Novel immune response to gluten in individuals with schizophrenia
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.
Section snippets
Subjects
Serum samples from 17 individuals with schizophrenia (9 female, 8 male; mean age 37.6 ± 3.0 y), selected because of previously documented elevated IgG and IgA antibodies to gliadin (hereon referred to as gluten-sensitive individuals with schizophrenia), were studied. The initial screening of patients for antibodies to gliadin had been done using a commercially available ELISA kit (IBL International). The characteristics of the population from which these individuals were selected have been
Anti-gliadin antibody
The levels of IgG and IgA anti-gliadin antibodies were compared in schizophrenia and celiac disease subjects who were previously found to be positive. As depicted in Fig. 1, the levels of IgG and IgA anti-gliadin antibodies were lower in the schizophrenia group as compared to the celiac disease group (P < 0.05 for IgG, P < 0.005 for IgA).
Anti-TG2 antibody
IgA antibodies against human TG2, which have a high sensitivity and specificity for celiac disease, were measured in all gluten-sensitive patients and controls.
Discussion
Schizophrenia is a complex disorder affecting approximately 1% of the population and is caused by a combination of genetic and environmental factors. The immune system is believed to play a considerable role in the disease process. Recently-reported single nucleotide polymorphism (SNP)-based genome-wide studies in schizophrenia populations show significant association with several markers spanning the major histocompatibility complex (MHC) region on chromosome 6 (Purcell et al., 2009, Shi et
Role of funding source
This work was supported by The Stanley Medical Research Institute Grant 08R-2061 and NIH-National Institute of Neurological Disorders and Stroke Grant 5R21NS055323-02. The funding agencies had no role in the study design, collection, analysis, interpretation of data, writing of the report, or the decision to submit the paper for publication.
Contributors
A. Alaedini and R. Yolken designed the study. All authors were involved in the acquisition, analysis, and interpretation of data. A. Alaedini and D. Samaroo undertook the statistical analyses and wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript.
Conflict of interest
All authors report no competing interests.
Acknowledgement
We thank Dr. Mary Ann Gawinowicz at the Protein Core Facility of Columbia University for mass spectrometric analyses and insightful discussions. We would also like to thank Ms. Maria Minaya for assistance in collecting and organizing the celiac disease specimens, and Ms. Nancy Laird for technical assistance in the preparation of gluten samples. We are grateful to all the participants involved in this project.
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