In Schizophrenia, Deficits in Natural IgM Isotype Antibodies Including those Directed to Malondialdehyde and Azelaic Acid Strongly Predict Negative Symptoms, Neurocognitive Impairments, and the Deficit Syndrome

Abstract

Schizophrenia is characterized by an interrelated activation of the immune-inflammatory response system (IRS) and the compensatory immune-regulatory system (CIRS), which downregulates the IRS. Deficit schizophrenia is characterized by a deficit in IgM-mediated autoimmune responses to tryptophan catabolites. The presence and correlates of IgM isotype antibodies to oxidative-specific epitopes (OSEs), nitroso (NO), and nitro (NO2) adducts in schizophrenia remain unknown. This study measured IgM antibodies to malondialdehyde (MDA), azelaic acid, phosphatidylinositol, oleic acid, NO-tryptophan, NO-albumin, NO-cysteinyl, and NO2-tyrosine in a sample of 80 schizophrenia patients, divided into those with and those without deficit schizophrenia, and 38 healthy controls. Deficit schizophrenia was characterized by significantly lower IgM antibody levels to all OSEs as compared with non-deficit schizophrenia and controls. Lowered IgM antibodies to MDA coupled with increased IgM levels to NO-cysteinyl and NO2-tyrosine strongly predict deficit schizophrenia versus non-deficit schizophrenia with an area under the ROC curve of 0.913. A large part of the variance (21.2–42.2%) in the negative symptoms of schizophrenia and excitation is explained by IgM antibody titers to MDA (inversely) and NO-cysteinyl and/or NO2-tyrosine (both positively). Lower IgM antibodies to MDA are significantly associated with impairments in episodic memory including direct and delayed recall. These findings further indicate that deficit schizophrenia is a distinct phenotype of schizophrenia, which is characterized by lower natural IgM antibody levels to OSEs and relative increments in nitrosylation and nitration of proteins. It is concluded that deficits in natural IgM attenuate CIRS functions and that this impairment may drive negative symptoms and impairments in episodic memory and thus deficit schizophrenia.

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

Fig. 1

References

  1. 1.

    Smith RS, Maes M (1995) The macrophage-T-lymphocyte theory of schizophrenia: additional evidence. Med Hypotheses 45:135–141

    CAS  PubMed  Google Scholar 

  2. 2.

    Roomruangwong C, Noto C, Kanchanatawan B, Anderson G, Kubera M, Carvalho AF, Maes M (2018) The role of aberrations in the immune-inflammatory response system (IRS) and the compensatory immune-regulatory reflex system (CIRS) in different phenotypes of schizophrenia: the IRS-CIRS theory of schizophrenia. Preprint, September 2018, DOI: https://doi.org/10.20944/preprints201809.0289.v1

  3. 3.

    van Kesteren CF, Gremmels H, de Witte LD, Hol EM, Van Gool AR, Falkai PG, Kahn RS, Sommer IE (2017) Immune involvement in the pathogenesis of schizophrenia: a meta-analysis on postmortem brain studies. Transl Psychiatry 7(3):e1075

    PubMed  PubMed Central  Google Scholar 

  4. 4.

    Orlovska-Waast S, Kohler-Forsberg O, Brix SW, Nordentoft M, Kondziella D, Krogh J, Benros ME (2018) Cerebrospinal fluid markers of inflammation and infections in schizophrenia and affective disorders: a systematic review and meta-analysis. Mol Psychiatry. https://doi.org/10.1038/s41380-018-0220-4

    PubMed  PubMed Central  Google Scholar 

  5. 5.

    Maurya PK, Noto C, Rizzo LB, Rios AC, Nunes SO, Barbosa DS, Sethi S, Zeni M et al (2016) The role of oxidative and nitrosative stress inaccelerated aging and major depressive disorder. Prog Neuro-Psychopharmacol Biol Psychiatry 65:134–144

    CAS  Google Scholar 

  6. 6.

