which are defined by a dimorphism at position 80 of the 1st domain.

This maternal–fetal immunological interaction that occurs at the site of placentation, involves two polymorphic gene systems, maternal KIRs and fetal HLA-C molecules. NK-cell function is therefore likely to vary in each pregnancy. Some KIR/HLA-C combinations might be more favourable to trophoblast-cell invasion, resulting in a greater increase of the in utero placental blood flow than other combinations as a result of the overall signals that the NK cell receives (Moffet and Loke 2006).

A small proportion of decidual T cells also express the HLA-E specific CD94-NKG2A inhibitory and CD94-NKG2C activating receptors. Decidual KIR+ and CD94-NKG2+ T cells mainly display a CD3+CD4-CD8- phenotype. However, decidual tissue also contains higher percentages of KIR and CD94-NKG2 expressing CD4+ and CD8+ T cells compared to peripheral blood. NK cell receptor expression on decidual T cells may provide an alternative means by which decidual T cells distinguish self (maternal) cells from allogeneic fetal cells, and act to modulate the decidual immune response (Tilburgs et al. 2009).

KIR-HLA-C genotype for NK cells may contribute to the immunological etiology of recurrent miscarriage (RM). In those species that have been studied in detail, such as humans and mice, there is no large influx of T or B cells to the implantation site in normal pregnancies. Any T cells present in failed pregnancies might be recruited following the demise of the fetus and the resulting inflammatory changes (Hong et al. 2008; Faridi and Agrawal 2011).

Decidual NK cells at the fetomaternal interface serve an immunoregulatory/angiogenic function to support placentation and are phenotypically identified by the expression of CD9, a tetraspanin involved in cell adhesion (Keskin et al. 2007). Mature peripheral blood CD16+ NK cells can be transformed into CD16 CD9+ NK cells with a decidual phenotype after prolonged exposure to transforming growth factor-beta (TGF-β). Recently it has been discovered, that similar change of NK-cell population occurs, when the patients are suffering from metastatic melanoma (Holtan et al. 2011). A specific immune population namely uterine natural killer (uNK) cells has been shown to promote placentation and thus the establishment of a successful pregnancy through the production of cytokines, chemokines and angiogenic factors. The fetal portion of the placenta is comprised, in part, of trophoblast cells. In humans, fetal extravillous trophoblast (EVT) cells invade the uterus and the uterine spiral arteries and are thus in close proximity to maternal immune cells. EVT cells were shown to express class Ia HLA-C, too. Syncytiotrophoblast cells, which cover the chorionic villi have direct contact with maternal blood (Riley 2008; Riley and Yokoyama 2008). Trophoblasts are of fetal origin, i.e. semi-allogeneic because of the paternal genes and these have to escape the effects of the maternal immune system.

Natural killer (NK) cells represent the major lymphocyte population in the decidua basalis of the human uterus during healthy early pregnancy. The activity of decidual NK (dNK) cells and their activation status are different from those of peripheral blood (PB)-NK cells. Decidual NK cells have been defined as CD56bright, CD16neg, and more recently CD160neg. They express a unique repertoire of NK cell receptors, identical among all donors tested. Decidual NK cells express in particular NKp46, NKp30 and NKp44activating receptors, contrasting with PB-NK cells which are devoid of NKp44-activating receptors. dNK cells cannot kill trophoblast cells during normal pregnancy because of the inhibitory potential of NKG2A. Whether such NKG2A-mediated inhibition is abolished during pregnancies complicated by pathologies including viral infection has not been revealed yet (El Costa et al. 2009).

Glycodelin A, secreted by the uterine mucosa and decidua is induced to high levels by progesterone between 12 and 16 weeks of pregnancy. The glycoprotein, an immunomodulator has been shown to be inhibitory to the survival and functions of almost all immune cells. The inhibition of cytotoxic T lymphocyte activity was brought about by the downregulation of transcription of the cytolytic effector molecules, granzyme B and perforin and the degranulation of cytolytic vesicles (SundarRaj et al. 2009; Soni and Karande 2010).

