Celiac disease viewed from insights in self-tolerance

Summary
Celiac Disease (CD) is a chronic enteropathy caused by an uncontrolled immune response to gluten proteins present in the daily diet.  It is the most common immune-mediated gastrointestinal disorder diagnosed both in childhood and adulthood, with an increasing global prevalence. Approx. 1% of the population in Western countries develop CD. The clinical symptoms are diarrhea, abdominal pain, malnutrition, fatigue, osteoporosis, infertility and in some cases cancer. The only available treatment for celiac disease is a strictly gluten-free diet (GFD).
There is a strong correlation between HLA genes and celiac disease. The human leukocyte antigen (HLA) system is a gene complex encoding the major histocompatibility complex (MHC) proteins in humans. Ca. 95% of celiac patients carry HLA-DQ2 molecules and the remaining 5% carry HLA-DQ8. These HLA-DQ molecules can bind modified gluten peptides and then present them to gluten-specific T cells in the small intestine, triggering an inappropriate immune response.
HLA-DQ2 and DQ8 are present in more than 30% of the Caucasian population. It is unknown why only 1% of individuals expressing these HLA types develop CD in countries where gluten-rich products are an important part of the daily diet. 
HLA genes also play an important role in the development of T cells in the thymus, where HLA molecules loaded with self-antigens interact with T-cell receptors on developing thymocytes. Only T cells that recognize self-antigens but are not activated by these self-antigens, are supposed to enter the periphery where they play an important role in the immune system. However, from studies in mice, we know that also naive T cells with stronger self-imprinting are selected in the thymus, and that these T cells respond better to foreign antigens. These strong self-imprinted T cells might encounter the same auto-antigens as the selecting self-antigens in the periphery, and might be activated by those self-antigens if proper regulation fails, leading to autoimmunity. 

In study 1, we identified T cells with specificity for an oral antigen that cross-react with a self-antigen in one transgenic mouse system and not in another mouse system, both containing transgenic T cells with the same specificity for the oral antigen, but differing in MHC type. T cells that cross-react with a self-antigen caused small intestinal pathology in mice similar to celiac disease in humans, if these T cells were exposed to their cognate antigen in the diet, in the absence of self-based immune regulation. Naive transgenic T cells that cross-react with self-antigens expressed higher CD45RB.

In study 2, we compared CD45RB and CD5 expression on naive T cells in blood samples from celiac patients (on GFD) and control subjects without celiac disease. In mouse studies, high expression of CD45RB has been associated with naive CD4 T cells with a greater pathogenic potential, whereas surface expression of CD5 on naive T cells is found to be proportional with self-imprinting in the thymus.  We found higher expression of CD45RB in celiac patients compared to controls, indicating that CD45RB might be a marker for disease. We observed a global increased expression of CD5 in DQ2 positive individuals compared to individuals with other HLA types, indicating that naive T cells educated in the context of self-peptide-HLA DQ2 might have received stronger self-based thymic imprinting.  Individuals with the HLA DQ2 haplotype might therefore display heightened protective immunity against pathogens and cancers but are also more at risk for autoimmunity in general.