    Maes M, Berk M, Goehler L, Song C, Anderson G, Gałecki P, Leonard B (2012) Depression and sickness behavior are Janus-faced responses to shared inflammatory pathways. BMC Med 10:66

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Maes M, Carvalho AF (2018) The Compensatory Immune-Regulatory Reflex System (CIRS) in depression and bipolar disorder. Mol Neurobiol 55:8885–8903. https://doi.org/10.1007/s12035-018-1016-x. Review

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Noto MN, Maes M, Nunes SO, Ota VK, Rossaneisf AC, Verri WA Jr, Cordeiro Q, Belangero SI, Gadelha A, Bressan RA, Noto C (2018) Activation of the immune-inflammatory response system and the compensatory immune-regulatory reflex system in antipsychotic naive first episode psychosis. Preprints Preprints2018090314.v2.

  9. 9.

    Anderson G, Maes M (2013) Schizophrenia: linking prenatal infection to cytokines, the tryptophan catabolite (TRYCAT) pathway, NMDA receptor hypofunction, neurodevelopment and neuroprogression. Prog Neuro-Psychopharmacol Biol Psychiatry 42:5–19

    CAS  Google Scholar 

  10. 10.

    Davis J, Moylan S, Harvey BH, Maes M, Berk M (2014) Neuroprogression in schizophrenia: pathways underpinning clinical staging and therapeutic corollaries. Aust N Z J Psychiatry 48:512–529

    PubMed  Google Scholar 

  11. 11.

    Davis J, Eyre H, Jacka FN, Dodd S, Dean O, McEwen S, Debnath M, McGrath J et al (2016) A review of vulnerability and risks for schizophrenia: beyond the two hit hypothesis. Neurosci Biobehav Rev 65:185–194

    PubMed  PubMed Central  Google Scholar 

  12. 12.

    Maes M, Bosmans E, Ranjan R, Vandoolaeghe E, Meltzer HY, De Ley M, Berghmans R, Stans G et al (1996) Lower plasma CC16, a natural anti-inflammatory protein, and increased plasma interleukin-1 receptor antagonist in schizophrenia: effects of antipsychotic drugs. Schizophr Res 21(1):39–50

    CAS  PubMed  Google Scholar 

  13. 13.

    Maes M, Bosmans E, Kenis G, De Jong R, Smith RS, Meltzer HY (1997) In vivo immunomodulatory effects of clozapine in schizophrenia. Schizophr Res 26(2–3):221–225

    CAS  PubMed  Google Scholar 

  14. 14.

    Kanchanatawan B, Sirivichayakul S, Ruxrungtham K, Carvalho AF, Geffard M, Anderson G, Maes M (2018) Deficit schizophrenia is characterized by defects in IgM-mediated responses to tryptophan catabolites (TRYCATs): a paradigm shift towards defects in natural self-regulatory immune responses coupled with mucosa-derived TRYCAT pathway activation. Mol Neurobiol 55(3):2214–2226

    CAS  PubMed  Google Scholar 

  15. 15.

    Roomruangwong C, Barbosa DS, de Farias CC, Matsumoto AK, Baltus THL, Morelli NR, Kanchanatawan B, Duleu S et al (2018) Natural regulatory IgM-mediated autoimmune responses directed against malondialdehyde regulate oxidative andnitrosative pathways and coupled with IgM responses to nitroso adducts attenuate depressive and physiosomatic symptoms at the end of term pregnancy. Psychiatry Clin Neurosci 72(2):116–130

    CAS  PubMed  Google Scholar 

  16. 16.

    Thiagarajan D, Frostegård AG, Singh S, Rahman M, Liu A, Vikström M, Leander K, Gigante B et al (2016) Human IgM antibodies to malondialdehyde conjugated with albumin are negatively associated with cardiovascular disease among 60-year-olds. J Am Heart Assoc 20(5):12

    Google Scholar 

  17. 17.

