Complement C1q formation of immune complexes with milk caseins and wheat glutens in schizophrenia

Abstract

Immune system factors including complement pathway activation are increasingly linked to the etiology and pathophysiology of schizophrenia. Complement protein, C1q, binds to and helps to clear immune complexes composed of immunoglobulins coupled to antigens. The antigenic stimuli for C1q activation in schizophrenia are not known. Food sensitivities characterized by elevated IgG antibodies to bovine milk caseins and wheat glutens have been reported in individuals with schizophrenia. Here, we examined the extent to which these food products might comprise the antigen component of complement C1q immune complexes in individuals with recent onset schizophrenia (n=38), non-recent onset schizophrenia (n=61) and non-psychiatric controls (n=63). C1q seropositivity was significantly associated with both schizophrenia groups (recent onset, odds ratio (OR)=8.02, p≤0.008; non-recent onset, OR=3.15, p≤0.03) compared to controls (logistic regression models corrected for age, sex, race and smoking status). Casein- and/or gluten-IgG binding to C1q was significantly elevated in the non-recent onset group compared to controls (OR=4.36, p≤0.01). Significant amounts of C1q-casein/gluten-related immune complexes and C1q correlations with a marker for gastrointestinal inflammation in non-recent onset schizophrenia suggests a heightened rate of food antigens in the systemic circulation, perhaps via a disease-associated altered intestinal permeability. In individuals who are in the early stages of disease onset, C1q activation may reflect the formation of immune complexes with non-casein- or non-gluten-related antigens, the presence of C1q autoantibodies, and/or a dissociated state of immune complex components. In conclusion, complement activation may be a useful biomarker to diagnose schizophrenia early during the course of the disease. Future prospective studies should evaluate the impacts of casein- and gluten-free diets on C1q activation in schizophrenia.

Figure 1

Immunoassays to measure total C1q IgG levels and C1q-food antigen associated immune complexes. Panel A: The immunoassay employed to measure total C1q IgG will detect C1q-associated immune complexes and autoantibodies generated against the C1q protein. HRP refers to the horseradish peroxidase conjugate of the secondary antibody. Panel B: The immunoassay developed here will detect casein- and gliadin-bound IgG contained in C1q-associated immune complexes.

Figure 2

Disease association of C1q antibody levels and C1q seropositivity. Panel A: C1q IgG antibody levels are displayed in histogram form. RO refers to recent onset. Cut-off refers to the absorbance value corresponding to 90% in the control population. “o” refers to values considered to be seronegative and “+” refers to values that are considered to be seropositive. Panel B: The percentage of individuals who were seropositive for total C1q immunoreactivity is diagrammed here. The p-value listed refers to the level of statistical significance following multinomial logistic regressions corrected for age, sex, race and smoking status. Diagnosis is the dependent variable and C1q seropositivity is the independent variable in these regressions. OR refers to odds ratio.

Figure 3

Prevalence of C1q-associated casein- and gliadin-IgG immune complexes per diagnosis and odds ratio association for disease. The percentage of individuals who were seropositive for immune complexes containing these food antigens is diagrammed here. RO refers to recent onset. OR refers to odds ratio. The p-value listed refers to the level of statistical significance following multinomial logistic regressions corrected for age, sex, race and smoking status.