1.8 MHC-Class-II-Expressing Macrophages and Dendritic Cells (DCs)

These cells are also present in the placental bed and could present trophoblast-cell-derived antigens indirectly to the maternal immune system. These decidual antigen-presenting cells might be pivotal in the expansion of both CD4+CD25+ and CD8+ regulatory T-cell populations that are present in utero during human pregnancy. The CD8+ regulatory T cells in the uterus are not MHC restricted but are specific for a member of the carcinoembryonic antigen family, an oncofetal trophoblast molecule, and selectively use the T-cell receptor V9. DC-10 represents a novel subset of tolerogenic DCs, which secrete high levels of IL-10, express ILT4 and HLA-G, and have the specific function to induce Tr1 cells (Gregori et al. 2010).

Monocytes and macrophages are most abundant maternal immune cells in the decidua basalis. They make up 20–30% of the decidual cells at the site of implantation which remains high throughout pregnancy. These cells regulate vascular grows, development of the placenta and are able to kill intracellular microbes, too. Monocyte/macrophages are activated by Th1 cytokines, such as IFN α and γ or bacterial lipopolysaccharides (LPS). In contrast to activation a “suppressive phenotype” which is induced by Th2 cytokines (IL4, IL10, IL13) and when they become linked with HLA-G molecules upon interaction with the trophoblast membranes at the maternal-fetal interface (Shakhawat et al. 2010).

1.9 Regulatory Immune Receptors of Trophoblast Cells

T cell activation requires engagement of the T cell receptors (TCR) with an antigenic peptide exposed by the major histocompatibility proteins. In addition to this TCR-generated signals, a costimulatory signal mediated through the interaction of members of the B7 protein family with the CD28 family of receptors is also required for naive T cell activation. The first members of this family identified were B7-1 (CD80) and B7-2 (CD86), which bind to both CD28 and/or CTLA-4. The binding of B7-1/B7-2 to CD28 generates a costimulatory signal, but the interaction with CTLA-4 leads to an inhibitory signal in activated T cells. B7-H1 is expressed in the human placenta throughout pregnancy and its expression increases as gestation progresses. B7-DC is consistently expressed on syncytiotrophoblast cells (Petroff et al. 2005).

The interaction between inducible costimulator ICOS and its ligand ICOSL is thought to regulate both Th1 and Th2 responses in vivo. CD28, a receptor for B7H1 and B7H2, is constitutively expressed on naive T cells, but ICOS is only up-regulated following T-cell receptor engagement and T-cell activation, and its expression in the peripheral blood is restricted to effector/memory T cells. In vitro stimulation by either ICOS or CD28 ligation promotes the production of interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α) (Th1), interleukin (IL)-4, IL-13 (Th2) and IL-17 (Th17), but IL-2 release is only increased after CD28 ligation. On the other hand a critical role has been described for ICOS, but not for CD28 in IL-10 production, what is extremely important for the establishment of immunotolerance. Furthermore ICOS was consistently expressed at greater levels on the surface of CD4+ and CD8+ decidual T cells when compared with peripheral T cells. ICOS was found to be strongly expressed on decidual TREG cells. TREG cells accumulate in the uterine decidua at a much higher density than that seen in the peripheral blood. The ICOS ligand, B7H2, was expressed on extra villous trophoblasts (EVTs) in the basal plate of term placentas. The ICOS-B7H2 pathway was suggested to play a role in antiviral defence. A subset of cytotoxic CD8+ T cells can recognize peptides derived from pathogens, such as cytomegalovirus, that are bound to HLA-E molecules. The binding of B7H2 on EVTs to ICOS on decidual T cells may cooperate with antigen presentation by trophoblast-expressed HLA-E to promote Tcell activities that prevent uteroplacental infection (Nagamatsu et al. 2011).

Macrophages and T cells are inhibited through the interaction of CD200 (OX2) and CD200R. CD200 is expressed on endothelial cells, thymocytes, activated T cells, B cells, dendritic cells, osteoblasts, neurons and trophoblast cells. CD200R is expressed predominantly on myeloid cells but has also been detected on specific T cell populations, thus demonstrating a more restricted expression pattern than its ligand (Gorczynski et al. 2004; Wilczyński 2006).

Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) are highly glycosylated proteins that belong to the immunoglobulin superfamily of cell adhesion molecules (IgCAMs). CEACAM molecules help maintain tissue architecture and cell polarity. Secreted CEACAMs resembling immunomodulatory CEACAM1-related trophoblast-specific pregnancy-specific glycoproteins (PSGs) found in both humans and rodents evolved only in a limited set of mammals. The appearance of PSG-like genes correlates with invasive trophoblast growth in these species (Kammerer and Zimmermann 2010). At the early blastocyst stage of preimplantation development there are two cell lineages. The inner cell mass, which gives rise to the embryo while the trophectoderm cells develop into trophoblast cells and the fetal portion of the placenta. CEACAM1 was shown to be carried by extravillous trophoblast cells but not by villous cytotrophoblasts or syncytiotrophoblasts (Bamberger et al. 2000).