    McMahon M, Skaggs B (2016) Autoimmunity: do IgM antibodies protect against atherosclerosis in SLE? Nat Rev Rheumatol 12(8):442–444

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Dietrich-Muszalska A, Olas B (2009) Modifications of blood platelet proteins of patients with schizophrenia. Platelets 20(2):90–96

    CAS  PubMed  Google Scholar 

  19. 19.

    Maia-de-Oliveira JP, Kandratavicius L, Nunes EA, Machado-de-Sousa JP, HallakJE DSM (2016) Nitric oxide’s involvement in the spectrum of psychotic disorders. Curr Med Chem 23(24):2680–2691

    CAS  PubMed  Google Scholar 

  20. 20.

    Kirkpatrick B, Buchanan RW, McKenney PD, Alphs LD, Carpenter WT Jr (1989) The schedule for the deficit syndrome: an instrument for research in schizophrenia. Psychiatry Res 30:119–123

    CAS  PubMed  Google Scholar 

  21. 21.

    Andreasen NC (1989) The scale for the assessment of negative symptoms (SANS): conceptual and theoretical foundations. Brit J Psychiatry suppl 7:49–58

    Google Scholar 

  22. 22.

    Kay SR, Fiszbein A, Opler LA (1987) The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 13:261–276

    CAS  Google Scholar 

  23. 23.

    Kittirathanapaiboon P, Khamwongpin M (2005) The Validity of the Mini International Neuropsychiatric Interview (M.I.N.I.) Thai Version. J Mental Health Thailand 13(3):125–135

  24. 24.

    Overall JE, Gorham DR (1962) The brief psychiatric rating scale. Psychol Re 10:799–812

    Google Scholar 

  25. 25.

    Kanchanatawan B, Thika S, Sirivichayakul S, Carvalho AF, Geffard M, Maes M (2018) In schizophrenia, depression, anxiety, and physiosomatic symptoms are strongly related to psychotic symptoms and excitation, impairments in episodic memory, and increased production of neurotoxic tryptophan catabolites: a multivariate and machine learning study. Neurotox Res 33(3):641–655

    CAS  PubMed  Google Scholar 

  26. 26.

    Fillenbaum GG, van Belle G, Morris JC, Mohs RC, Mirra SS, Davis PC, Tariot PN, Silverman JM, Clark CM, Welsh-Bohmer KA, … Heyman A (2008) Consortium to Establish a Registry for Alzheimer's Disease (CERAD): the first twenty years. Alzheimer's & dementia : the journal of the Alzheimer's Association 4(2):96–109

  27. 27.

    CANTAB (2018) The most validated cognitive research software. http://www.cambridgecognition.com/cantab/. October 1, 2018.

  28. 28.

    Kanchanatawan B, Hemrungrojn S, Thika S, Sirivichayakul S, Ruxrungtham K, Carvalho AF, Geffard M, Anderson G et al (2018) Changes in tryptophan catabolite (TRYCAT) pathway patterning are associated with mild impairments in declarative memory in schizophrenia and deficits in semantic and episodic memory coupled with increased false-memory creation in deficit schizophrenia. Mol Neurobiol 55(6):5184–5201

    CAS  PubMed  Google Scholar 

  29. 29.

    Sirivichayakul S, Kanchanatawan B, Thika S, Carvalho AF, Maes M (2018) Eotaxin, an endogenous cognitive deteriorating chemokine (ECDC), is a major contributor to cognitive decline in normal people and to executive, memory, and sustained attention deficits, formal thought disorders, and psychopathology in schizophrenia patients. Neurotox Res. https://doi.org/10.1007/s12640-018-9937-8

    PubMed  Google Scholar 

  30. 30.

    Daverat P, Geffard M, Orgogozo JM (1989) Identification and characterization of anti-conjugated azelaic acid antibodies in multiple sclerosis. J Neuroimmunol 22(2):129–134

    CAS  PubMed  Google Scholar 

  31. 31.

    Boullerne A, Petry KG, Geffard M (1996) Circulating antibodies directed against conjugated fatty acids in sera of patients with multiple sclerosis. J Neuroimmunol 65(1):75–81

    CAS  PubMed  Google Scholar 

  32. 32.

