Skip to main content
SpringerLink
Log in

The Immune System and Depression: From Epidemiological to Clinical Evidence

  • Chapter
  • First Online:
Microorganisms and Mental Health

Part of the book series: Current Topics in Behavioral Neurosciences ((CTBN,volume 61))

Abstract

Depression is a frequent mental disorder with a substantial contribution to years lived with disability worldwide. In the search for new treatment targets, the immune system’s contribution to the pathogenesis of depression has received increased attention as immune activation has been associated with depression in various epidemiological and case-control studies. Epidemiological studies have shown that immune exposures such as severe infections and autoimmune disorders increase the risk of depression. Furthermore, immune system activation has been indicated in case-control studies of depression revealing higher levels of key pro-inflammatory cytokines among patients with depression than healthy controls, particularly in blood and to some extent in the cerebrospinal fluid. Moreover, brain imaging studies indicate increased microglial activity during depression, and gut microbiota studies have documented alterations of gut microbiota composition to be associated with depression. Based on findings from animal and human studies, several immune-mediated molecular mechanisms have been suggested to underlie the association between increased immunological activity and depression. However, the research is challenged by the heterogeneity of the depression diagnosis and – to some extent – the precision of currently available technology for immune biomarker quantification, particularly regarding the assessment of low-grade neuroinflammation. Nonetheless, an enhanced understanding of the complex interactions between the immune system and the brain in the context of depression could pave the way for precision medicine approaches with immune-modulating treatment as a promising additional option in the treatment of depression.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 139.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 179.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 179.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

BBB:

Blood-brain barrier

CNS:

Central nervous system

CRP:

C-reactive protein

CSF:

Cerebrospinal fluid

EBV:

Epstein–Barr virus

HLA:

Human leukocyte antigen

IgG:

Immunoglobulin G

IL:

Interleukin

NMDAR:

N-methyl-D-aspartate receptor

NLRP3:

NOD-, LRR- and pyrin domain-containing protein 3

TNF-ɑ:

Tumor necrosis factor-ɑ

TSPO:

18-kDa translocator protein

WCC:

White cell count

References

  • Abbott NJ, Rönnbäck L, Hansson E (2006) Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci 7(1):41–53

    Article  CAS  PubMed  Google Scholar 

  • Atzeni F, Masala IF, Bagnasco M, Lanata L, Mantelli F, Sarzi-Puttini P (2021) Comparison of efficacy of Ketoprofen and Ibuprofen in treating pain in patients with rheumatoid arthritis: a systematic review and meta-analysis. Pain Ther 10(1):577–588

    Article  PubMed  PubMed Central  Google Scholar 

  • Baumeister H, Parker G (2012) Meta-review of depressive subtyping models. J Affect Disord 139(2):126–140

    Article  Google Scholar 

  • Benros ME, Waltoft BL, Nordentoft M, Ostergaard SD, Eaton WW, Krogh J et al (2013) Autoimmune diseases and severe infections as risk factors for mood disorders: a nationwide study. JAMA Psychiat 70(8):812–820

    Article  Google Scholar 

  • Beurel E, Toups M, Nemeroff CB (2020) The bidirectional relationship of depression and inflammation: double trouble. Neuron 107(2):234–256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bi Y, Shen J, Chen S-C, Chen J-X, Xia Y-P (2021) Prognostic value of neutrophil to lymphocyte ratio in acute ischemic stroke after reperfusion therapy. Sci Rep 11(1):6177

    Article  PubMed  PubMed Central  Google Scholar 

  • Bodis G, Toth V, Schwarting A (2018) Role of human leukocyte antigens (HLA) in autoimmune diseases. Methods Mol Biol 1802:11–29

    Article  CAS  PubMed  Google Scholar 

  • Boku S, Nakagawa S, Toda H, Hishimoto A (2018) Neural basis of major depressive disorder: beyond monoamine hypothesis. Psychiatry Clin Neurosci 72(1):3–12

    Article  CAS  PubMed  Google Scholar 

  • Bromet E, Andrade LH, Hwang I, Sampson NA, Alonso J, de Girolamo G et al (2011) Cross-national epidemiology of DSM-IV major depressive episode. BMC Med 9:90

    Article  PubMed  PubMed Central  Google Scholar 

  • Brown SJ, Huang X-F, Newell KA (2021) The kynurenine pathway in major depression: what we know and where to next. Neurosci Biobehav Rev 127:917–927

