Original Article

A Study of Autoantibodies against Some Central Nervous System Antigens and the IL-35 Serum Level in Schizophrenia


Schizophrenia (SCZ) is a debilitating mental disorder with various causes involving complex interactions between genetic factors and environmental agents. The immune system plays a vital role in the pathology and function of the nervous system. Interleukin 35 (IL-35) is a regulatory and anti-inflammatory cytokine that can prevent autoimmune and inflammatory diseases. This study aimed to investigate the role of autoantibodies against some central nervous system (CNS) antigens and IL-35 serum levels in patients with Schizophrenia.
This case-control study involved 80 participants. The serum levels of IL-35 were measured by enzyme-linked immunosorbent assay and the autoantibodies in the CNS by indirect immunofluorescence assay (IFA).
The serum levels of IL-35 were decreased in patient groups compared to healthy subjects. Autoantibodies against N-methyl-D-aspartate receptor (NMDAR) and myelin-associated glycoprotein (MAG) were positive in 15% (6/40) and 7.5% (3/40), respectively; however, no antibodies against myelin, aquaporin-4 (AQP4), myelin oligodendrocyte glycoprotein (MOG), voltage-gated potassium channel (VGKC), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR), γ-butyric acid receptor type B1 γ-butyric acid receptor type B1 (GABABR), antidipeptidyl peptidase-like protein-6 (DPPX), immunoglobulin-like cell adhesion molecule 5 (IgLON5), Glycine receptor (R) and acetylcholine receptor (Ach R) were detected (No statistics were computed). 
We found that decreased serum IL-35 levels and the existence autoantibodies against NMDAR antigen may contribute to the pathogenesis of SCZ.

1. Cho SJ, Kim J, Kang YJ, Lee SY, Seo HY, Park JE, et al. Annual prevalence and incidence of schizophrenia and similar psychotic disorders in the Republic of Korea: a national health insurance data-based study. Psychiatry Investig. 2020;17(1):61-70
2. Jakobsen AS, Pedersen ML. Schizophrenia in Greenland. Dan Med J. 2021;68(2):A03200159.
3. Rao W-W, Zhang Y-S, Ng CH, Cui L-J, Li J-F, Li L, et al. Prevalence of schizophrenia and its association with socio-demographic correlates in an agricultural region of China. Asian J Psychiatr. 2021;64:102743.
4. Collaborators G. 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. 2018. Lancet. 2018;392(10159):1789-1858.
5. Edition F. Diagnostic and statistical manual of mental disorders. Am Psychiatric Assoc. 2013;21:591-643
6. Arab A, Mohebbi A, Afshar H, Moradi A. Multi-factorial Etiology of Bipolar Disorder and Schizophrenia in Iran: No Evidence of Borna Disease Virus Genome. Med Lab J. 2018;12(5):42-9.
7. Ayano G. Schizophrenia: a concise overview of etiology, epidemiology diagnosis and management: review of literatures. J Schizophrenia Res. 2016;3(2):2-7.
8. Horváth S, Mirnics K. Immune system disturbances in schizophrenia. Biol Psychiatry. 2014;75(4):316-23.
9. Laskaris L, Di Biase MA, Everall I, Chana G, Christopoulos A, Skafidas E, et al. Microglial activation and progressive brain changes in schizophrenia. Br J Pharmacol. 2016;173(4):666-80.
10. Monji A, Kato TA, Mizoguchi Y, Horikawa H, Seki Y, Kasai M, et al. Neuroinflammation in schizophrenia especially focused on the role of microglia. Prog Neuropsychopharmacol Biol Psychiatry. 2013;42(8):115-21.
11. Najjar S, Pahlajani S, De Sanctis V, Stern JN, Najjar A, Chong D. Neurovascular unit dysfunction and blood–brain barrier hyperpermeability contribute to schizophrenia neurobiology: a theoretical integration of clinical and experimental evidence. Front Psychiatry. 2017;8(2):83-9.
12. Pollak TA, Drndarski S, Stone JM, David AS, McGuire P, Abbott NJ. The blood–brain barrier in psychosis. Lancet Psychiatry. 2018;5(1):79-92.