Proteomic analysis revealed high levels of soluble TNF receptor 1 in placenta, suggesting that blockade of the TNF-α pathway was a mechanism of disease suppression. Placenta contributed to the immune tolerance of pregnancy by locally inhibiting the TNF-α pathway (Landek-Salgado et al. 2011).

1.10 Maternal-Fetal Immunological Tolerance

Human FoxP3+CD4+ T cells can be separated into three functionally and phenotypically different subpopulations based on the expression of FoxP3, cell surface phenotype, the degree of DNA methylation of the FoxP3 gene, DNA microarray profile, proliferation status in the physiological state, cytokine secreting capacity, TCR repertoire, and in vitro suppressive activity. (1) CD45RA+FoxP3low resting TREG cells, (2) CD45RAFoxP3high activated TREG cells, and (3) cytokine-secreting CD45RAFoxP3low non-TREG cells. With this dissection of FoxP3+ T cells into subpopulations the dynamics of TREG cell differentiation in vitro, in vivo, and ex vivo in normal and disease states may be understood. The results indicate that functional and numerical analysis of each FoxP3+ subset is essential for assessing immunological states (Miyara et al. 2005, 2009). Naive TREG cells were found to be resistant to CD95L induced apoptosis (Fritzsching et al. 2006).

Immune responses to infection are uniquely regulated during gestation to allow for antimicrobial defence and tissue repair, whilst preventing damage to developing fetal organs or the triggering of preterm labour. During fetal development, interleukin (IL)-23, IL-10 and IL-6, as well as T-helper-17 (Th17)-mediated immune responses, are upregulated, whereas tumour necrosis factor-α (TNF-α) and IL-1β- and Th1-mediated immune responses are downregulated in the intrauterine environment (both the fetal compartment and the amniotic compartment).

Infection-related immunity during gestation is preferentially directed towards combating extracellular microbial pathogens. Amniotic fluid and the neonatal circulation contain multiple components that improve the ability of the developing neonate to tolerate microbial-induced immune activation. The repertoire of immune mechanisms to control infection and inflammation differ between fetal and adult life. The dual mechanisms of resistance to infection and tolerance to infection-induced immune activation prevent damage to the developing fetus and the triggering of premature labour (Le Bouteiller et al. 2009; Witkin et al. 2011).

The embryo expresses paternal antigens foreign to the mother and therefore may be viewed as an allograft, yet in normal pregnancy the embryo does not undergo maternal immune rejection. A Th1/Th2 ratio increase has been linked to early pregnancy failure. Recently, CD4+CD25brightFoxp3+ regulatory TREG cells were recognized to play a crucial role in the maintenance of normal immune tolerance. These TREG cells may also contribute to the maintenance of pregnancy. The emerging concept of the Th17/TREG balance has challenged the conventional paradigm of Th1/Th2 hypothesis. CD4+ interleukin (IL)-17A+ T (Th17) cells and CD4+CD25brightFoxp3+ regulatory T (TREG) cells in peripheral blood were analyzed by flow cytometry; IL-17 concentrations in cell culture supernates were quantitatively determined by enzyme-linked immunosorbtion assay; and IL-17A positive cells in decidua tissues were measured by immunohistochemistry (Bettelli et al. 2006; Schumacher et al. 2007). Low serum interleukin 17 concentration was found to be associated with preterm birth (Hee et al. 2011). Human gammadelta T cells expressing the Vγ2Vδ2 T cell-receptors (TCR) play important roles in immune responses to microbial pathogens by monitoring prenyl pyrophosphate isoprenoid metabolites. Most adult Vγ2Vδ2 cells are memory cytotoxic cells that produce IFN-gamma. Recently, murine gammadelta T cells were found to be major sources of IL-17A in antimicrobial and autoimmune responses. IL-17A and IL-22 production by Vγ2Vδ2 cells were characterised, too. IL-17A-producing memory Vγ2Vδ2 cells exist at low but significant frequencies in adult humans (1:2762 T cells). Vγ2Vδ2 cells produce IL-22 (1:1864 T cells), although few produce both IL-17A and IL-22. Many IL-17A + Vγ2Vδ2 cells of adult humans also produce IFN-gamma (Tgammadelta1/17). Human neonatal Vγ2Vδ2 cells stimulated with the bacterial Ag, (ε)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate, and various cytokines and mAbs in vitro resulted that IL-6, IL-1β, and TGF-β are required to generate Tgammadelta17 cells in neonates, whereas Tgammadelta1/17 cells additionally required IL-23. In adults, memory Tgammadelta1/17 and Tgammadelta17 cells required IL-23, IL-1β, and TGF-β, but not IL-6. IL-22-producing cells showed similar requirements. Both neonatal and adult IL-17A Vγ2Vδ2 cells expressed elevated levels of retinoid-related orphan receptor γ-T. These data suggested that, like Th17 alphabeta T cells, Vγ2Vδ2 T cells can be polarized into Tgammadelta17 and Tgammadelta1/17 populations with distinct cytokine requirements for their initial polarization and later maintenance (Ness-Schwickerath et al. 2010).

