Increasing evidence supports the categorization of celiac disease (CD) as an autoimmune disorder. The association of CD with other autoimmune diseases is striking: type 1 diabetes mellitus, autoimmune thyroiditis, Sjogren syndrome, connective tissue diseases occur more frequently in patients with CD than in the general population. Similarly to many autoimmune disorders, CD shows a gender bias with a female to male ratio of about 2:1. Furthermore, multiple autoimmune phenomena are observed in CD, the most characteristic of which is the presence of high titers of autoantibodies against tissue transglutaminase 2 (TG2) in patient sera. TG2-specific immunoglobulin A (IgA) are primarily used for diagnosis, with sensitivity and specificity close to 100%. Even in patients who show negative serum TG2-specific antibodies, it seems that such antibodies are still produced locally, as suggested by the presence of deposits in the small intestine (1). In fact, it has been shown that in the small intestinal mucosa of untreated patients with CD around 10% of plasma cells are TG2-specific cells (2). Antibodies from different patients target the same conformational TG2 epitope formed by spatially close amino acids of adjacent domains (3). Monoclonal antibodies from single plasma cells have a restricted usage of variable heavy and variable light chains segments (2). CD associated anti-TG2 antibodies have limited inhibitory activity (2) and their role in CD pathogenesis is still unclear. TG2 is a multifunctional enzyme that has been involved in a variety of physiological functions, including matrix assembly and tissue repair, receptor signaling, proliferation, cell motility, and endocytosis. A role of TG2 in CD beyond its established function in deamidation and presentation of gluten peptides to the adaptive immune system is thus suspected, although not clearly delineated. In vitro studies have suggested that TG2 IgA autoantibodies might modulate enterocyte differentiation and proliferation (4); they also inhibit angiogenesis ex vivo and in vivo and impair vascular functionality (5). IgA against extracellular forms of TG2 present in the liver, muscle and lymph nodes, have been detected in patients with CD, indicating that this TG2 is accessible to the gut-derived autoantibodies also in those locations. Moreover, anti-TG3 or -TG6 rather than -TG2 autoantibodies are present in dermatitis herpetiformis and in neurological manifestation of gluten sensitivity, respectively, suggesting that the heterogeneity of disease manifestations may reside in the specificity of the autoimmune response. The mechanisms leading to their production in CD are not completely known. The upregulation and activation of TG2 observed in inflamed sites may generate additional antigenic epitopes, by cross-linking or deamidating external or endogenous proteins. Unmasking of normally hidden epitopes in an inflamed environment, with more efficient antigen processing and presentation, has also been hypothesized as an important mechanism resulting in autoimmunity. The most accepted hypothesis to explain the observed dependence on the presence of dietary gluten for the production of anti-TG2 autoantibodies is that gluten-reactive CD4 T cells provide the required help to TG2-specific B cells in a hapten carrier–like manner by involvement of TG2-gluten complexes (6). Of note, anti-TG2 are not the only autoantibodies present in patients with CD, indeed antibodies to actin and calreticulin have also been detected in the sera of patients with CD. Recent efforts to dissect the autoantibody response in CD integrating genomic and proteomic technologies and performing high-throughput large-scale screening have led to the identification of 13 new CD-associated autoantigens (7).
CELIAC DISEASE AND TYPE 1 DIABETES MELLITUS SHARE GENES AND MECHANISMS
Similar to other autoimmune diseases, CD is a polygenic disorder with genes coding for the HLA class II molecules (DQ2.5 and DQ8) playing a major role. Interestingly, HLA-DQ2-DQ8 heterozygous show high risk for type 1 diabetes mellitus (T1D) development and in fact HLA-DQ8 transdimer has been shown to bind efficiently both gliadin peptides and peptides derived from GAD65 and IA-2 (8). The mechanisms governing the recognition of gluten by HLA molecules in CD have been extensively investigated and similarities have been shown with recognition of pancreatic autoantigens in T1D. HLA-DQ8 and -DQ2 alleles, involved in both diseases, show preference for negatively charged peptides and it is likely that also in T1D posttranslational modifications occur.