    Amara A, Constans J, Chaugier C, Sebban A, Dubourg L, Peuchant E, Pellegrin JL, Leng B et al (1995) Autoantibodies to malondialdehyde-modified epitope in connective tissue diseases and vasculitides. Clin Exp Immunol 101(2):233–238

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Faiderbe S, Chagnaud JL, Geffard M (1992) Anti-phosphoinositide auto-antibodies in sera of cancer patients: isotypic and immunochemical characterization. Cancer Lett 66(1):35–41

    CAS  PubMed  Google Scholar 

  34. 34.

    Geffard M, Bodet D, Dabadie MP, Arnould L (2003) Identification of antibodies in sera of breast cancer patients. Immuno-Analyse & Biologie Special 18:248–253

  35. 35.

    Boullerne AI, Petry KG, Meynard M, Geffard M (1995) Indirect evidence for nitricoxide involvement in multiple sclerosis by characterization of circulating antibodies directed against conjugated S-nitrosocysteine. J Neuroimmunol 60(1–2):117–124

    CAS  PubMed  Google Scholar 

  36. 36.

    Boullerne AI, Rodriguez JJ, Touil T, Brochet B, Schmidt S, Abrous ND, Le Moal M, Pua JR et al (2002) Anti-S-nitrosocysteine antibodies are a predictive marker for demyelination in experimental autoimmune encephalomyelitis: implications for multiple sclerosis. J Neurosci 22(1):123–132

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Cosgrove JP, Church DF, Pryor WA (1987) The kinetics of the autoxidation of polyunsaturated fatty acids. Lipids 22(5):299–304

    CAS  PubMed  Google Scholar 

  38. 38.

    Gutteridge JM (1995) Lipid peroxidation and antioxidants as biomarkers of tissue damage. Clin Chem 41(12 Pt 2):1819–1828

    CAS  PubMed  Google Scholar 

  39. 39.

    Shichiri M (2014) The role of lipid peroxidation in neurological disorders. J Clin Biochem Nutr 54(3):151–160

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Ayala A, Muñoz MF, Argüelles S (2014) Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxidative Med Cell Longev 2014:360438

    Google Scholar 

  41. 41.

    Busch CJ, Binder CJ (2017) Malondialdehyde epitopes as mediators of sterile inflammation. Biochim Biophys Acta Mol Cell Biol Lipids 1862(4):398–406

    CAS  PubMed  Google Scholar 

  42. 42.

    Tsiantoulas D, Perkmann T, Afonyushkin T, Mangold A, Prohaska TA, Papac-Milicevic N, Millischer V, Bartel C et al (2015) Circulating microparticles carryoxidation-specific epitopes and are recognized by natural IgM antibodies. J Lipid Res 56(2):440–448

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Weismann D, Binder CJ (2012) The innate immune response to products of phospholipid peroxidation. Biochim Biophys Acta 1818(10):2465–2475

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Maes M, Mihaylova I, Leunis JC (2007) Increased serum IgM antibodies directedagainst phosphatidyl inositol (Pi) in chronic fatigue syndrome (CFS) and majordepression: evidence that an IgM-mediated immune response against Pi is onefactor underpinning the comorbidity between both CFS and depression. Neuro Endocrinol Lett 28(6):861–867

    PubMed  Google Scholar 

  45. 45.

    Maes M, Mihaylova I, Kubera M, Leunis JC, Geffard M (2011) IgM-mediated autoimmune responses directed against multiple neoepitopes in depression: new pathways that underpin the inflammatory and neuroprogressive pathophysiology. J Affect Disord 135(1–3):414–418

    CAS  PubMed  Google Scholar 

  46. 46.

    Güneş M, Camkurt MA, Bulut M, Demir S, İbiloğlu AO, Kaya MC, Atlı A, Kaplan İ et al (2016) Evaluation of paraoxonase, arylesterase and malondialdehyde levels in schizophrenia patients taking typical, atypical and combined antipsychotic treatment. Clin Psychopharmacol Neurosci 14(4):345–350

    PubMed  PubMed Central  Google Scholar 

  47. 47.