13. De Picker LJ, Morrens M, Chance SA, Boche D. Microglia and brain plasticity in acute psychosis and schizophrenia illness course: a meta-review. Front Psychiatry. 2017;8(2):238-41.
14. Schlaaff K, Dobrowolny H, Frodl T, Mawrin C, Gos T, Steiner J, et al. Increased densities of T and B lymphocytes indicate neuroinflammation in subgroups of schizophrenia and mood disorder patients. Brain Behav Immun. 2020;88(12):497-506.
15. Van Mierlo HC, Broen JC, Kahn RS, de Witte LD. B-cells and schizophrenia: A promising link or a finding lost in translation? Brain Behav Immun. 2019;81(5):52-62.
16. Whelan R, St Clair D, Mustard CJ, Hallford P, Wei J. Study of novel autoantibodies in schizophrenia. Schizophr Bull. 2018; 17;44(6):1341-9.
17. Conen S, Gregory CJ, Hinz R, Smallman R, Corsi-Zuelli F, Deakin B, et al. Neuroinflammation as measured by positron emission tomography in patients with recent onset and established schizophrenia: implications for immune pathogenesis. Mol Psychiatry. 2021;26(9):5398-5406.
18. Fond G, Lançon C, Korchia T, Auquier P, Boyer L. The role of inflammation in the treatment of schizophrenia. Front Psychiatry. 2020;11(2):160-3.
19. Just D, Månberg A, Mitsios N, Stockmeier CA, Rajkowska G, Uhlén M, et al. Exploring autoantibody signatures in brain tissue from patients with severe mental illness. Transl Psychiatry. 2020;10(1):401-9.
20. Novellino F, Saccà V, Donato A, Zaffino P, Spadea MF, Vismara M, et al. Innate immunity: a common denominator between neurodegenerative and neuropsychiatric diseases. Int J Mol Sci. 2020;21(3):1115-9.
21. Pylayeva-Gupta Y. Molecular pathways: interleukin-35 in autoimmunity and cancer. Clin Cancer Res. 2016;22(20):4973-8.
22. Zhang J, Zhang Y, Wang Q, Li C, Deng H, Si C, et al. Interleukin‐35 in immune‐related diseases: protection or destruction. Immunology. 2019;157(1):13-20.
23. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13(2):261-76
24. Marder SR, Cannon TD. Schizophrenia. N Engl J Med. 2019;381(18):1753-61
25. Eftekharian MM, Omrani MD, Arsang-Jang S, Taheri M, Ghafouri-Fard S. Serum cytokine profile in schizophrenic patients. Hum Antibodies. 2019;27(1):23-9.
26. Mantere O, Saarela M, Kieseppä T, Raij T, Mäntylä T, Lindgren M, et al. Anti-neuronal anti-bodies in patients with early psychosis. Schizophr Res. 2018;192(41):404-7.
27. Gałecka M, Bliźniewska-Kowalska K, Orzechowska A, Szemraj J, Maes M, Berk M, et al. Inflammatory versus Anti-inflammatory Profiles in Major Depressive Disorders—The Role of IL-17, IL-21, IL-23, IL-35 and Foxp3. J Pers Med. 2021;11(2):66-9.
28. Nakano S, Morimoto S, Suzuki S, Tsushima H, Yamanaka K, Sekigawa I, et al. Immunoregulatory role of IL-35 in T cells of patients with rheumatoid arthritis. Rheumatology (Oxford). 2015;54(8):1498-506.
29. Ning X, Jian Z, Wang W. Low serum levels of interleukin 35 in patients with rheumatoid arthritis. Tohoku J Exp Med. 2015;237(2):77-82.
30. Ouyang H, Shi Y-b, Wang Z, Feng S, Kong S-m, Lu Y, et al. Decreased interleukin 35 and CD4+ EBI3+ T cells in patients with active systemic lupus erythematosus.. Am J Med Sci. 2014;348(2):156-61.
31. Wang W, Li P, Yang J. Decreased circulating interleukin-35 levels are related to interleukin-4-producing CD8+ T cells in patients with allergic asthma. Iran J Allergy Asthma Immunol. 2015;14(4):379-85.