TREG cells are defined as CD4+CD25+Foxp3+CD127 lymphocytes. Among women who were not atopic, nulliparous women had lower percentages of TREG cells over time compared with parous women. Atopic women with pets in the home during pregnancy had lower percentages of TREG cells than atopic women who did not have pets. The trajectory was not affected by the other factors investigated. It was concluded by the authors that within women change in percentages of TREG cells may vary by time in relation to delivery, as well as by maternal atopic status and exposure to pets and number of prior births. The data did not indicate an overall decline in TREG cells in the postpartum period (Wegienka et al. 2011).

TREG cells have demonstrated their ability to efficiently control autoimmune diseases. The number of TREG cells decreases in several autoimmune diseases, and adoptive transfer of purified TREG cells improves the autoimmune disorders (Crispin et al. 2003; Tang et al. 2004). Meanwhile, several studies have reported that TREG frequencies in circulation increase during normal early pregnancy, peaking during the second trimester and then declining postpartum, and decrease in women with unexplained recurrent spontaneous abortion URSA (Yang et al. 2008a). It has been suggested that the enrichment of CD4+CD25+TREG in decidua may explain the local mechanisms of immunological tolerance and play a role in the maintenance of pregnancy. TREG cells exert their function partly by secretion of anti-inflammatory cytokines IL-10 and TGF-β1 (Zheng et al. 2004; Awasthi et al. 2007). Additionally, TGF-β1 can promote Foxp3 expression by inducing TREG differentiation from CD4+ CD25 T cells.

Th17 cells expressing retinoic acid–related orphan receptor γ (ROR γ t) play critical roles in the development of autoimmunity and allergic reactions by producing IL-17. Th17 and TREG cells have reciprocal developmental pathways and opposite effects, although TREG cells can convert into Th17 cells in the inflammatory milieu in vitro and in vivo the requirement for the differentiation of naive CD4 T cells into effector T helper cells that produce IL-17 was the availability of costimulatory molecules CD28 and ICOS but was independent of the cytokines and transcription factors required for T helper type 1 or type 2 differentiation. IL-17 expression characterizes a unique T helper lineage that regulates tissue inflammation (Park et al. 2005). Th17/TREG subsets may therefore have evolved to induce or regulate tissue inflammation, analogous to the dichotomous Th1/Th2 T-cell subsets.

The proportions of Th17 cells and IL-17A concentration in peripheral blood in patients with URSA were significantly higher than those in non-pregnant women and normal pregnant women, providing evidence that Th17 cells may reverse the mechanisms mediating maternal immune tolerance of conceptus antigens and therefore may destroy the maintenance of pregnancy. IL-17F regulates proinflammatory gene expression in vitro, and this requires IL-17 receptor A, tumor necrosis factor receptor–associated factor 6, and Act1. In vivo, overexpression of IL-17F in lung epithelium led to infiltration of lymphocytes and macrophages and mucus hyperplasia in mice. IL-17F is an important regulator of inflammatory responses that seems to function differently than IL-17 in immune responses and diseases (Yang et al. 2008b).

The proportion of Th17 cells (see page 59) and IL-17A concentrations were both significantly higher in patients with unexplained recurrent spontaneous abortions (URSA) than in normal early pregnant (NEP) and non-pregnant (NP) persons. TREG frequencies were significantly lower in patients with URSA than in NEP patients, and the ratio of Th17 to TREG was significantly higher in the URSA group than in the other two. Additionally, the percentage of IL-17A cells in deciduas was significantly higher in patients with URSA than in NEP patients (Liu et al. 2010).

