Celiac Disease Comorbidity with Other Autoimmune Diseases


source : emedicine

The two most accredited theories to explain this comorbidity propose: (1) untreated celiac disease leads to the onset of other autoimmune disorders in genetically susceptible individuals or (2) this association is secondary to linkage disequilibrium of genes predisposing for both celiac disease and the associated autoimmune disease(s). The first hypothesis is supported by the evidence that tTG, the recognized autoantigen involved in the pathogenesis of celiac disease, seems to be only one of the autoantigens involved in gluten-dependent autoimmune reactions. Other autoantigens which are normally ‘cryptic’ can be unmasked and cause a self-aggressive immunological response following the gliadin-initiated inflammatory process.[3] In fact, persistent stimulation by some pro-inflammatory cytokines such as interferon-γ and tumor necrosis factor-α can cause further processing of autoantigens and their presentation to T lymphocytes by macrophage-type immunocompetent cells (so-called antigen-presenting cells). The phenomenon of antigen spreading has been described in well-defined natural models such as Type 1 diabetes (T1D), whose clinical manifestations appear after the patient has produced an autoimmune response to various autoantigens (i.e. anti-insulin, anti-β cell, etc.) and might also be present in celiac disease. This would explain the high incidence of autoimmune diseases and the presence of a large number of organ-specific autoantibodies in a certain number of celiac subjects on a gluten-containing diet.

The report by Ventura et al. [4] that studied the prevalence of autoimmune disorders in celiac disease in relation to the duration of exposure to gluten seems to support this theory. Over a 6-month period, 909 pediatric patients with celiac disease, 1268 healthy controls and 163 patients with Crohn’s disease were evaluated for the presence of autoimmune disorders. The authors[4] detected a prevalence of autoimmune disorders among celiac disease patients higher than in controls, but similar to that detected in Crohn’s disease patients. Prevalence of autoimmune disorders in celiac disease was increased with increasing age at diagnosis. In a logistic regression model, age at diagnosis was the only significant predictor variable of the odds of developing an autoimmune disorder.[4] Based on this evidence, the authors concluded that the prevalence of autoimmune disorders in celiac disease is related to the duration of exposure to gluten. The same group screened sera from 491 subjects with T1D, 824 relatives and 4000 healthy control subjects for antiendomysium antibodies (EMA), followed by confirmatory intestinal biopsy in positive subjects. The authors found that the prevalence of celiac disease was 5.7% among diabetic patients and 1.9% among relatives – values significantly higher than those found among control subjects.] The prevalence of autoimmune disorders in diabetic patients with celiac disease was significantly higher than in subjects with T1D alone. The prevalence of autoimmune disorders in relatives that were diagnosed with celiac disease was significantly higher than in those who tested negative for EMA. The authors concluded that it would be appropriate to routinely screen diabetic patients and their relatives for celiac disease in order to prevent the onset of additional autoimmune disorders.

A report from Cataldo and Marino suggest that the increased prevalence of autoimmune disorders is also increased in first-degree relatives of celiac disease patients. The authors reported a 6-fold increase of autoimmune diseases among relatives – a risk that increased with age. A subgroup of these relatives was diagnosed with silent celiac disease and their prevalence of autoimmune disorders as compared to first-degree relatives not affected by celiac disease was significantly higher with an odds ratio of 6.3. The authors concluded that first-degree relatives of celiac disease patients have an increased risk of autoimmune disease, most likely related to unrecognized and, therefore, untreated celiac disease.

Different conclusions were reached by Sategna Guidetti et al., whose results favor the linkage disequilibrium hypothesis. The authors screened for the presence of autoimmune disorders in 605 healthy controls (16-84 years old) and 422 celiac disease patients (16-84 years old) that had been on a gluten-free diet (GFD) for at least 1 year. A logistic regression analysis, setting the prevalence of autoimmunity as the dependent variable, was employed to control for independent covariates as predictors of the risk of autoimmunity. The authors found a 3-fold higher prevalence of autoimmunity in patients as compared to controls. Mean duration of gluten exposure was 31.2 and 32.6 years for patients with or without autoimmunity. Logistic regression showed that increased age at diagnosis of celiac disease was related to the prevalence of autoimmune disease, whereas ‘actual gluten exposure’, which takes into account diet compliance, follow up and age at diagnosis of autoimmune disorders, was not predictive for the risk of developing autoimmune diseases. Therefore, the authors concluded that the increased prevalence of autoimmune diseases in patients with a late celiac disease diagnosis does not correlate with duration of gluten intake nor does gluten withdrawal protect patients with a late diagnosis from autoimmune diseases.


The Role of Gluten as a Trigger of Autoimmunity

Funda et al. [8] explored the role of gluten as a trigger of the autoimmune process outside celiac disease using the nonobese diabetes (NOD) mouse model for diabetes. The authors showed that the early introduction of a GFD substantially lowered diabetes incidence in NOD mice (15%) compared to mice on the standard diet (64%). In addition, mice on the GFD developed diabetes significantly later (244 ± 24 days) compared to those on the standard diet (197 ± 8 days). Based on these results, the authors concluded that a GFD both delayed and to a large extent prevented diabetes in NOD mice that had never been exposed to gluten. These results have been recently confirmed by Maurano et al., who demonstrated that NOD mice fed a standard diet showed reduced villous height, increased intraepithelial infiltration by CD3+ cells and enhanced expression of H2-IA and interferon-γ mRNA when compared with mice on the GFD. The cumulative diabetes incidence at 43 weeks of age was 65% in the latter and 97% in the former (P < 0.01). Mice fed a wheat-containing diet also showed increased epithelial infiltration and a higher incidence of diabetes.

The role of gluten exposure in T1D pathogenesis has been also confirmed in human studies. Early introduction of gluten to children at high risk for T1D produces T1D-associated islet autoantibodies. Feeding gluten-containing foods in the first 3 months of life yields a 4-fold greater risk of developing islet cell autoantibodies (and potentially subsequent diabetes) than exclusive breast feeding. Children starting gluten foods between 4 and 6 months of age demonstrated no such association. Similarly, in the absence of overt clinical symptoms of T1D, some celiac disease children produce diabetes autoantibodies in a gluten-dependent manner.  In diabetic patients, intestinal challenge with gluten produces mucosal recruitment of lymphocytes, similar to that seen in celiac disease patients. The most direct evidence of the role of gluten as an ‘instigator’ of the autoimmune response in T1D has, however, been recently provided by Sblattero et al.. The authors monitored the effects of a GFD on anti-tTG antibody synthesis in the intestinal mucosa of a patient with T1D and a subjects at high risk of diabetes [anti-islet cell antibody (ICA)-positive], both carrying HLA-DQ2/DQ8, but lacking serum anti-tTG Intestinal specimens from both subjects and samples of peripheral blood lymphocytes were used to make phage-antibody libraries to look for lymphocytes synthesizing anti-tTG antibodies. In both subjects, positive tTG antibody clones were isolated only from the intestinal lymphocyte libraries. After 12 months of GFD the subject at risk of T1D sero-converted from ICA-positive to ICA-negative. In both subjects, biopsies were normal, and analysis of new phage antibody libraries showed complete elimination of anti-tTG clones in the T1D subject and 90% reduction in the subject at risk of T1D. In this subject, reduced response to tTG and elimination of ICA after GFD suggest that an early intervention may abort and then revert the autoimmune process, indicating a possible temporary protection from the disease if a GFD is promptly implemented.



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