Genome-wide association studies (GWAS) so far allowed the identification of 39 non-HLA CD-associated loci that together contain 115 different genes. Most of them control T-cell activation and recruitment. Fifty percent of CD-associated SNPs might affect the expression of other genes, few having been found within coding sequences. Sixty-four percent of the CD-associated loci are shared with at least one other autoimmune disease (eg, T1D), further reinforcing the concept of common pathogenic mechanisms (Fig. 1). The association of CD with the TLR7-TLR8 gene is particularly interesting since TLR7 and TLR8 are innate receptors for single-stranded viral RNA. A role for viral infections has been advocated in CD as well as in other autoimmune conditions. The genetic link with innate antiviral responses seems less strong in CD than in T1D, in which a combination of GWAS and eQTL data has revealed an association with a whole network of antiviral innate immune genes. IL-2/21 is another susceptibility locus shared between CD and T1D. IL-21 plays an important role in interferon-γ production, proliferation and survival of NK and CD8 T cells. Interestingly, IL-21 is highly expressed in active CD patients, but it is downregulated in potential CD (normal jejunal architecture despite positive CD autoantibodies) (9), supporting its role in the development of villous atrophy. Strong analogies with T1D are suggested by a recent study showing how IL-21-producing CD4 T cells that express the gut CCR9 homing receptor can target the pancreas of NOD mice and promote CD8-dependent tissue damage (10). Besides the adoptive immune response, characterized by the activation of lamina propria antigluten specific CD4 T cells, additional signals are required for the development of full-blown CD. Innate immune signals and the expression of epithelial stress markers have been advanced as potential “second hits” required to induce full activation of cytotoxic IELs. Impaired expression of MIC and HLA-E molecules occur in the intestinal epithelium of untreated patients with CD, as part of the stress response of intestinal epithelial cells induced by either gluten peptides and/or infections. MIC and HLA-E are ligands for NKG2D and CD94, respectively, which are NK-like receptors expressed in intraepithelial lymphocytes. Of note, similar mechanisms act in the NOD model of TID as well. Indeed, RAE-1, the mouse homolog of MIC-A, was found upregulated in prediabetic pancreatic islets, whereas NKG2D was expressed on autoreactive intrapancreatic CD8 T cells and using an anti-NKG2D nondepleting antibody prevented progression to diabetes. IL-15, a key innate cytokine involved in CD pathogenesis, plays a major role in upregulating NK receptors on IELs and promoting T-cell receptor–independent killing ability. Furthermore, IL-15 expression is increased in islet cells in the prediabetic stage, and inhibition of IL-15 delays diabetes development (11). Despite the strong association with MHC class II, in most autoimmune diseases CD8 effector cells play an important role in driving tissue damage. In T1D CD8 T cells are involved in pancreatic islets distruction; analogously, in CD CD8 T lymphocytes can recognize gliadin peptides in the context of class I molecules (12), and, more recently, gluten exposure has been shown to evoke the appearance of activated gut-homing CD8 α/β and γ/δ T cells in the peripheral blood (13).
GLUTEN AS A TRIGGER OF AUTOIMMUNITY
Human and animal studies suggest that dietary gluten could be involved in the etiopathogenesis of T1D. Several lines of evidence show that patients diagnosed as having CD later in life had a higher rate of T1D than age-matched patients diagnosed as having CD at a young age (eg, <3 years old). This indicates that a longer exposure to dietary gluten increases the risk of developing T1D. Furthermore, 2 large human prospective cohort studies have established an association between an early infant diet containing gluten and the development of autoantibodies against pancreatic islets. Both studies found an increased risk of islet autoimmunity when children were exposed to gluten-containing cereals early in life. Several studies in nonobese diabetic (NOD) mice as well as biobreeding (BB) rats have documented that the pathogenesis of T1D is influenced by diet. It has been demonstrated that a gluten-free diet largely prevented diabetes onset in NOD mice; however, the mechanisms by which dietary gluten could influence the incidence of T1D are not fully understood. Recent studies have demonstrated that the gut microflora plays an important role in shaping the immune responses, as well as in the development of autoimmunity (including T1D) in animal models and humans. Dietary gluten could play its diabetogenic role through altering the gut microbiome (14). Gliadin could directly influence regulatory T cells as well as Th17 cells in mucosal compartments (15). Certainly gliadin peptides elicit mucosal inflammation, as shown in ex vivo experiments on jejunal biopsies of T1D patients and in vivo rectal challenge studies. The ultimate mechanisms by which gliadin is directly or indirectly able to exert a proinflammatory (and prodiabetogenic) effect remain to be understood.
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