In decidua IL-17 was localized in both cytotrophoblast and syncytiotrophoblast cells of URSA and normal early pregnant patients. It is likely that Th17 cells also play a role in the local mechanisms of pregnancy. In addition, the decidua expressed more Th17 cells in patients with URSA than in normal early pregnant patients, further suggesting that Th17 cells destroy pregnancy. The vitamin A metabolites, including retinoic acid (RA), form ligands for retinoic acid-related nuclear receptors and together they play pleiotropic roles in various biological processes. RA also functions as a key modulator of transforming growth factor-beta (TGF-beta)-driven immune deviation, capable of suppressing the differentiation of interleukin-17 secreting T helper cells (TH17) and conversely promoting the generation of Foxp3+ T regulatory (TREG) cells. The role of RA in the reciprocal TGF-beta-driven differentiation of TH17 and TREG is important also in the control a functional immune system, in particular at the mucosal interface of the intestine (Mucida et al. 2007, 2009).

It has been shown that IL-10 is not only required for the generation of virus-specific FoxP3 T cells but it also has a suppressive effect on the proliferation of virus-specific FoxP3CD8 T cells. These data are consistent with recent reports demonstrating in the lymphocytic choriomeningitis virus mouse model that IL-10 is a single key molecule that directly induces suppression of virus-specific CD8 T cells (Billerbeck et al. 2007).

The programmed death ligand 1 (PDL-1) and the PD-1-PDL-1 axis is thought to maintain peripheral tolerance at the fetomaternal interface together with the TREG cells (Guleria et al. 2005; Habicht et al. 2007). The expression of PDL-1 in human placenta by villous syncytiotrophoblasts and cytotrophoblast, the fetal cells that lie in close contact with maternal blood and tissue makes it possible for this pathway to be critical in local immune response in vivo during pregnancy (Okazaki and Honjo 2006; Petroff et al. 2003, 2005). PD-1 but not CTLA-4 was found to abrogate the effect of TREG cells in mice (Wafula et al. 2009). PD-1-PCD-1 regulate accumulation of human fetal antigen-specific CD8+ T cells, too (Taglauer et al. 2008, 2009).

1.11 Toll-Like Receptors at the Maternal-Fetal Interface

A family of pattern recognition receptors (PRR) is representing the innate immunity and are called toll-like receptors (TLRs). These are expressed not only in the immune cells but also in non-immune cells such as trophoblasts and decidual cells; moreover, their expression patterns vary according to the stage of pregnancy. PRR and TLRs were shown to be activated as a network of different consequences i.e. inflammation, stimulation or immunemodulation (Heil et al. 2004; Kumazaki et al. 2004; Trinchieri and Sher 2007).

Immature NK cells were detected at the fetomaternal interface in NOD/SCID mice. These cells were hyposensitive to the stimulation of selected TLR agonists. Such a status seemed to be beneficial for the maintenance of pregnancy (Lin et al. 2009).

In the human placenta, however, TLR ligand-exposed trophoblasts, compared to controls, secrete more proinflammatory cytokines and chemokines to enhance immune cell migration (Koga et al. 2009).

At term, TLR activation by a yet unknown ligand may lead to the production of proinflammatory cytokines (IL-1, 6 and 8) and prostaglandin synthesis resulting in cervical ripening, membrane rupture, and uterine contractions resulting in the induction of labor. Prior to term, bacterial products such as LPS may induce the same cascade of events by activating TLRs leading to preterm labor (Riley and Nelson 2010).

Intracellular inducer (poly I:C for TLR 3) is only able to induce the production of RANTES and NF-κB if it is packed into liposomes in order to rich the endosomal receptor. This RANTES production was abolished by siRNA for TLR3 indicating the specificity of the induction (Nakada et al. 2009, 2011, Gonzalez et al. 2007). The Toll-like receptors, their location of their expression and the main inducers are summarised in Table 1.3.
Table 1.3

Specificity and localisation of Toll-like receptors (Koga and Mor 2008; Riley and Nelson 2010)

Cytoplasmic membrane

Endoplasmic reticulum membrane

Ligands

References

TLR-1/2

 

Triacyl lipopeptides, glycolipids

Triantafilou et al. (2006)

TLR-2/6

 

