Brain antibodies in the cortex and blood of people with schizophrenia and controls

L J Glass,P Tooney,D Brown,D Sinclair,S J Fung,V S Catts,M O'Donnell,C Shannon Weickert,K Naude,T W Weickert,D Boerrigter,D Liu,C Galletly,R Lenroot

doi:10.1038/tp.2017.134

Abstract

The immune system is implicated in the pathogenesis of schizophrenia, with elevated proinflammatory cytokine mRNAs found in the brains of ~40% of individuals with the disorder. However, it is not clear if antibodies (specifically immunoglobulin-γ (IgG)) can be found in the brain of people with schizophrenia and if their abundance relates to brain inflammatory cytokine mRNA levels. Therefore, we investigated the localization and abundance of IgG in the frontal cortex of people with schizophrenia and controls, and the impact of proinflammatory cytokine status on IgG abundance in these groups. Brain IgGs were detected surrounding blood vessels in the human and non-human primate frontal cortex by immunohistochemistry. IgG levels did not differ significantly between schizophrenia cases and controls, or between schizophrenia cases in ‘high’ and ‘low’ proinflammatory cytokine subgroups. Consistent with the existence of IgG in the parenchyma of human brain, mRNA and protein of the IgG transporter (FcGRT) were present in the brain, and did not differ according to diagnosis or inflammatory status. Finally, brain-reactive antibody presence and abundance was investigated in the blood of living people. The plasma of living schizophrenia patients and healthy controls contained antibodies that displayed positive binding to Rhesus macaque cerebellar tissue, and the abundance of these antibodies was significantly lower in patients than controls. These findings suggest that antibodies in the brain and brain-reactive antibodies in the blood are present under normal circumstances.

Highlights

There is increasing evidence of immune abnormalities in people with schizophrenia
In the blood, increased concentration of cytokines, interferon (IFN)-γ, interleukin (IL)-1β, soluble IL-2 receptor, IL-6, IL-12, transforming growth factor (TGF)β and tumor necrosis factor (TNF)-α, are found in people with schizophrenia when compared to controls.[1,2]
Dorsolateral prefrontal cortex (DLPFC), increased mRNA expression of IL-6, IL-1β and IL-8 cytokines can be found in some people with schizophrenia.[3,4,5,6]

Summary

Introduction

There is increasing evidence of immune abnormalities in people with schizophrenia. In the blood, increased concentration of cytokines, interferon (IFN)-γ, interleukin (IL)-1β, soluble IL-2 receptor (sIL-2R), IL-6, IL-12, transforming growth factor (TGF)β and tumor necrosis factor (TNF)-α, are found in people with schizophrenia when compared to controls.[1,2] In the brain, dorsolateral prefrontal cortex (DLPFC), increased mRNA expression of IL-6, IL-1β and IL-8 cytokines can be found in some people with schizophrenia.[3,4,5,6] Transcript levels of various immune regulators and their chaperone proteins are altered in the prefrontal cortex of subjects with schizophrenia.[7,8] Antipsychotic medications can have immunomodulatory effects,[9,10,11] often lowering cytokine levels in addition to alleviating positive symptoms of schizophrenia. Blood levels of IL-1β, IL-6, IL-12, IFN-γ, TNF-α, sIL-2R and TGF-β have been found to be elevated in unmedicated first-episode psychosis[1,9,12] and chronically medicated patients,[13,14] indicating that antipsychotic treatment neither solely explains, nor completely remediates, immune activation in schizophrenia. To date, it is unclear whether antibodies play a role in immune dysregulation in schizophrenia. Playing an integral part in the secondary immune response, IgG antibodies bind complement, facilitate phagocytosis through opsonization, and direct cytotoxic activities of natural killer cells.[15]

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