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

Abstract

Deficit schizophrenia is accompanied by mucosa-associated activation of the tryptophan catabolite (TRYCAT) pathway, as indicated by increased IgA responses to noxious (NOX) TRYCATs, but not regulatory or protective (PRO) TRYCATs, suggesting increased neurotoxic, excitotoxic, inflammatory, and oxidative potential. No previous studies examined IgM-mediated autoimmune responses to the TRYCAT pathway in deficit versus nondeficit schizophrenia. We measured IgM responses to NOX TRYCATs, namely, quinolinic acid (QA), 3-OH-kynurenine (3HK), picolinic acid (PA), and xanthurenic (XA) acid, and PRO TRYCATs, including kynurenic acid (KA) and anthranilic acid (AA), in 40 healthy controls and 40 deficit and 40 nondeficit schizophrenic patients. We computed the IgM responses to NOX (QA + PA + 3HK + XA)/PRO (AA + KA) ratio and ∆ differences in IgA - IgM TRYCAT values and NOX/PRO ratio. Deficit schizophrenia is characterized by significantly attenuated IgM responses to all TRYCATs and NOX/PRO ratio and highly increased ∆IgA - IgM NOX/PRO ratio as compared to nondeficit schizophrenia and healthy controls. The negative symptoms of schizophrenia are significantly and positively associated with increased IgM responses directed against the KA/3HK ratio and ∆IgA - IgM NOX/PRO ratio. The findings support the view that deficit schizophrenia is a distinct subtype of schizophrenia that may be significantly discriminated from nondeficit schizophrenia. Deficit schizophrenia is accompanied by a highly specific defect in IgM isotype-mediated regulatory responses directed to the TRYCAT pathway. Lowered IgM regulatory responses together with mucosa-derived activation of the TRYCAT pathway may contribute to neuroprogression, negative symptoms, and deficit schizophrenia. All in all, a highly specific defect in the compensatory (anti-)inflammatory reflex system (CIRS), namely, natural IgM-mediated regulatory responses, may underpin deficit schizophrenia.

Natural regulatory IgM‐mediated autoimmune responses directed against malondialdehyde regulate oxidative and nitrosative pathways and coupled with IgM responses to nitroso adducts attenuate depressive and physiosomatic symptoms at the end of term pregnancy

“…IgM antibody responses are highly inducible and upregulation of IgM autoantibody levels is one of the strategies for survival through regulation of inflammatory responses in chronic responses . Therefore, IgM responses to MDA may be part of the compensatory anti‐inflammatory responses system . The results of the present study suggest that attenuated natural IgM‐mediated autoimmune responses during pregnancy are accompanied by lowered regulation and thus increased susceptibility to protein oxidation and elevated NO production.…”

“…51,59 Decreased IgM levels also occur in various neuropsychiatric disorders, including Alzheimer's disease, deficit schizophrenia, and bipolar disorder. 52,60,61 The third major finding of this study is that a history of mood disorders is positively associated with end of term DPSS and IgM responses to NO adducts, whilst the latter negatively impact on DPSS. These findings corroborate previous reports that mood disorders are accompanied by elevated IgM responses to nitrosylated proteins, suggesting that these IgM responses are a trait marker of depression.…”

“…51 Therefore, IgM responses to MDA may be part of the compensatory antiinflammatory responses system. 18,52 The results of the present study suggest that attenuated natural IgM-mediated autoimmune responses during pregnancy are accompanied by lowered regulation and thus increased susceptibility to protein oxidation and elevated NO production. Previously, we found that non-pregnant major depression is accompanied by increased IgM responses to MDA, 30 suggesting that non-pregnant major depression is accompanied by increased natural autoimmune responses, which tend to downregulate the primary immunoinflammatory response.…”

“…Patients with SLE generally have lower IgM levels than controls but a higher number of apoptotic cells in the circulation . Decreased IgM levels also occur in various neuropsychiatric disorders, including Alzheimer's disease, deficit schizophrenia, and bipolar disorder …”

Supervised machine learning to decipher the complex associations between neuro-immune biomarkers and quality of life in schizophrenia

“…At 8.00 a.m. fasting blood was sampled the same day we completed interviews and CERAD tests. Blood was frozen at -80 o C until thawed for assay of IgA and IgM responses directed to QA, 3HK, PA, XA, KA and AA (Kanchanatawan et al, 2018b;2018c). Briefly, "The 6 TRYCATs were dissolved in 200 μL dimethylsulfoxide (DMSO) (Acros).…”