Diacyl lipopeptides, lipotechoic acid, zymozan

Aliprantis et al. (1999, 2000)

 

TLR-3/TRIF-IRF3

Double stranded RNA

Alexopoulou et al. (2001)

TLR-4

 

LPS, envelop proteins, glycoinositol phospholipids, mannan

Beijar et al. (2006) and Kumazaki et al. (2004)

TLR-5

 

Flagellins

Patni et al. (2009)

 

TLR-7

Single stranded RNA

Diebold et al. (2004)

 

TLR-8

Single stranded RNA

Heil et al. (2004)

 

TLR-9

Unmethylated CpG DNA

Lund et al. (2003), HSV

TLR-11

 

Profilin of protozoa

Yarovinsky et al. (2005)

1.12 Complement Activation and Pregnancy

Activation of the classical or lectin pathway (C4d) of complement activation showed significant positive correlation to C3 activation (C3a) both in healthy pregnant women and preeclamptic patients. However, the correlation between C3 and the terminal pathway activation was dominating only in patients with preeclampsia, but not in healthy pregnant women. During pregnancy the complement system is activated through the classical pathway and/or lectin pathway with increased terminal complex formation both in the third trimester of normal pregnancy, and to a further extent in preeclampsia, as indicated by the elevated concentrations of activation markers in the systemic circulation. Excessive activation of the terminal pathway is associated with fetal growth restriction in preeclamptic women (Derzsy et al. 2010; Csuka et al. 2010).

Freshly isolated human first trimester trophoblast cells (CTBs) synthesize complement molecules C4, C3 and the late complement components and HTR8/SVneo trophoblast cells secrete C6 in a measurable amount. HTR8/SVneo trophoblast cells secrete C6 in a measurable amount. The production of complement components was up-regulated by IFNgamma, while IL-1alpha and TNFalpha had no effect on their expression. Complement synthesis by trophoblast cells potentially contributes to placental immune defence from pathogen infection (Bulla et al. 2009).

Uncontrolled complement activation puts at risk the survival of the fetus detected in mouse models of recurrent miscarriages and preeclampsia. Increased circulating levels of complement proteins, and their activation fragments were found in patients with preeclampsia, recurrent miscarriages and intrauterine growth restriction. C1q deserves special consideration for its role in promoting trophoblast invasion of deciduas, a crucial step in normal placental development (Girardi et al. 2011). Autoantibodies to C1q were reacted in both healthy and diseased people with the globular part of C1q indicating that the onset of IgG mediated autoimmune response might occur when the molecule has interacted with its ligands via the globular-subunit-B as part of gC1q (Stoyanova et al. 2011).

Eculizumab a humanised monoclonal antibody which prevents the hydrolysis of C5 was found to prevent maternal hemolytic illnesses, without impairment of the development of the fetus (Kelly et al. 2010).

1.13 The Prevention of Fetal Damage by Inhibitory Asymmetric Maternal Antibodies

Specific antibodies, unable to precipitate soluble antigens have been observed many years ago (Heidelberger and Kendall 1935). Asymmetric IgG was shown to be the consequence of assymmetric presence of a carbohydrate moiety on one of the Fab fragments. This modification prevents the activation of complement, cytotoxic activity, opsonising ability, antigen clearance and precipitating activity of the molecules. The proportion of asymmetric IgG was much higher, averaging 44.4% in the case of antibodies extracted from the human placenta.

Antipaternal antibodies were detected in the sera of seven of ten pregnant women. The concentration of antipaternal antibodies was about three times higher in the asymmetric IgG fraction than in the symmetric one. It has been suggested, that asymmetric IgG molecules with antipaternal antigen specificity might function as blocking antibodies in order to prevent possible impairment of the fetus (Malan Borel et al. 1991). Hybridoma cell lines OKT8 (anti-CD8) and 112B4 (anti-DNP) are synthesising both symmetric and asymmetric molecules of the IgG2a and IgG1 subclasses in which anti-paternal antibodies have been detected. In the presence of 5–10% placental supernatant in the culture medium the proportion of asymmetric antibodies increased from 15–17% to 27–28% indicating its possible stimulatory effect to the cell lines (Margni et al. 1992; Margni and Malan Borel 1998).

Progesteron induced blocking factor (PIBF) was shown to enhance production of Th2-type cytokines; thus, it might stimulate also antibody production of B-cells. The ratio of asymmetric IgG was significantly higher in the supernates of hybridoma cells in the presence of PIBF in comparison to cells without PIBF in the medium. Blocking of PIBF receptors by inhibitors or treatment of the cells with PIBF receptor-specific antibodies prevented the excess production of asymmetric antibodies (Kelemen et al. 1996).