    Wu JQ, Kosten TR, Zhang XY (2013) Free radicals, antioxidant defense systems, and schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 46:200–206

    CAS  PubMed  Google Scholar 

  48. 48.

    Maes M, Kubera M, Mihaylova I, Geffard M, Galecki P, Leunis JC, Berk M (2013) Increased autoimmune responses against auto-epitopes modified by oxidative andnitrosative damage in depression: implications for the pathways to chronicdepression and neuroprogression. J Affect Disord 149(1–3):23–29

    CAS  PubMed  Google Scholar 

  49. 49.

    Liu T, Zhong S, Liao X, Chen J, He T, Lai S, Jia Y (2015) A meta-analysis of oxidative stress markers in depression. PLoS One 10(10):e0138904

    PubMed  PubMed Central  Google Scholar 

  50. 50.

    Boll KM, Noto C, Bonifácio KL, Bortolasci CC, Gadelha A, Bressan RA, Barbosa DS, Maes M et al (2017) Oxidative and nitrosative stress biomarkers in chronic schizophrenia. Psychiatry Res 253:43–48

    CAS  PubMed  Google Scholar 

  51. 51.

    Díaz-Zaragoza M, Hernández-Ávila R, Viedma-Rodríguez R, Arenas-Aranda D, Ostoa-Saloma P (2015) Natural and adaptive IgM antibodies in the recognition of tumor-associated antigens of breast cancer (review). Oncol Rep 34(3):1106–1114

    PubMed  PubMed Central  Google Scholar 

  52. 52.

    Litvinov D, Selvarajan K, Garelnabi M, Brophy L, Parthasarathy S (2010) Anti-atherosclerotic actions of azelaic acid, an end product of linoleic acid peroxidation, in mice. Atherosclerosis 209(2):449–454

    CAS  PubMed  Google Scholar 

  53. 53.

    Passi S, Picardo M, Zompetta C, De Luca C, Breathnach AS, Nazzaro-Porro M (1991) The oxyradical-scavenging activity of azelaic acid in biological systems. Free Radic Res Commun 15(1):17–28

    CAS  PubMed  Google Scholar 

  54. 54.

    Fitton A, Goa KL (1991) Azelaic acid. A review of its pharmacological properties andtherapeutic efficacy in acne and hyperpigmentary skin disorders. Drugs 41(5):780–798

    CAS  PubMed  Google Scholar 

  55. 55.

    Pelle MT, Crawford GH, James WD (2004) Rosacea: II. Therapy. J Am Acad Dermatol 51:499–512

    PubMed  Google Scholar 

  56. 56.

    Akamatsu H, Komura J, Asada Y, Miyachi Y, Niwa Y (1991) Inhibitory effect of azelaic acid on neutrophil functions: a possible cause for its efficacy in treating pathogenetically unrelated diseases. Arch Dermatol Res 283(3):162–166

    CAS  PubMed  Google Scholar 

  57. 57.

    Binder CJ (2012) Naturally occurring IgM antibodies to oxidation-specific epitopes. Adv Exp Med Biol 750:2–13

    CAS  PubMed  Google Scholar 

  58. 58.

    Medina JM, Tabernero A (2002) Astrocyte-synthesized oleic acid behaves as a neurotrophic factor for neurons. J Physiol Paris 96(3–4):265–271

    CAS  PubMed  Google Scholar 

  59. 59.

    Ananthanarayanan B, Ni Q, Zhang J (2005) Signal propagation from membrane messengers to nuclear effectors revealed by reporters of phosphoinositide dynamics and Akt activity. Proc Natl Acad Sci U S A 102(42):15081–15086

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Maes M, Mihaylova I, Leunis JC (2006) Chronic fatigue syndrome is accompanied by an IgM-related immune response directed against neopitopes formed by oxidative or nitrosative damage to lipids and proteins. Neuro Endocrinol Lett 27(5):615–621

    CAS  PubMed  Google Scholar 

  61. 61.

