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 al., 2009
; Stefansson et al., 2009
). Dating back to the 1950s, schizophrenia has been linked to anti-gliadin antibodies and celiac disease in several studies (Bender, 1953
; Cascella et al., 2009
; Dohan et al., 1972
; Graff and Handford, 1961
; Jin et al., 2008
; Reichelt and Landmark, 1995
). A number of case reports and small trials also indicate significant positive response to gluten-free diet in some individuals with schizophrenia (Kalaydjian et al., 2006
). Considering the limited response to traditional therapies by many individuals with schizophrenia and the side effects of current treatments, identification of a subset of patients who might benefit from an effective dietary approach without significant side effects would represent an important step forward in the understanding and treatment of the disease. However, the currently limited knowledge of the significance of anti-gliadin antibodies in the context of schizophrenia in general, combined with the results of a number of studies that do not support a link with celiac disease, have cast doubt on the relevance of gluten and gluten sensitivity to schizophrenia (Lambert et al., 1989
; Ludvigsson et al., 2007
In this study, our aim was to address these issues by assessing the prevalence of celiac disease-associated biomarkers and through the characterization of the anti-gluten immune response at the molecular level in individuals with schizophrenia and elevated anti-gliadin antibodies and in control subjects. We found no correlation between elevated anti-gliadin antibodies and the presence of increased anti-TG2 antibody levels or celiac-associated HLA genes in individuals with schizophrenia. Considering the high negative predictive value of the anti-TG2 antibody and HLA markers for celiac disease, it can be concluded with high certainty that the majority of these patients do not have celiac disease. We have also shown that the anti-gliadin antibody responses in celiac disease and gluten-sensitive individuals with schizophrenia are not necessarily directed at the same molecules. Equally interesting is the finding that the antibodies in schizophrenia do not appear to show significant affinity for deamidated gliadin peptides, again implying the absence of celiac disease in the majority of gluten-sensitive individuals with schizophrenia. As such, the anti-gluten immune response in schizophrenia patients is likely to be independent of the TG2 enzyme and to not require HLA-DQ2 and/or -DQ8 molecules for driving the process of antigen presentation and antibody production.
It is important to note that the sample size in this study is not large enough to exclude the possibility of celiac-associated markers (HLA-DQ2/DQ8 genes, anti-TG2 antibodies, anti-deamidated gliadin antibodies), and thereby celiac disease, being more prevalent in schizophrenia patients than in normal healthy individuals. However, it is adequately large to determine with high certainty that unlike in celiac disease, the anti-gluten immune response in schizophrenia is not associated with the above-mentioned biomarkers and therefore does not imply celiac disease in the overwhelming majority of individuals. This agrees with the results of a recently published large study, which found that most schizophrenia patients with elevated anti-gliadin antibody titers do not have anti-TG2 and anti-endomysial antibodies (Cascella et al., 2009
). Nevertheless, anti-TG2 antibodies were reported to be found in 5.4% of schizophrenia patients versus 0.80% of the control group, implying increased prevalence of celiac disease among schizophrenia patients. However, this finding contradicts the absence of any difference in the incidence of anti-endomysial antibody between the two groups in the same study. Antibodies to endomysial tissue primarily target the TG2 enzyme and a very high correlation between anti-TG2 and anti-endomysial antibodies has been established previously (Rostom et al., 2006
The observation that some schizophrenia patients have elevated anti-gliadin antibodies is intriguing. While the majority of these individuals do not appear to have celiac disease, the presence of antibodies to gluten points to the existence of shared mechanisms with celiac disease. Increased intestinal permeability, a presumed essential event in the triggering of celiac disease, may be one such factor. In fact, abnormal intestinal permeability in the absence of established bowel disease has been described in some individuals with chronic psychiatric disorders (Wood et al., 1987
). More recent studies indicate that common variants of the gene myosin IXB (MYO9B
), which encodes a myosin molecule involved in actin remodeling of epithelial enterocytes, might be associated with an increased risk of developing celiac disease and schizophrenia (Jungerius et al., 2008
; Monsuur et al., 2005
). If confirmed by other investigators, the reported shared genetic susceptibility would shed light on the mechanism of impairment of the epithelial barrier in at least a subset of celiac and schizophrenia patients and partly explain the prevalence of the immune response to gluten peptides, albeit being targeted at different protein species and epitopes, in both diseases.
Can the observed anti-gliadin antibodies have a role in the etiopathogenesis of schizophrenia in some patients? While antibodies to gluten have not been shown to have a pathogenic role in any disease, some possibilities may be considered. Antibodies to foreign proteins have been shown to cross-react with certain self antigens and elicit disease (Raveche et al., 2005
; Yuki et al., 2004
). As such, they can act as autoantibodies and have the potential to exert a pathogenic effect through various mechanisms, including direct interaction with their target, activation of complement, or binding to Fc receptors on macrophages, neutrophils, and other immune cells (Alaedini and Green, 2008
; Dalakas, 2008
). Antibodies can also be involved in disease pathogenesis through the activation of toll-like receptor pathways and secretion of various inflammatory molecules that affect the function of other cells, some of which could very well have a role in cognitive and neurodevelopmental defects (Crow, 2007
; Nawa and Takei, 2006
). The reported association of elevated titers of antibodies against different pathogens with impaired cognitive function in schizophrenia might be influenced by such a mechanism (Shirts et al., 2008
). Alternatively, the antibody response might not play any role itself, instead being only indicative of the presence of immunogenic gluten peptides in the circulation. Increased urinary excretion of gluten peptides in patients with schizophrenia has been observed previously (Reichelt and Landmark, 1995
). Referred to as gluten exorphins, these peptides have been shown to have potent opioid-like properties and to affect hormonal balance, behavior, and learning in animal models (Fanciulli et al., 2005
; Fanciulli et al., 2002
; Takahashi et al., 2000
). Therefore, the reported effect of gluten-free diet in some patients might be explained by the direct role some gluten peptides can exert on the nervous system.
Increased levels of anti-gliadin antibodies in schizophrenia point to a mechanism involving the disruption of intestinal permeability and immunologic abnormalities in some individuals with schizophrenia. However, the mechanism of the observed antibody reactivity to gluten in schizophrenia appears to be fundamentally different from celiac disease. As such, the heightened immune response to gluten deserves further attention and research in determining its importance and relevance to the pathogenesis of schizophrenia, independent of concomitant celiac disease. Further detailed characterization of the antibody response to gluten and other dietary proteins of concern, including casein, is likely to enhance our understanding of the significance of the immune system and its response to foreign antigens in schizophrenia and other neuropsychiatric abnormalities. The elucidation of this relationship may lead to new methods for the diagnosis, prevention, and treatment of schizophrenia and related disorders.