The proportion of asymmetric tetanus and diphteria antitoxins were 3–5 times higher in pregnants, than in nonpregnant women. The difference disappeared about 1 month after delivery. The concentration of asymmetric cord blood antibodies was found to be also 4–5 times elevated, indicating that the transplacental transfer had not been influenced by the asymmetric nature of IgG (Pasetti et al. 1997). The cytokine combination IL-4 + IL-10 + IL-6 stimulated the asymmetric IgG production to the highest degree. The authors observed, that the maternal lymphocytes could be better stimulated than the lymphocytes of the cord blood (Canellada et al. 2002). IL-6 was found to regulate directly the synthesis of asymmetric IgG populations in the B-cells during pregnancy (Gutiérrez et al. 2001).

Good correlation was observed in women with recurrent early abortions of unknown etiology, between the production of anti-husband lymphocytes and the success of a subsequent pregnancy. Women who suffered from recurrent spontaneous abortions of unknown etiology, without autoimmune abnormalities and without antipaternal antibodies, was found to profit from a therapy using the husband’s leucocyte infusions, which allowed them to give birth to a normal child in 85% of the cases, whereas without treatment the success rate was only 37% of the pregnancies (Reznikoff-Etievant 1988). Increased production of placental isoferritin seemed to be the explanation of the increased immunosuppression (Moroz et al. 1993).

Regulatory T cells act in an antigen-specific manner during pregnancy and mouse experiments strongly suggest that IL-10 is involved in regulatory T cell-mediated protection of the fetus. These data contribute to the knowledge of the basic mechanisms regulating immune tolerance during pregnancy, a major biologic question with important medical implications. Japanese physicians have observed, that the incidence of abortions of the same women is 20% higher in the case of pregnancies from a second husband than from the first one.

