Reaction to gluten can involve either an allergic reaction (wheat allergy) or a nonallergic response (gluten sensitivity) or an autoimmune response in subjects genetically predisposed (CD). The most important finding of this study is the elevated proportion of schizophrenia patients, compared with a comparison sample of individuals not selected for schizophrenia, with moderate to high titer of AGA of the IgA type indicating the existence of a specific immune response to gluten in this population. One out of 4.3 people with schizophrenia was positive for IgA-AGA as compared with only one out of 32.1 in the control population.
A preliminary study,27
based on a small number of patients and controls (N
13), reported a “median” increase in specific IgA-AGA in patients with a Diagnostic and Statistical Manual of Mental Disorders
(Third Edition Revised) (DSM-III-R
) diagnosis of schizophrenia. Interestingly, the increase in IgA-AGA was the same in a control group of patients free of neuroleptic treatment for 3 months indicating that the IgA elevation was independent from medications. No difference in IgA-AGA level was observed when the patients were divided into clinical subtypes. The study's relevance is limited by the small sample size and the lack of comparison prevalence data. Another study28
found decreased levels of IgA and IgG in response to cell constituents like actin, tubulin, and myosin in the serum of DSM-III-R
patients with schizophrenia, but AGA was not measured. This last finding seems to suggest a lesser damage to cells in patients with schizophrenia compared with normal controls.
If we consider the serologic test combination representing CD (ie, EMA and/or tTG plus AGA-IgA), the calculated prevalence (N
29) in the CATIE schizophrenia sample is 2.1%, more than double of the general population estimate. Previous estimates of CD in schizophrenia have indicated a proportion of 2.6%.19
Because most studies examining CD in schizophrenia, published to date, did not use optimally sensitive detection methods, like the assay for tTG antibodies developed in the late 90s,23
they are likely to have underestimated the true proportion positive. A recent study reported results solely on the presence of anti-EMA and not other markers for CD or gluten sensitivity. This study showed no positive cases in the 50 subjects sampled.29
The same was found in a population-based study that showed no association between CD and a diagnosis of schizophrenia.30
A recent Scandinavian report31
showed an association of CD diagnosed according to International Classification of Diseases, Eighth, Ninth, and Tenth Revisions
, criteria and risk of nonaffective psychosis but not schizophrenia.
These findings are consistent with our results from the CATIE sample that has showed a moderately increased prevalence of tTG antibodies, a dramatically increased prevalence of AGA-IgA, and a low prevalence of anti-EMA. A possible explanation for this discrepancy is that, while both assays detect antibodies against the same autoantigen (transglutaminase), the tTG assay is an ELISA test (more sensitive) compared with the operator-dependent anti-EMA antibody test (immunofluorescence assay). It is also possible that patients with schizophrenia suffer from mild intestinal tissue damage, as subjects with milder intestinal tissue damage are thought to test positive for tTG and negative with EMA. Another explanation could be related to the existence of an extraintestinal source of tTG in the CATIE population given that the discrepancy between the 2 tests is usually detected in specific autoimmune diseases, such as type 1 diabetes, autoimmune hepatitis, and autoimmune thyroid conditions.32
We believe that the most likely explanation is that patients with schizophrenia suffer from mild intestinal tissue damage that might also be consistent with the extremely low number of EMA-positive cases found in this study. A recent study33
has showed that subjects with gluten sensitivity have normal intestinal permeability and normal expression of tight junction proteins suggesting a different pathogenic mechanism from CD.
The serologic characterization of our sample appears to identify 2 groups of patients. The major group is represented by patients with elevated AGA-IgA identifiable as having gluten sensitivity and the second group with a smaller but still unusually high proportion with a combination of antibodies more characteristic of CD (ie, EMA and/or tTG plus AGA-IgA). Although it is unknown why there is a preferential immunologic response with IgA to gluten constituents by patients with schizophrenia while normal controls respond with both IgA and IgG in almost equal percentages (3.3% IgG and 3.1% IgA in controls vs 1.4% IgG and 23.1% IgA in CATIE patients), we can hypothesize that a subgroup of patients with schizophrenia might have a genetically regulated mechanism that favors the switch of immunoglobulin response toward IgA. Alternatively, this subgroup of patients might have an increased concentration of transforming growth factor β (TGF-β) that usually regulates the switch toward the production of IgA,34
or altered levels of cytokines like interleukin (IL)-13 that stimulate the production of TGF-β35
might be invoked to explain our findings.
An association between CD and schizophrenia was noted in reports spanning back to the 1950s.36,37
An interpretation of these early findings was that gluten may serve as an environmental trigger for schizophrenia in genetically susceptible individuals and that patients with schizophrenia share one or more genes with CD.38
The majority of individuals with CD possess HLA-DQ2 (DQA1*05/DQB1802 haplotype) and the remainder HLADQ8 (DQA1*0301/DQB1*0302 haplotype).39
Schizophrenia has also been associated with HLA-DQB140
though the results have been more controversial compared with CD and the initial findings not always replicated41,42
raising the possibility of a lack of association with this HLA locus or that the well-known heterogeneity of schizophrenia may have confounded the results. Genetic linkage studies for non-HLA loci for CD and for schizophrenia suggest otherwise several areas of overlap. A genetic marker, 6p23-p22.3, implicated in CD in a study in western Ireland43
is adjacent to the dysbindin locus (6p22.3), which has been implicated in schizophrenia in an independent study of the same population.44
Recent studies have also shown susceptibility regions for CD in chromosome 11q2345
that overlaps with a potential schizophrenia susceptibility region.46
A more recent study has suggested MY09B marker for both diseases on chromosome 19 though the value of this finding is difficult to interpret given that variants were located at the intron and not the exon of the gene.47
A genome-wide association study for CD has identified risk variants in the region harboring cytokines IL-2 and IL-2148
indicating a potential overlap with reported abnormal cytokines functioning in schizophrenia including IL-2.49
Schizophrenia is conceptualized by many as a heterogeneous disorder. A growing literature suggests that immune mechanisms are responsible for schizophrenia or some proportion of it. The literature includes epidemiologic data showing that a history of autoimmune disease in the subject, or in the parent, prior to onset, raises risk for schizophrenia by 45%.17
Limitations of this study include its retrospective nature and the use of a historical control group not drawn from the same area or at the same time of the CATIE population. As already stated, wheat consumption in the United States is thought to be evenly distributed, so it is unlikely that the CATIE sample wheat consumption was different from that of the control group such that our findings would be explained by exposure to different environmental factors. A second limitation is the lack of confirmatory biopsy in those case subjects who met criteria for CD based on serum tests. Another limitation is the use of different diagnostic kits for tTG analysis though the data cannot be explained on the basis of the different kits used given that both use equivalent methods for antibody detection.
There are numerous comparisons of immunologic parameters of persons with schizophrenia to healthy persons, with results of varying consistency across different studies. Our results confirm the existence of a subgroup of patients with antibody characteristics associated with the presence of a specific immune response to gluten. We have failed to identify clinical aspects associated with such immune response. Nonetheless, the findings may have potential implications for the treatment of these subjects given that a gluten-free diet can contribute to the improvement of their symptoms.