Dietary antigens, epitope recognition, and immune complex formation in recent onset psychosis and long-term schizophrenia

Stanley Division of Developmental Neurovirology, Department of Pediatrics, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Blalock 1105, Baltimore, MD 21287-4933, USA.
Schizophrenia Research (Impact Factor: 3.92). 03/2011; 126(1-3):43-50. DOI: 10.1016/j.schres.2010.12.001
Source: PubMed


Peptides derived from dietary antigens such as bovine milk caseins are opioid receptor ligands and contribute to schizophrenia-associated hyperpeptidemia and hyperpeptiduria. The IgG antibody response to bovine caseins is increased in schizophrenia and recent onset psychosis. To identify specific casein peptide sequences that are antigenic in patients vs controls, we measured serum IgG binding to 10-26 amino acid long linear epitopes of casein with immunoassays for the entire group (n=95 recent onset psychosis; n=103 long-term schizophrenia; n=65 control), and with peptide microarray libraries in a casein-sensitive subset (n=14 recent onset; n=10 control). In the entire group, we compared anti-casein peptide IgG vs anti-whole casein IgG and evaluated whether peptide immune complexes contributed to IgG binding results. Anti-whole casein IgG levels correlated with anti-casein peptide IgG in controls only (R2=0.17-0.25, p≤0.002-0.03). In recent onset psychosis, IgG binding to linear peptide sequences was significantly decreased 3.8-5.7-fold compared to controls in immunoassays (OR 0.18-0.26, p≤0.0001-0.001). In peptide microarrays, recent onset patients again showed significantly reduced IgG binding and fewer epitopes than controls (p≤0.00001-0.05). Anti-peptide IgG levels did not differ between patients with long-term schizophrenia and controls. Finally, significantly more recent onset individuals had casein peptide-IgG immune complexes than controls (OR 4.96, p≤0.001). These findings suggest an immunological specificity that differs in early vs later stages of neuropsychiatric diseases and an IgG saturation by casein-derived peptides that may in part explain the reduced IgG binding to small linear epitopes observed in these patients.

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    • "These findings gave convincing evidence that dysfunction of the immune system may be related to the pathogenesis of schizophrenia. Serological analyses have revealed increased levels of circulating antibodies to wheat gluten and milk casein in patients with schizophrenia (Reichelt and Landmark 1995; Dickerson et al. 2010; Cascella et al. 2011; Severance et al. 2011; Jin et al. 2012). It is possible that the HLA system could bridge the gap between the genetic predisposition and environmental triggers in the development of the illness. "
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    ABSTRACT: Schizophrenia is a complex mental disorder with unknown aetiology. Both candidate gene and genome-wide association (GWA) studies suggest that the human leukocyte antigen (HLA) system may play a part in development of the illness, but the causal HLA variant(s) remain(s) unclear. Previous studies showed that the DRB1*0101 and DRB1*13 alleles might be associated with a high risk of schizophrenia. Therefore, the present study was undertaken to test their association with the disease by genotyping seven DRB1-tagging single nucleotide polymorphisms (SNPs) in a British population. The results showed that, of the previously reported variants that were associated with schizophrenia, the DRB1*1303 allele was the only one marginally associated with a protective effect on the illness in our sample set (χ 2 = 4.138, P = 0.042, odds ratio (OR) = 0.42, 95 % confidence interval (CI) 0.27–0.66). Interestingly, a significant association was found for rs424232 (χ 2 = 9.404, P = 0.002, OR = 0.69, 95 % CI 0.54–0.88), which is a tag SNP for the DRB1*1303 allele and located near to the NOTCH4 gene that is a schizophrenia susceptibility locus confirmed by GWA studies. Analysis with the Haploview program demonstrated that rs424232 was in complete linkage disequilibrium with rs3130297 and rs3131296 present in the NOTCH4 locus. While we have failed to confirm association of the candidate alleles in the DRB1 gene with a high risk of schizophrenia, the present work suggests that the association signal detected in the HLA class II locus may extend a relatively long distance, and more work is needed in order to identify the true causal variants within this region or nearby.
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    ABSTRACT: Hyperpeptiduria and opioid excess have been re-ported in schizophrenia. According to Prof. Dr. L. Lindström, Sweden opioids may explain the patho-physiology of this syndrome. Therefore it is critical to elucidate the presence and nature of opioids in schi-zophrenia and diagnostic sub groups. First morning urine from untreated schizoaffective patients (ICD-10: F 25.1) was separated on HPLC and peaks that elute where different opioid standards appear, freeze dried, re-dissolved in methanol/water (50/50) and 10 mM formic acid. Mass spectrometry and MS/MS or frag-mentation mass spectrometry was performed. We found fragmentation pattern of beta-casomorphin 1 -3 and 1 -4 (bovine) identical to synthetic standards from Bachem. The aggregation tendency of peptides was much in evidence. The reported exorphins were found in the urine from 8 of 12 untreated schizoaffec-tive patients.
    Full-text · Article · Jan 2012 · Open Journal of Psychiatry
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    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.
    No preview · Article · Jul 2012 · Neurobiology of Disease
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