1.14 Virus Infections of Trophoblasts, Placenta and Fetus

Herpes simplex type 2 (HSV-2) and echovirus-19 replicated in placental macrophages in vitro (Oliveira et al. 1993). SV-40 polyomavirus was seen to replicate in extravillous trophoblasts and the inhibition of metalloproteinase expression impaired invasive potential of the cells (Logan et al. 1996). BK polyomavirus can infect several fetal organs, but was not found to be responsible for abortions (Boldorini et al. 2010). It has been revealed, that the herpes simplex type 1 and HCMV infection influence the expression of HLA-A and B antigens, but the expression of HLA-C and -G in the infected trophoblast cells decreases (Schust et al. 1999). Exacerbation of herpes simplex virus infection during pregnancy is associated with damage to syncytiotrophoblast inflicted by herpesvirus either directly or via TNF-α (due to contact of NK lymphocytes with villus surface). A sharp decrease in the content of heat shock protein with a molecular weight of 70 kDa and activation of caspase-3 were noted in placenta homogenates. This may lead to disturbances in syncytiotrophoblast cytosol structure and increase the relative content of apoptotic nuclei (Lutsenko et al. 2010). Human cytomegalovirus HCMV can infect villus trophoblasts in vitro and cause the decrease of early pregnancy villous EVT’s invasive function (Tao et al. 2011). Indoleamine 2,3-dioxygenase (IDO) is highly expressed in the placenta and is known to prevent maternal immune rejection. HCMV infection inhibited IDO activity in the early placenta. IFN-γ-induced IDO activity was suppressed by HCMV in both early and term placenta. Early placental dysfunction through the inhibition of IDO activity may reveal a possible mechanism for miscarriages (Lopez et al. 2011). Epstei-Barr virus (EBV) can replicate ex vivo in syncytiotrophoblast cells (Tóth et al. 1997). HCMV, HHSV, HHV-6, and-7 and B-19 parvovirus were found in samples taken from abortions or unexplained fetal death in utero (Al-Buhtori et al. 2011). Hepattis B virus (HBV) can replicate in trophoblast cells ex vivo (Zhang et al. 2011). The presence of adeno-associated Dependovirus (AAV) in decidual or trophoblastic cells in cases of abortion implies that the virus could have causal association and abortion. The occurrence of AAV was found to be much higher the case of abortions than in the saples taken from intentional abortions (Pereira et al. 2010). Human bocavirus (HBoV) seropositivity was found to be very frequent in pregnants, but this virus was not shown to harm the offspring (Enders et al. 2009). The globosid receptor for human parvovirus B-19 was found to be expressed in syncytiotrophoblast cells (Wegner and Jordan 2004). B-19 parvovirus was also found in samples taken from abortions or unexplained fetal death in utero (Al-Buhtori et al. 2011). Human endogenous retrovirus W (HERV-W) was expressed in syncytiotrophoblast cells, and the envelope proteins (syncytin 1 and 2) induce the fusion of cytotrophoblast cells (Malden et al. 2000; Mi et al. 2000; Blaise et al. 2005; Noorali et al. 2009; Vargas et al. 2009). Ex vivo, human herpesvirus 8 (HHV-8) DNA and a latent viral antigen were detected in placental samples from HHV-8-seropositive women. These findings demonstrate that HHV-8, like other human herpesviruses, may infect placental cells in vitro and in vivo (Di Stefano et al. 2008). Vertical transmission may occur through CD4+ endothelial tissues or CD4+ fetal Hofbauer cells. Trophoblasts and floating villi have CD4-receptors, which make them potential candidates for human immunodeficiency virus (HIV) infection. Placental cytokines and chemokines influence HIV replication in trophoblasts. Genetic analysis of HIV-1 sequences verify the interaction of HIV-1 and placental tissue. The vertical transmission of HIV-1 characterized by selection of genotype variant that escape the mother’s immune system (Vidricaire and Tremblay 2007; Al-Husaini 2009). Interleukin 6 and tumor necrosis factor α were shown to potentiate HIV-1 replication in explants of syncytiotrophoblasts (Bácsi et al. 2001). HIV-infected women display different immunologic profiles from HIV-negative women, which may have importance for the induction of fetal-maternal tolerance and in part explain the increased risk of abortion in HIV-infected women (Kolte et al. 2011). The presence of papillomaviruses in the cord blood shows, that these are also able to pass the maternal-fetal barrier (Hermonat et al. 1998; Younes et al. 2007, 2009; You et al. 2008; Sarkola et al. 2008). The Hungarian Case-control Surveillance of Congenital Abnormalities dataset (1980–1996) comprises records of 22,843 neonates with different specified congenital abnormalities, and 38,151 matched controls without defects. A total of 17 (0.07%) mothers of neonates with abnormalities and 25 (0.07%) mothers of neonates without defects were affected by genital warts during the study pregnancy indicating that papillomaviruses do not play a role in the development of fetal abnormalities (Bánhidy et al. 2010). West Nile virus was also able to multiply in trophoblast cells (Julander et al. 2006). Human T-cell leukemiavirus (HTLV-1 and HHV-6) and human herpesvirus 6 (Csoma et al. 2002). Coxsackieviruses can replicate in trophoblast cells, too (Euscher et al. 2001). Measles virus was shown to replicate in the placenta in twins of unvaccinated mothers (Ohyama et al. 2001). The different subgenera of rubellavirus were suggested to affect the fetuses i.e. the most isolates in France belonged to subgenus “E” (Vauloup-Fellous et al. 2010). Death of the mother and fetus, abortion, premature delivery, or death of a live-born baby soon after birth are common complications of Hepatitis E virus (HEV) infection during pregnancy (Smith 2001). Rift valley fever virus (RVFV) is causing frequently abortions (Ikegami and Makino 2011).

Some viral infections during pregnancy may be asymptomatic, about one-half of all preterm deliveries were associated with histological evidence of inflammation of the placenta, i.e. acute or chronic chorioamnionitis. Even in the absence of fetal viral infection, the inflammatory response originating in the placenta and decidua induced an inflammatory process with potential damage in fetal organs (Cardenas et al. 2010). One factor of the impairment of fetal development and of the formation of multiple congenital abnormality syndrome is the high fever of the women during pregnancy (Czeizel et al. 2008). Pelvic inflammatory diseases during pregnancy were shown to induce fetal malformations detected on the basis of a population-based case-control study (Ács et al. 2008).

In contrast to the numerous preventive functions of the maternal-fetal barriers, about 5% of the pregnancies suffer irreversible impairments. These are summarised in Table 1.2. based on the excellent review of Pandey et al. (2005).

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© Springer Science+Business Media B.V. 2012

Authors and Affiliations

  1. 1.Division of VirologyNational Center for EpidemiologyBudapestHungary

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