    Article  CAS  PubMed  Google Scholar 

  • Carson MJ, Doose JM, Melchior B, Schmid CD, Ploix CC (2006) CNS immune privilege: hiding in plain sight. Immunol Rev 213:48–65

    Article  PubMed  PubMed Central  Google Scholar 

  • Chen P, Jiang T, Ouyang J, Chen Y (2009) Depression, another autoimmune disease from the view of autoantibodies. Med Hypotheses 73(4):508–509

    Article  CAS  PubMed  Google Scholar 

  • Corriger A, Pickering G (2019) Ketamine and depression: a narrative review. Drug Des Devel Ther 13:3051–3067

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Costerus JM, Brouwer MC, van de Beek D (2018) Technological advances and changing indications for lumbar puncture in neurological disorders. Lancet Neurol 17(3):268–278

    Article  PubMed  Google Scholar 

  • Dahm L, Ott C, Steiner J, Stepniak B, Teegen B, Saschenbrecker S et al (2014) Seroprevalence of autoantibodies against brain antigens in health and disease. Ann Neurol 76(1):82–94

    Article  CAS  PubMed  Google Scholar 

  • Dalmau J, Gleichman AJ, Hughes EG, Rossi JE, Peng X, Lai M et al (2008) Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol 7(12):1091–1098

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice-Gordon R (2011) Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol 10(1):63–74

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Daneman R, Prat A (2015) The blood-brain barrier. Cold Spring Harb Perspect Biol 7(1):a020412

    Article  PubMed  PubMed Central  Google Scholar 

  • Desai MK, Brinton RD (2019) Autoimmune disease in women: endocrine transition and risk across the lifespan. Front Endocrinol (Lausanne) 10:265

    Article  PubMed  Google Scholar 

  • DiSabato DJ, Quan N, Godbout JP (2016) Neuroinflammation: the devil is in the details. J Neurochem 139(Suppl 2):136–153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ehrenreich H (2017) Autoantibodies against the N-methyl-d-aspartate receptor subunit NR1: untangling apparent inconsistencies for clinical practice. Front Immunol 8:181

    Article  PubMed  PubMed Central  Google Scholar 

  • Enache D, Pariante CM, Mondelli V (2019) Markers of central inflammation in major depressive disorder: a systematic review and meta-analysis of studies examining cerebrospinal fluid, positron emission tomography and post-mortem brain tissue. Brain Behav Immun 81:24–40

    Article  PubMed  Google Scholar 

  • Endres D, Perlov E, Dersch R, Baumgartner A, Hottenrott T, Berger B et al (2016) Evidence of cerebrospinal fluid abnormalities in patients with depressive syndromes. J Affect Disord 198:178–184

    Article  PubMed  Google Scholar 

  • Fan Y, Pedersen O (2021) Gut microbiota in human metabolic health and disease. Nat Rev Microbiol 19(1):55–71

    Article  CAS  PubMed  Google Scholar 

  • Franceschini A, Capece M, Chiozzi P, Falzoni S, Sanz JM, Sarti AC et al (2015) The P2X7 receptor directly interacts with the NLRP3 inflammasome scaffold protein. FASEB J Off Publ Fed Am Soc Exp Biol 29(6):2450–2461

    CAS  Google Scholar 

  • Gabay C (2006) Interleukin-6 and chronic inflammation. Arthritis Res Ther 8(Suppl 2):S3

    Article  PubMed  PubMed Central  Google Scholar 

  • Garrido-Mesa N, Zarzuelo A, Gálvez J (2013) Minocycline: far beyond an antibiotic. Br J Pharmacol 169(2):337–352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goldsmith DR, Rapaport MH, Miller BJ (2016) A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression. Mol Psychiatry 21(12):1696–1709

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Granerod J, Ambrose HE, Davies NW, Clewley JP, Walsh AL, Morgan D et al (2010) Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study. Lancet Infect Dis 10(12):835–844

    Article  PubMed  Google Scholar 

  • Gronemann FH, Petersen J, Alulis S, Jensen KJ, Riise J, Ankarfeldt MZ et al (2021) Treatment patterns in patients with treatment-resistant depression in Danish patients with major depressive disorder. J Affect Disord 287:204–213

