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FRIMED2-FRIPRO forskerprosjekt, medisin og helse

Exploring T cell – B cell collaboration resulting in autoimmunity

Alternative title: Undersøkelse av T-celle -- B-celle samarbeid som resulterer i autoimmunitet

Awarded: NOK 12.0 mill.

Autoimmune diseases occur when the body’s immune system starts attacking its own, healthy cells. Both genes and factors in the environment, which are often unknown, are involved in development of autoimmune diseases. In particular, so called MHC class II genes appear to be important. How these MHC class II genes put people at risk for autoimmune disease is not clear. In the current project, we hypothesize that interactions between two specific cells of the immune system – T cells and B cells – can explain the genetic association with certain MHC class II genes. We will explore this hypothesis in the setting of celiac disease. Celiac disease is a common autoimmune disease that is caused by intolerance to cereal gluten proteins. The patients have antibodies to a component of the body itself: the enzyme transglutaminase-2. These so-called autoantibodies are only formed in individuals who express certain MHC class II variant molecules, specifically HLA-DQ2.5 and to a lesser degree HLA-DQ2.2 and HLA-DQ8, and only when these individuals eat gluten. B cells are the cells that produce antibodies. They also express MHC class II and use this to present fragments of proteins to T cells. In this project we will use transgenic mice that express HLA-DQ2.5 and disease-relevant B-cell and T-cell receptors from celiac patients to study how specific B cells and T cells interact. In particular, we will address the role of HLA-DQ2.5 by using reagents that block the function of this molecule. The project will give fundamental knowledge into why MHC class II genes are risk factors in autoimmune diseases.

This project aims to give a proof-of-principle of the mechanism underlying the major role of MHC class II genes in autoimmunity. Central in the project will be studies of cross-talks between pathogenic T cells and B cells. As such cross-talks in vivo take place primarily in organized tissues, whole organism models are required. Thus, the project will utilize experimental mouse models. Taking advantage of the identification of adaptive immune receptors of culprit T cells (T-cell receptors, TCRs) and B cells (B-cell receptors, BCRs) of celiac disease patients, a collection of unique TCR and BCR transgenic mouse strains have been established. In combination with a novel HLA-DQ2.5 knockin mouse strain, these humanized mouse strains serve as a powerful tool-box for exploring the role of HLA-DQ2.5 in the formation of antibodies to the autoantigen of celiac disease, transglutaminase 2 (TG2). In celiac patients anti-TG2 antibodies are formed in a gluten dependent (i.e. gluten eating) and HLA dependent (i.e. positivity for HLA-DQ2.5/DQ2.2/DQ8) manner. Mechanistically, this gluten and HLA dependence can be explained by gluten-specific T cells providing help to TG2-specific B cells via the involvement of TG2-gluten complexes. In the project this mechanistic model will be explored by testing of interaction between antigen-specific T cells and B cells of the humanized mice. In particular the role of HLA-DQ2.5 in facilitating production of anti-TG2 antibody will be probed by blocking with anti-HLA-DQ and anti-HLA-DQ2.5/peptide monoclonal antibodies. The project will give new insights with demonstration of key pathogenic principles in celiac disease, a poster child of MHC associated diseases. Altogether, the project should provide fundamental knowledge into processes causing MHC association with disease – a scientific area where our insights into the underlying molecular mechanisms are appallingly scarce.

Funding scheme:

FRIMED2-FRIPRO forskerprosjekt, medisin og helse