32. Corsi-Zuelli F, Deakin B. Impaired regulatory T cell control of astroglial overdrive and microglial pruning in schizophrenia. Neurosci Biobehav Rev. 2021;125(12):637-53.
33. Sahbaz C, Zibandey N, Kurtulmus A, Duran Y, Gokalp M, Kırpınar I, et al. Reduced regulatory T cells with increased proinflammatory response in patients with schizophrenia. Psychopharmacology (Berl). 2020;237(6):1861-71.
34. Parshukova D, Smirnova LP, Ermakov EA, Bokhan NA, Semke AV, Ivanova SA, et al. Autoimmunity and immune system dysregulation in schizophrenia: IgGs from sera of patients hydrolyze myelin basic protein. J Mol Recognit. 2019;32(2):e2759.
35. Sæther SG, Rø ADB, Larsen JB, Vaaler A, Kondziella D, Reitan SK. Biomarkers of autoimmunity in acute psychiatric disorders. J Neuropsychiatry Clin Neurosci Summer. 2019;31(3):246-253.
36. Reale M, Costantini E, Greig NH. Cytokine imbalance in schizophrenia. Front Psychiatry. 2021;12(2):536257.
37. Adell A. Brain NMDA receptors in schizophrenia and depression. Biomolecules. 2020;10(6):947-9.
38. Alherz F, Alherz M, Almusawi H. NMDAR hypofunction and somatostatin-expressing GABAergic interneurons and receptors: A newly identified correlation and its effects in schizophrenia. Schizophr Res Cogn. 2017 Mar 9;8:1-6. doi: 10.1016/j.scog.2017.02.001. PMID: 28740825; PMCID: PMC5514309.
39. Nakazawa K, Sapkota K. The origin of NMDA receptor hypofunction in schizophrenia. Pharmacol Ther. 2020;205(8):107426.
40. Uno Y, Coyle JT. Glutamate hypothesis in schizophrenia. Psychiatry Clin Neurosci. 2019;73(5):204-15.
41. Steiner J, Walter M, Glanz W, Sarnyai Z, Bernstein H-G, Vielhaber S, et al. Increased prevalence of diverse N-methyl-D-aspartate glutamate receptor antibodies in patients with an initial diagnosis of schizophrenia: specific relevance of IgG NR1a antibodies for distinction from N-methyl-D-aspartate glutamate receptor encephalitis. JAMA Psychiatry. 2013;70(3):271-8.
42. Tong J, Huang J, Luo X, Chen S, Cui Y, An H, et al. Elevated serum anti-NMDA receptor antibody levels in first-episode patients with schizophrenia. Brain Behav Immun. 2019;81(9):213-9.
43. Masopust J, Andrýs C, Bažant J, Vyšata O, Kuca K, Vališ M. Anti-NMDA receptor antibodies in patients with a first episode of schizophrenia. Neuropsychiatr Dis Treat. 2015;11(2):619-23.
44. Chen C-H, Cheng M-C, Liu C-M, Liu C-C, Lin K-H, Hwu H-G. Seroprevalence survey of selective anti-neuronal autoantibodies in patients with first-episode schizophrenia and chronic schizophrenia. Schizophr Res. 2017;190(8):28-31.
45. Hoffmann C, Stevens J, Zong S, van Kruining D, Saxena A, Küçükali Cİ, et al. Alpha7 acetylcholine receptor autoantibodies are rare in sera of patients diagnosed with schizophrenia or bipolar disorder. PLoS One. 2018;13(12):e0208412.
IssueVol 21 No 4 (2022) QRcode
SectionOriginal Article(s)
DOI https://doi.org/10.18502/ijaai.v21i4.10291
Autoantibodies Interleukin 35 microglia Neurogenic inflammation Schizophrenia

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How to Cite
Soltani M, Beshkar P, Mokhtarian K, Anjomshoa M, Mohammad-Rezaei M, Azadegan-Dehkordi F, Mirzaei Y, Majidi J, Bagheri N. A Study of Autoantibodies against Some Central Nervous System Antigens and the IL-35 Serum Level in Schizophrenia. Iran J Allergy Asthma Immunol. 2022;21(4):441-448.