Novel immune response to gluten in individuals with schizophrenia

Abstract

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.

Introduction

There is increasing evidence for the involvement of immunologic factors in schizophrenia (Patterson, 2008, Torrey and Yolken, 2001). Among the various reported immunologic abnormalities, increased immune sensitivity to gluten and association with celiac disease have been described in several reports (Bender, 1953, Cascella et al., 2009, Dohan et al., 1972, Graff and Handford, 1961, Jin et al., 2008, Reichelt and Landmark, 1995). Glutens, made up of two main fractions, gliadins and glutenins, are the main storage proteins of wheat and are comprised of about 100 different proteins in a given wheat cultivar (variety). When the various wheat cultivars are considered, the number of different gluten proteins is even greater, although almost all cultivars are made up of the same main types, α-type (also known as α/β type), γ-type, ω-type, low-molecular-weight glutenin subunits, and high-molecular-weight glutenin subunits (Jabri et al., 2005). Gluten sensitivity may be defined as a state of heightened immune response to ingested gluten, the most common clinical manifestation of which is celiac disease, an inflammatory enteropathy that is characterized by villous atrophy and lymphocytic infiltration in the small intestine in genetically predisposed individuals (Alaedini and Green, 2005). Genetic susceptibility for celiac disease is associated with close genetic linkage to class II human leukocyte antigens (HLA) DQ2 (DQA1 *05/DQB1 02) and DQ8 (DQA1 *0301/DQB1 *0302) that are involved in the presentation of gluten peptides to T cells (Louka and Sollid, 2003). Presence of antibodies to gluten and to the enzyme transglutaminase 2 (TG2) is a hallmark of celiac disease. The TG2 protein is an important element of the disease, not only as a target autoantigen, but also as an enzyme that enhances the immunostimulatory effect of gluten peptides through the deamidation and conversion of glutamines to glutamate residues (Briani et al., 2008). In fact, antibodies to selectively deamidated gluten are now known to be more specific for celiac disease than antibodies against the native species (Mothes, 2007, Naiyer et al.,).

The clinical presentation of celiac disease is highly variable, ranging from asymptomatic to severe malnutrition. In the now commonly diagnosed atypical form, gastrointestinal symptoms may be absent or less pronounced, while patients present with extra-intestinal features such as anemia, osteoporosis, short stature, and infertility (Alaedini and Green, 2005). Neurologic and psychiatric abnormalities have also been reported to be associated with celiac disease in various studies (Bushara, 2005). In addition, elevated levels of anti-gliadin antibody have been associated with some of these deficits, even in the apparent absence of the characteristic mucosal pathology (Burk et al., 2001, Bushara et al., 2001, Hadjivassiliou et al., 1998). The current literature indicates shared immunologic abnormalities and genetic associations between schizophrenia and celiac disease and is suggestive of an elevated relative risk of non-affective psychosis in celiac patients (Jungerius et al., 2008, Kalaydjian et al., 2006, Wei and Hemmings, 2005). A number of case studies and small trials indicate significant positive response to gluten-free diet in some individuals with schizophrenia (Kalaydjian et al., 2006). However, methodological shortcomings in some of these studies and contradictory findings by other groups have led to a lack of consensus on the relevance of gluten in schizophrenia (Kalaydjian et al., 2006). Specifically, the prevalence of true celiac disease versus anti-gliadin antibodies in patients with schizophrenia is a subject of contention. In addition, little is known about the specificity and mechanism of the immune response to gluten in these patients, or its role in disease pathogenesis. The aim of this study was to investigate the link between gluten sensitivity and schizophrenia by characterizing the immune response in patients and control subjects. Our results reveal an immunologic response to gluten in individuals with schizophrenia that is clearly different from that in celiac disease.