Clinical and Immunological Features of Celiac Disease in Patients With Type 1 Diabetes Mellitus

Umberto Volta; Francesco Tovoli; Giacomo Caio

Disclosures

Expert Rev Gastroenterol Hepatol. 2011;5(4):479-487. 

In This Article

Five-year View

In the next 5 years, further studies are expected to improve our knowledge on the pathogenic factors underlying CD and T1DM. Researchers should focus their attention on genetic aspects, environmental factors and intestinal barrier function.

The interplay between specific susceptibility genes and environmental factors underlies the aberrant immune response triggering the onset of both CD and T1DM.[1] The HLA class II loci, HLA-DQB1 and HLA-DRB1 on chromosome 6p21, involved in genetic predisposition for the development of both disorders, act in combination with many other non-HLA loci across the genome. Other chromosome regions outside the HLA-region have recently been associated with CD by using the genome-wide association approach.[70] In T1DM, 15 non-HLA regions have been established to be implicated in T1DM and multiple sclerosis.[71,72] It has already been reported that the 12q24/SH2B3 locus is shared between T1DM and CD, and other loci, namely 4q27/IL2–IL21 and 3p21/CCR3, might be involved in the development of both disorders.[70] The existence of common pathogenic pathways between CD and T1DM needs to be further proved. In both disorders, the key elements regulating the destruction of tissues by an inappropriate immune response include genetic factors together with innate and adaptive immune regulation and triggering environmental factors. A better identification of specific genetic markers underlying autoimmune disorders could be useful to unravel the pathological mechanisms of autoimmune disorders such as CD and T1DM and might provide targets for their prevention and management.

New studies should elucidate the role of environmental factors such as gluten and viral infections (rotavirus and enteroviruses) in the development of both diseases. As is well known, gluten modulates the innate immune response in CD with activation of CD4+ T lymphocytes that are responsible for the intestinal CD damage; it is possible to hypothesize that these lymphocytes migrate from the small bowel to endocrine pancreas, having a role in triggering T1DM.[36,37] A similar mechanism has been postulated to explain joint manifestations found in many gastrointestinal disorders and characterized by the finding of α4/β7 CD4+ T lymphocyte of intestinal origin in the synovial fluid.[73] Viral infections seem to be important in triggering both CD and T1DM, but the mechanisms and the spectrum of involved viruses in the pathogenesis of both disorders needs to be better clarified.

Accumulated evidence suggests that the gut and gut-associated lymphoid tissue are involved in the pathogenesis of many autoimmune disorders.[74] Besides genetic and environmental factors, the classic paradigm of autoimmune pathogenesis has recently been challenged by the addition of a third element, the loss of intestinal barrier function. Loss of intestinal barrier function might be secondary to dysfunction of intercellular tight junctions, a key component in the pathogenesis of autoimmune disorders. Indeed, both in CD and T1DM a dysfunction of intestinal barrier through an overexpression of zonulin and consequent increased permeability has been well documented. New therapeutic strategies aimed at re-establishing intestinal barrier function will offer an innovative approach for modulating these autoimmune disorders. Finally, the identification of an animal model of comorbid CD and T1DM, taking advantage of the already known examples of NOD mice and celiac Rhesus macaque, would be of valuable help for improving our knowledge of the pathogenesis of such an association.[36,75]

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