Understanding how gluten drives autoimmunity in celiac disease

Celiac disease is a common disorder caused by intolerance to cereal gluten proteins. Surprisingly, the patients have antibodies to a component of the human body itself - to the enzyme transglutaminase 2. These antibodies - so-called autoantibodies - are only formed when the patients are consuming gluten. Autoantibodies to transglutaminase 2 are a hallmark of celiac disease. If a person is making such antibodies, it is very likely that the person suffers from celiac disease. Doctors harness this feature to diagnose the disease. The goal of the project is to understand why autoantibodies to transglutaminase are formed. Antibodies are produced by B cells. To produce antibodies, B cells need help from T cells. An experimental system has been developed with use of transgenic mice that have got introduced into their genomes the antigen receptors of disease-relevant B cells and T cells of celiac disease patients. We are studying how these B cells and T cells talk to each other in mice. The studies have given mechanistic insight into why an autoimmune response against transglutaminase 2 develops in celiac patients who eat gluten. Autoimmune disease can be prevented by removal of B cells expressing antigen receptors that attack components of the own body from the pool of B cells that we have. Another way is that such autoreactive B cells exist, but are kept silent. In our transgenic mice model, we have now shown that neither is the case for B cells recognizing transglutaminase 2. We have shown that these B cells exist and produce antibodies when they receive help from T cells.

The most important result of this project regards how autoimmunity develops in celiac disease. Coeliac disease is driven by an immune response to foreign cereal gluten proteins, and as part of this immune response the patients develop highly disease specific autoantibodies to the enzyme transglutaminase 2 (TG2). In this project we demonstrate in mouse model that there is no B-cell tolerance induction to TG2, and further that B cells of mice carrying a celiac disease derived B-cell receptor that recognize TG2 can produce antibodies when these cells are provided T-cell help. When the antigen is a complex between gluten peptide and TG2, this T-cell help can be provided by gluten specific T cells. This mechanism explains why celiac disease patients make autoantibodies to TG2 when they consume gluten. The findings have broad relevance to autoimmunity as they fuel the notion that autoimmunity can be driven by an immune response to a foreign antigen.en.

Among the most disease-specific autoantibodies in humans are those reactive with transglutaminase 2 (TG2). IgA anti-TG2 antibodies are diagnostic for celiac disease, and strikingly, they are only formed when celiac patients are consuming cereal gluten proteins. In this project we will harness new humanized mouse models to investigate a) whether and to which extent there is B-cell tolerance to TG2 and b) how anti-TG2 autoantibodies can be formed in response to exposure to the exogenous antigen gluten. We have established novel transgenic mouse strains that carry a B-cell receptor of a TG2-specific plasma cell and a T-cell receptor of a gluten-specific T cell - both based on immune cells isolated from lesions of celiac disease patients. Our preliminary results indicate that there is minimal or no B-cell tolerance to the TG2 autoantigen despite the fact that the transgenic knockin B-cell receptor has equal affinity for human and mouse TG2. This suggests that the main control of antibody production to TG2 operates at the level of provision of T-cell help. Conceivably, gluten-specific T cells can provide such help by involvement of hapten-carrier like TG2-gluten complexes. Preliminary data from adoptive transfer experiments with transgenic T cells and B cells indicate that gluten-specific T cells indeed can provide such help. Further experiments providing mechanistic insight into the T-cell/B-cell collaboration involved in TG2 autoantibody production will be undertaken. Work of the project should provide answers to fundamental questions related to celiac disease, and it should help to advance the understanding of autoimmune diseases in general.