    Article  PubMed  Google Scholar 

  • Guan W-J, Ni Z-Y, Hu Y, Liang W-H, Ou C-Q, He J-X et al (2020) Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med

    Google Scholar 

  • Haase S, Linker RA (2021) Inflammation in multiple sclerosis. Ther Adv Neurol Disord 14:17562864211007688

    Article  Google Scholar 

  • Hammer C, Stepniak B, Schneider A, Papiol S, Tantra M, Begemann M et al (2014) Neuropsychiatric disease relevance of circulating anti-NMDA receptor autoantibodies depends on blood-brain barrier integrity. Mol Psychiatry 19(10):1143–1149

    Article  CAS  PubMed  Google Scholar 

  • Hampel H, Kotter HU, Padberg F, Korschenhausen DA, Moller HJ (1999) Oligoclonal bands and blood--cerebrospinal-fluid barrier dysfunction in a subset of patients with Alzheimer disease: comparison with vascular dementia, major depression, and multiple sclerosis. Alzheimer Dis Assoc Disord 13(1):9–19

    Article  CAS  PubMed  Google Scholar 

  • Hasselbalch IC, Søndergaard HB, Koch-Henriksen N, Olsson A, Ullum H, Sellebjerg F et al (2018) The neutrophil-to-lymphocyte ratio is associated with multiple sclerosis. Mult Scler J Exp Transl Clin 4(4):2055217318813183

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hattori K, Ota M, Sasayama D, Yoshida S, Matsumura R, Miyakawa T et al (2015) Increased cerebrospinal fluid fibrinogen in major depressive disorder. Sci Rep 5:11412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hegen H, Auer M, Zeileis A, Deisenhammer F (2016) Upper reference limits for cerebrospinal fluid total protein and albumin quotient based on a large cohort of control patients: implications for increased clinical specificity. Clin Chem Lab Med 54(2):285–292

    Article  CAS  PubMed  Google Scholar 

  • Herken J, Prüss H (2017) Red flags: clinical signs for identifying autoimmune encephalitis in psychiatric patients. Front Psych 8:25

    Google Scholar 

  • Hillhouse TM, Porter JH (2015) A brief history of the development of antidepressant drugs: from monoamines to glutamate. Exp Clin Psychopharmacol 23(1):1–21

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Horsdal HT, Köhler-Forsberg O, Benros ME, Gasse C (2017) C-reactive protein and white blood cell levels in schizophrenia, bipolar disorders and depression – associations with mortality and psychiatric outcomes: a population-based study. Eur Psychiatry 44:164–172

    Article  CAS  PubMed  Google Scholar 

  • Howard DM, Adams MJ, Clarke T-K, Hafferty JD, Gibson J, Shirali M et al (2019) Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions. Nat Neurosci 22(3):343–352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Howren MB, Lamkin DM, Suls J (2009) Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom Med 71(2):171–186

    Article  CAS  PubMed  Google Scholar 

  • Kadry H, Noorani B, Cucullo L (2020) A blood-brain barrier overview on structure, function, impairment, and biomarkers of integrity. Fluids Barriers CNS 17(1):69

    Article  PubMed  PubMed Central  Google Scholar 

  • Kara SP, Altunan B, Unal A (2021) Investigation of the peripheral inflammation (neutrophil-lymphocyte ratio) in two neurodegenerative diseases of the central nervous system. Neurol Sci Off J Ital Neurol Soc Ital Soc Clin Neurophysiol:1–9

    Google Scholar 

  • Kaufmann FN, Costa AP, Ghisleni G, Diaz AP, Rodrigues ALS, Peluffo H et al (2017) NLRP3 inflammasome-driven pathways in depression: clinical and preclinical findings. Brain Behav Immun 64:367–383

    Article  CAS  PubMed  Google Scholar 

  • Kelley KW, Bluthé R-M, Dantzer R, Zhou J-H, Shen W-H, Johnson RW et al (2003) Cytokine-induced sickness behavior. Brain Behav Immun 17(Suppl 1):S112–S118

    Article  CAS  PubMed  Google Scholar 

  • Kelley N, Jeltema D, Duan Y, He Y (2019) The NLRP3 inflammasome: an overview of mechanisms of activation and regulation. Int J Mol Sci 20(13)

