An Investigation into the Gliadin-Specific Immune Response in Schizophrenia
A link between gluten consumption and the development of schizophrenia has been described in the literature. Furthermore increased levels of circulating antibodies directed against the gluten component, known as gliadin, have been observed in patients with schizophrenia. All studies reported to date measured antibodies against a mixture of native gliadin protein molecules, whereas dietary gliadin is partially digested, resulting in relatively long, indigestible, peptide fragments. In this study, levels of plasma antibodies against indigestible gliadin fragments were measured using an Enzyme-linked Immunosorbent Assay using a total of 405 archived plasma samples collected from patients with schizophrenia (n=169, 132 males and 37 females, aged 42.0 ± 13.3 years) and control subjects (n = 236, 159 males and 77 females, aged 44.7 ± 12.5 years). Patients were recruited from the North of Scotland in the period between 2003 and 2008 by NHS Grampian under Professor David St. Clair. Based on a genome-wide association study, 4 single nucleotide polymorphisms (SNPs) of interest were genotyped and their association with schizophrenia determined. Previously genotyped Human Leukocyte Antigen-DQ (HLA-DQ) variant data were also used to analyse HLA-DQ associations with plasma anti-gliadin antibody levels (AGA). Two cell-line based models were used to examine the effects of gliadin peptide incubation on cell maturation and/or differentiation of antigenpresenting cells. The main finding of this thesis is that levels of plasma IgG against a γ-gliadin fragment, designated AAQ6C, are elevated in serum samples from patients with schizophrenia. Furthermore the gliadin-derived peptides were able to induce the maturation of a dendritic celllike model, albeit with a reduced pro-inflammatory phenotype. A link between HLA-DQ variants and AGA remains elusive, despite the associations described in this thesis. This thesis concludes that an immune response against AAQ6C is associated with schizophrenia. Although the mechanistic implications of this finding are unclear, it suggests that pathological contributions are unlikely to be mediated by cross-reactivity to proteins in the 4 central nervous system. The ability of the peptide antigens to induce the maturation of dendritic cells demonstrated that these peptides have immunogenic activity. The broader implications of this could be assessed with studies of the immunological response to gliadin peptides in the context of schizophrenia through the use of primary cell models.
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