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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