    Google Scholar 

  • Kendler KS, Gatz M, Gardner CO, Pedersen NL (2006) A Swedish national twin study of lifetime major depression. Am J Psychiatry 163(1):109–114

    Article  PubMed  Google Scholar 

  • Kettenmann H, Kirchhoff F, Verkhratsky A (2013) Microglia: new roles for the synaptic stripper. Neuron 77(1):10–18

    Article  CAS  PubMed  Google Scholar 

  • Kim K, Lee S-G, Kegelman TP, Su Z-Z, Das SK, Dash R et al (2011) Role of excitatory amino acid transporter-2 (EAAT2) and glutamate in neurodegeneration: opportunities for developing novel therapeutics. J Cell Physiol 226(10):2484–2493

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kohler CA, Freitas TH, Maes M, de Andrade NQ, Liu CS, Fernandes BS et al (2017) Peripheral cytokine and chemokine alterations in depression: a meta-analysis of 82 studies. Acta Psychiatr Scand 135(5):373–387

    Article  CAS  PubMed  Google Scholar 

  • Köhler-Forsberg O, Buttenschøn HN, Tansey KE, Maier W, Hauser J, Dernovsek MZ et al (2017) Association between C-reactive protein (CRP) with depression symptom severity and specific depressive symptoms in major depression. Brain Behav Immun 62:344–350

    Article  PubMed  Google Scholar 

  • Kohler-Forsberg O, Lydholm CN, Hjorthoj C, Nordentoft M, Mors O, Benros ME (2019) Efficacy of anti-inflammatory treatment on major depressive disorder or depressive symptoms: meta-analysis of clinical trials. Acta Psychiatr Scand 139(5):404–419

    Article  CAS  PubMed  Google Scholar 

  • Korszun A, Moskvina V, Brewster S, Craddock N, Ferrero F, Gill M et al (2004) Familiality of symptom dimensions in depression. Arch Gen Psychiatry 61(5):468–474

    Article  PubMed  Google Scholar 

  • Kruse JL, Lapid MI, Lennon VA, Klein CJ, Toole OO, Pittock SJ et al (2015) Psychiatric autoimmunity: N-methyl-D-aspartate receptor IgG and beyond. Psychosomatics 56(3):227–241

    Article  PubMed  Google Scholar 

  • Kuek A, Hazleman BL, Ostör AJK (2007) Immune-mediated inflammatory diseases (IMIDs) and biologic therapy: a medical revolution. Postgrad Med J 83(978):251–260

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kunugi H, Hori H, Ogawa S (2015) Biochemical markers subtyping major depressive disorder. Psychiatry Clin Neurosci 69(10):597–608

    Article  PubMed  Google Scholar 

  • Lang K, Prüss H (2017) Frequencies of neuronal autoantibodies in healthy controls: estimation of disease specificity. Neurol Neuroimmunol Neuroinflammation 4(5):e386

    Article  Google Scholar 

  • Lynch SV, Pedersen O (2016) The human intestinal microbiome in health and disease. N Engl J Med 375(24):2369–2379

    Article  CAS  PubMed  Google Scholar 

  • Lynch CJ, Gunning FM, Liston C (2020) Causes and consequences of diagnostic heterogeneity in depression: paths to discovering novel biological depression subtypes. Biol Psychiatry 88(1):83–94

    Article  CAS  PubMed  Google Scholar 

  • Mac Giollabhui N, Ng TH, Ellman LM, Alloy LB (2020) The longitudinal associations of inflammatory biomarkers and depression revisited: systematic review, meta-analysis, and meta-regression. Mol Psychiatry

    Google Scholar 

  • Magyari M, Sorensen PS (2020) Comorbidity in multiple sclerosis. Front Neurol 11:851

    Article  PubMed  PubMed Central  Google Scholar 

  • Malhi GS, Mann JJ (2018) Depression. Lancet 392(10161):2299–2312

    Article  PubMed  Google Scholar 

  • Mazza MG, Lucchi S, Tringali AGM, Rossetti A, Botti ER, Clerici M (2018) Neutrophil/lymphocyte ratio and platelet/lymphocyte ratio in mood disorders: a meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry 84:229–236

    Article  PubMed  Google Scholar 

  • Melief CJM (2021) Special review: the future of immunotherapy. Immunother Adv 1(1). https://doi.org/10.1093/immadv/ltaa005

