A link between celiac disease and schizophrenia has been postulated for several years, based primarily on reports of elevated levels of antibody to gliadin in patients. We sought to examine the proposed connection between schizophrenia and celiac disease by characterizing the molecular specificity and mechanism of the anti-gliadin immune response in a subset of individuals with schizophrenia. Blood samples from individuals with schizophrenia and elevated anti-gliadin antibody titer were examined for celiac disease-associated biomarkers, including antibodies to transglutaminase 2 (TG2) enzyme and deamidated gliadin peptides, as well as the HLA-DQ2 and -DQ8 MHC genes. The anti-gliadin antibody response was further characterized through examination of reactivity towards chromatographically separated gluten proteins. Target proteins of interest were identified by peptide mass mapping. In contrast to celiac disease patients, an association between the anti-gliadin immune response and anti-TG2 antibody or HLA-DQ2 and -DQ8 markers was not found in individuals with schizophrenia. In addition, the majority of individuals with schizophrenia and anti-gliadin antibody did not exhibit antibody reactivity to deamidated gliadin peptides. Further characterization of the antibody specificity revealed preferential reactivity towards different gluten proteins in the schizophrenia and celiac disease groups. These findings indicate that the anti-gliadin immune response in schizophrenia has a different antigenic specificity from that in celiac disease and is independent of the action of transglutaminase enzyme and HLA-DQ2/DQ8. Meanwhile, the presence of elevated levels of antibodies to specific gluten proteins points to shared immunologic abnormalities in a subset of schizophrenia patients. Further characterization and understanding of the immune response to gluten in schizophrenia may provide novel insights into the etiopathogenesis of specific disease phenotypes.

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