The Role of Aberrations in the Immune-inflammatory Reflex System (IRS) and the Compensatory Immune-regulatory Reflex System (CIRS) in Different Phenotypes of Schizophrenia: The IRS-CIRS Theory of Schizophrenia

Abstract

In this paper we propose a novel theoretical framework, which was previously developed for major depression and bipolar disorder, namely the compensatory immune-regulatory reflex system (CIRS), as applied to the neuro-immune pathophysiology of schizophrenia and its phenotypes, including first episode psychosis (FEP), acute relapses, chronic and treatment resistant schizophrenia (TRS), comorbid depression, and deficit schizophrenia. These schizophrenia phenotypes and manifestations are accompanied by increased production of positive acute phase proteins, including haptoglobin and α2-macroglobulin, complement factors, and macrophagic M1 (IL-1β, IL-6 and TNF-α), T helper (Th)-1 (interferon-γ and IL-2R), Th-2 (IL-4, IL-5), Th-17 (IL-17) and T regulatory (Treg; IL-10 and transforming growth factor (TGF)-β1) cytokines, cytokine-induced activation of the tryptophan catabolite (TRYCAT) pathway as well as chemokines, including CCL-11 (eotaxin), CCL-2, CCL-3 and CXCL-8. While the immune profiles in the different schizophrenia phenotypes indicate activation of the immune-inflammatory response system (IRS), there are simultaneous signs of CIRS activation, including increased levels of the IL-1 receptor antagonist (sIL-1RA), sIL-2R and tumor necrosis factor-a receptors, Th-2 and Treg phenotypes with increased IL-4 and IL-10 production, and increased levels of TRYCATs and haptoglobin, α2-macroglobulin and other acute phase reactants, which have immune-regulatory and anti-inflammatory effects. Signs of activated IRS and CIRS pathways are also detected in TRS, chronic and deficit schizophrenia indicating that these conditions are accompanied by a new homeostatic setpoint between upregulated IRS and CIRS components. In FEP, increased baseline CIRS activity is a protective factor which may predict favorable clinical outcomes. Moreover, impairments in the CIRS are associated with deficit schizophrenia and greater impairments in semantic and episodic memory. It is concluded that CIRS plays a key role in the pathophysiology of schizophrenia by negatively regulating the primary IRS and contributing to recovery from the acute phase of illness. Components of the CIRS may offer promising therapeutic targets for schizophrenia.

In Schizophrenia, PON1 Q192R Genotypes and/or Lowered Paraoxonase 1 (PON1) Enzymatic Activity are Significantly Associated with the Deficit Syndrome, Negative Symptoms, Formal Thought Disorders, Psychomotor Retardation, Excitation and Increased IgA Levels to Gram-Negative Microbiota

“…SCZ is accompanied by activation of the immune-inflammatory response system (IRS) and IRS biomarkers are significantly associated with negative and psychotic symptoms as well as cognitive impairments (Maes et a., 1994;1997;Brinholi et al, 2015;Kanchanatawan et al, 2018a;Sirivichayakul et al 2019a;Maes et al, 2019b;2019d). The current theory is that products of immune activation, including M1 macrophage, T helper (Th)-1 and Th-2 subsets exert neurotoxic effects on neuronal cell in the brain thereby inducing neuroprogression including neurocognitive deficits and symptoms of SCZ and DS (Noto et al, 2019;Roomruangwong et al, 2019). For example, the cytotoxic and neurotoxic properties of increased tryptophan catabolites (TRYCATs) such as picolinic acid, xanthurenic acid, and quinolinic acid are further augmented by increased levels of eotaxin (CLL11), a Th-2-related product, that may contribute to neurocognitive deficits, negative symptoms, and the overall severity of SCZ (OSOS) 2019d).…”

In Schizophrenia, Increased Plasma Igm/Iga Responses to Gut Commensal Bacteria are Associated with Negative Symptoms, Neurocognitive Impairments and the Deficit Phenotype

“…There is now evidence that first episode psychosis (FEP) and acute psychotic relapses as well as chronic schizophrenia, treatment resistant and stable-phase schizophrenia are characterized by activation of the immune-inflammatory response system (IRS) (Smith and Maes, 1995;Anderson and Maes, 2013;Roomrunagwong et al, 2018b;Miller et al, 2011). The findings indicate an acute phase response, with increased levels of positive acute phase proteins, increased complement factors, and activation of M1 macrophagic, T helper (Th)-1 and Th-17 immune cell phenotypes (Maes et al, 1997b;Roomruangwong et al, 2018b).…”

“…These schizophrenia phenotypes are not only accompanied by an activated IRS, but also by a concomitant activation of the compensatory immune-regulatory responses system (CIRS) including activated Th-2 and T regulatory (Treg) immune phenotypes and increased levels of soluble cytokine receptor levels that have immune regulatory effects, such as soluble interleukin-2 receptor (sIL-2R), soluble tumor necrosis factor (sTNF-R)1 and sTNF-R2, and sIL-1R antagonist (sIL-1RA) levels (Roomruangwong et al, 2018b). As such, the CIRS exerts many immuneregulatory and anti-inflammatory activities, which tend to downregulate the IRS (Roomruangwong et al, 2018b). This is important since immune products of the IRS (IL-6, IL-1, TNF-α) as well as the CIRS (IL-4, IL-13, CCL-11 or eotaxin) may exert cytotoxic and neurotoxic effects thereby driving neuroprogression (Davis et al, 2014;Noto et al, 2018;Roomruangwong et al, 2018b;.…”

“…As such, the CIRS exerts many immuneregulatory and anti-inflammatory activities, which tend to downregulate the IRS (Roomruangwong et al, 2018b). This is important since immune products of the IRS (IL-6, IL-1, TNF-α) as well as the CIRS (IL-4, IL-13, CCL-11 or eotaxin) may exert cytotoxic and neurotoxic effects thereby driving neuroprogression (Davis et al, 2014;Noto et al, 2018;Roomruangwong et al, 2018b;.…”

“…Distinct schizophrenia-related phenotypes including FEP are characterized by a significantly elevated IRS / CIRS ratio, indicating a net immune-inflammatory response that does not appear to be sufficiently attenuated by an activated CIRS (Noto et al, 2018;Roomruangwong et al, 2018b). Moreover, schizophrenia is accompanied by deficits in the CIRS and hence more prominent IRS responses after immune challenges ( Noto et al, 2018;Roomruangwong et al, 2018b). For example, the levels of plasma Clara Cell secretory protein (CC16), an endogenous disulfide-bridged protein with protective and anti-inflammatory properties, are significantly decreased in schizophrenia patients ( Maes et al, 1996;1997a).…”