  • Middleton J, Neil S, Wintle J, Clark-Lewis I, Moore H, Lam C et al (1997) Transcytosis and surface presentation of IL-8 by venular endothelial cells. Cell 91(3):385–395

    Article  CAS  PubMed  Google Scholar 

  • Miller AH, Pariante CM (2020) Trial failures of anti-inflammatory drugs in depression. Lancet Psychiatry 7:837

    Article  PubMed  Google Scholar 

  • Miller AH, Raison CL (2016) The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol 16(1):22–34

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moldavski A, Wenz H, Lange BE, Rohleder C, Leweke FM (2021) Case report: severe adolescent major depressive syndrome turns out to be an unusual case of anti-NMDA receptor encephalitis, Frontiers in psychiatry, vol 12, p 679996

    Google Scholar 

  • Moustafa AT, Moazzami M, Engel L, Bangert E, Hassanein M, Marzouk S et al (2020) Prevalence and metric of depression and anxiety in systemic lupus erythematosus: a systematic review and meta-analysis. Semin Arthritis Rheum 50(1):84–94

    Article  PubMed  Google Scholar 

  • Mousten IV, Sørensen NV, Christensen RH, Benros M (2022) Cerebrospinal fluid biomarkers in patients with unipolar depression compared to healthy controls: a comprehensive systematic review and meta-analysis. JAMA Psychiat. [Epub ahead of print]

    Google Scholar 

  • Nettis MA, Veronese M, Nikkheslat N, Mariani N, Lombardo G, Sforzini L et al (2020) PET imaging shows no changes in TSPO brain density after IFN-α immune challenge in healthy human volunteers. Transl Psychiatry 10(1):89

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nikolova VL, Smith MRB, Hall LJ, Cleare AJ, Stone JM, Young AH (2021) Perturbations in gut microbiota composition in psychiatric disorders: a review and meta-analysis. JAMA Psychiat

    Google Scholar 

  • Nudel R, Benros ME, Krebs MD, Allesøe RL, Lemvigh CK, Bybjerg-Grauholm J et al (2019) Immunity and mental illness: findings from a Danish population-based immunogenetic study of seven psychiatric and neurodevelopmental disorders. Eur J Hum Genet 27(9):1445–1455

    Article  PubMed  PubMed Central  Google Scholar 

  • Omori W, Hattori K, Kajitani N, Tsuchioka MO, Boku S, Kunugi H et al (2020) Increased matrix metalloproteinases in cerebrospinal fluids of patients with major depressive disorder and schizophrenia. Int J Neuropsychopharmacol 23(11):713–720

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Orlovska-waast S, Köhler-forsberg O, Wiben S, Merete B, Kondziella D, Krogh J et al (2019) Cerebrospinal fluid markers of inflammation and infections in schizophrenia and affective disorders: a systematic review and meta-analysis. Mol Psychiatry 24:869–887

    Article  CAS  PubMed  Google Scholar 

  • Osimo EF, Pillinger T, Rodriguez IM, Khandaker GM, Pariante CM, Howes OD (2020) Inflammatory markers in depression: a meta-analysis of mean differences and variability in 5,166 patients and 5,083 controls. Brain Behav Immun 87:901–909

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ousman SS, Kubes P (2012) Immune surveillance in the central nervous system. Nat Neurosci 15(8):1096–1101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pollak TA, Lennox BR, Müller S, Benros ME, Prüss H, Tebartz van Elst L et al (2020) Autoimmune psychosis: an international consensus on an approach to the diagnosis and management of psychosis of suspected autoimmune origin. The lancet. Psychiatry 7(1):93–108

    PubMed  Google Scholar 

  • Ransohoff RM (2016) How neuroinflammation contributes to neurodegeneration. Science 353(6301):777–783

    Article  CAS  PubMed  Google Scholar 

  • Rea TD, Russo JE, Katon W, Ashley RL, Buchwald DS (2001) Prospective study of the natural history of infectious mononucleosis caused by Epstein-Barr virus. J Am Board Fam Pract 14(4):234–242

    CAS  PubMed  Google Scholar 

  • Restrepo-Martinez M, Ramirez-Bermudez J, Bayliss L, Espinola-Nadurille M (2020) Characterisation and outcome of neuropsychiatric symptoms in patients with anti-NMDAR encephalitis. Acta Neuropsychiatr 32(2):92–98