    Maes M, Kubera M, Leunis JC, Berk M, Geffard M, Bosmans E (2013) In depression, bacterial translocation may drive inflammatory responses, oxidative and nitrosative stress (O&NS), and autoimmune responses directed against O&NS-damaged neoepitopes. Acta Psychiatr Scand 127(5):344–354

    CAS  PubMed  Google Scholar 

  62. 62.

    Bodet D, Glaize G, Dabadie M-P, Geffard M (2004) Suivi immunobiologique de malades atteints de sclérose en plaques Immunobiological follow-up for multiple sclerosis. Immuno-analyse & Biologie Spécialisée 19:138–147

  63. 63.

    Maes M, Mihaylova I, Kubera M, Leunis JC, Twisk FN, Geffard M (2012) IgM-mediated autoimmune responses directed against anchorage epitopes are greater in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) than in major depression. Metab Brain Dis 27(4):415–423

    CAS  PubMed  Google Scholar 

  64. 64.

    Morris G, Walder K, Carvalho AF, Tye SJ, Lucas K, Berk M, Maes M (2018) The role of hypernitrosylation in the pathogenesis and pathophysiology of neuroprogressive diseases. Neurosci Biobehav Rev 84:453–469

    CAS  PubMed  Google Scholar 

  65. 65.

    Morris G, Berk M, Klein H, Walder K, Galecki P, Maes M (2017) Nitrosative stress, hypernitrosylation, and autoimmune responses to Nitrosylated proteins: new pathways in neuroprogressive disorders including depression and chronic fatigue syndrome. Mol Neurobiol 54(6):4271–4291

    CAS  PubMed  Google Scholar 

  66. 66.

    Radi R (2013) Protein tyrosine nitration: biochemical mechanisms and structural basis of functional effects. Acc Chem Res 46(2):550–559

    CAS  PubMed  Google Scholar 

  67. 67.

    Moylan S, Berk M, Dean OM, Samuni Y, Williams LJ, O'Neil A, Hayley AC, Pasco JA et al (2014) Oxidative & nitrosative stress in depression: why so much stress? Neurosci Biobehav Rev 45:46–62

    CAS  PubMed  Google Scholar 

  68. 68.

    Geffard M, Bodet D, Martinet Y, Dabadie MP (2002) Detection of the specific IgM and IgA circulating in sera of multiple sclerosis patients: interest and perspectives. Immuno-Analyse & Biology Specification 17:302–310

Download references

Acknowledgements

The study was supported by the Asahi Glass Foundation, Chulalongkorn University Centenary Academic Development Project and Ratchadapiseksompotch Funds, Faculty of Medicine, Chulalongkorn University, grant numbers RA60/042 and RA61/050.

Author information

Affiliations

Authors

Contributions

All the contributing authors have participated in the manuscript. MM and BK designed the study. BK recruited patients and completed diagnostic interviews and rating scale measurements. MM carried out the statistical analyses. All authors (BK, SS, MM, and AC) contributed to the interpretation of the data and writing of the manuscript. All authors approved the final version of the manuscript.

Corresponding author

Correspondence to Michael Maes.

Ethics declarations

The study was conducted according to International and Thai ethics and privacy laws.

Conflict of Interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Maes, M., Kanchanatawan, B., Sirivichayakul, S. et al. In Schizophrenia, Deficits in Natural IgM Isotype Antibodies Including those Directed to Malondialdehyde and Azelaic Acid Strongly Predict Negative Symptoms, Neurocognitive Impairments, and the Deficit Syndrome. Mol Neurobiol 56, 5122–5135 (2019). https://doi.org/10.1007/s12035-018-1437-6

Download citation

Keywords

  • Immune
  • Inflammation
  • Natural IgM autoimmune
  • Oxidative stress
  • Kynurenine
  • Schizophrenia
  • Psychosis