    Article  PubMed  Google Scholar 

  • Ripke S, Wray NR, Lewis CM, Hamilton SP, Weissman MM, Breen G et al (2013) A mega-analysis of genome-wide association studies for major depressive disorder. Mol Psychiatry 18(4):497–511

    Article  CAS  PubMed  Google Scholar 

  • Rose NR (2017) Autoimmune diseases. In: Quah SR (ed) International encyclopedia of public health, 2nd edn. Academic Press, Oxford, pp 192–195. https://www.sciencedirect.com/science/article/pii/B9780128036785000291

    Chapter  Google Scholar 

  • Savitz J (2020) The kynurenine pathway: a finger in every pie. Mol Psychiatry 25(1):131–147

    Article  PubMed  Google Scholar 

  • Shi K, Tian D-C, Li Z-G, Ducruet AF, Lawton MT, Shi F-D (2019) Global brain inflammation in stroke. Lancet Neurol 18(11):1058–1066

    Article  PubMed  Google Scholar 

  • Simonsen CS, Flemmen HØ, Lauritzen T, Berg-Hansen P, Moen SM, Celius EG (2020) The diagnostic value of IgG index versus oligoclonal bands in cerebrospinal fluid of patients with multiple sclerosis. Mult Scler J Exp Transl Clin 6(1):2055217319901291

    PubMed  PubMed Central  Google Scholar 

  • Sørensen NV, Orlovska-Waast S, Jeppesen R, Klein-Petersen AW, Christensen RH, Benros ME (2022) Neuroinflammatory biomarkers in the cerebrospinal fluid from 106 patients with recent onset depression compared to 106 individually matched healthy controls. Biol Psychiatry. [Epub ahead of print]

    Google Scholar 

  • Spencer et al (2018) Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the global burden of disease study 2017. Lancet 392(10159):1789–1858

    Article  Google Scholar 

  • Sproston NR, Ashworth JJ (2018) Role of C-reactive protein at sites of inflammation and infection. Front Immunol 9:754

    Article  PubMed  PubMed Central  Google Scholar 

  • Steiner J, Teegen B, Schiltz K, Bernstein H-G, Stoecker W, Bogerts B (2014) Prevalence of N-methyl-D-aspartate receptor autoantibodies in the peripheral blood: healthy control samples revisited. JAMA Psychiat 71(7):838–839

    Article  Google Scholar 

  • Streit WJ, Mrak RE, Griffin WST (2004) Microglia and neuroinflammation: a pathological perspective. J Neuroinflammation 1(1):14

    Article  PubMed  PubMed Central  Google Scholar 

  • Tanaka T, Narazaki M, Kishimoto T (2014) IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol 6(10):a016295

    Article  PubMed  PubMed Central  Google Scholar 

  • Taquet M, Geddes JR, Husain M, Luciano S, Harrison PJ (2021) 6-month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: a retrospective cohort study using electronic health records. Lancet Psychiatry 8(5):416–427

    Article  PubMed  PubMed Central  Google Scholar 

  • Torres-Aguilar H, Sosa-Luis SA, Aguilar-Ruiz SR (2019) Infections as triggers of flares in systemic autoimmune diseases: novel innate immunity mechanisms. Curr Opin Rheumatol 31(5):525–531

    Article  CAS  PubMed  Google Scholar 

  • Troubat R, Barone P, Leman S, Desmidt T, Cressant A, Atanasova B et al (2020) Neuroinflammation and depression: a review. Eur J Neurosci

    Google Scholar 

  • Turkheimer FE, Rizzo G, Bloomfield PS, Howes O, Zanotti-Fregonara P, Bertoldo A et al (2015) The methodology of TSPO imaging with positron emission tomography. Biochem Soc Trans 43(4):586–592. https://doi.org/10.1042/BST20150058

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Valkanova V, Ebmeier KP, Allan CL (2013) CRP, IL-6 and depression: a systematic review and meta-analysis of longitudinal studies. J Affect Disord 150(3):736–744

    Article  CAS  PubMed  Google Scholar 

  • Varatharaj A, Galea I (2017) The blood-brain barrier in systemic inflammation. Brain Behav Immun 60:1–12

    Article  CAS  PubMed  Google Scholar 

  • Varfolomeev E, Vucic D (2018) Intracellular regulation of TNF activity in health and disease. Cytokine 101:26–32

    Article  CAS  PubMed  Google Scholar 

  • Vindegaard N, Benros ME (2020) COVID-19 pandemic and mental health consequences: systematic review of the current evidence. Brain Behav Immun 89:531–542

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vindegaard N, Speyer H, Nordentoft M, Rasmussen S, Benros ME (2020) Gut microbial changes of patients with psychotic and affective disorders: a systematic review. Schizophr Res

    Google Scholar 

  • Vindegaard N, Petersen LV, Lyng-Rasmussen BI, Dalsgaard S, Benros ME (2021) Infectious mononucleosis as a risk factor for depression: a nationwide cohort study. Brain Behav Immun 94:259–265

    Article  PubMed  Google Scholar 

  • Visentin APV, Colombo R, Scotton E, Fracasso DS, da Rosa AR, Branco CS et al (2020) Targeting inflammatory-mitochondrial response in major depression: current evidence and further challenges. Oxid Med Cell Longev 2020:2972968

    Article  PubMed  PubMed Central  Google Scholar 

  • Wang X, Zhang L, Lei Y, Liu X, Zhou X, Liu Y et al (2014) Meta-analysis of infectious agents and depression. Sci Rep 4:4530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang L, Wang F-S, Gershwin ME (2015) Human autoimmune diseases: a comprehensive update. J Intern Med 278(4):369–395

    Article  CAS  PubMed  Google Scholar 

  • Wei YB, Liu JJ, Villaescusa JC, Åberg E, Brené S, Wegener G et al (2016) Elevation of Il6 is associated with disturbed let-7 biogenesis in a genetic model of depression. Transl Psychiatry 6(8):e869

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Willner P, Scheel-Krüger J, Belzung C (2013) The neurobiology of depression and antidepressant action. Neurosci Biobehav Rev 37(10 Pt 1):2331–2371

    Article  CAS  PubMed  Google Scholar 

  • Wingo TS, Liu Y, Gerasimov ES, Gockley J, Logsdon BA, Duong DM et al (2021) Brain proteome-wide association study implicates novel proteins in depression pathogenesis. Nat Neurosci 24(6):810–817

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wium-Andersen MK, Ørsted DD, Nielsen SF, Nordestgaard BG (2013) Elevated C-reactive protein levels, psychological distress, and depression in 73, 131 individuals. JAMA Psychiat 70(2):176–184

    Article  CAS  Google Scholar 

  • Wray NR, Ripke S, Mattheisen M, Trzaskowski M, Byrne EM, Abdellaoui A et al (2018) Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression. Nat Genet 50(5):668–681

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang J, Zheng P, Li Y, Wu J, Tan X, Zhou J et al (2020) Landscapes of bacterial and metabolic signatures and their interaction in major depressive disorders. Sci Adv 6(49)

    Google Scholar 

  • Zorrilla EP, Luborsky L, McKay JR, Rosenthal R, Houldin A, Tax A et al (2001) The relationship of depression and stressors to immunological assays: a meta-analytic review. Brain Behav Immun 15(3):199–226

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The present work was funded by an unrestricted grant from The Lundbeck Foundation (grant number R268-2016-3925).

Author information

Authors and Affiliations

  1. Biological and Precision Psychiatry, Copenhagen Research Centre for Mental Health, Mental Health Centre Copenhagen, Copenhagen University Hospital, Hellerup, Denmark

    Nina Vindegaard Sørensen & Michael Eriksen Benros

  2. Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Nina Vindegaard Sørensen & Michael Eriksen Benros

Authors
  1. Nina Vindegaard Sørensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael Eriksen Benros
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael Eriksen Benros .

Editor information

Editors and Affiliations

  1. Laureate Inst for Brain Research, Tulsa, OK, USA

    Jonathan Savitz

  2. Psychiatry and Behavioral Sciences Dept, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Robert H. Yolken

Rights and permissions

Reprints and permissions

Copyright information

© 2022 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Sørensen, N.V., Benros, M.E. (2022). The Immune System and Depression: From Epidemiological to Clinical Evidence. In: Savitz, J., Yolken, R.H. (eds) Microorganisms and Mental Health. Current Topics in Behavioral Neurosciences, vol 61. Springer, Cham. https://doi.org/10.1007/7854_2022_369

Download citation

Publish with us

Policies and ethics

Search

Navigation