This project explores impaired lymphocyte-extracellular matrix interactions as the basis of immune-mediated pathology. Dystrophic epidermolysis bullosa (DEB) is a genetic skin fragility disorder. The protein at fault is collagen VII (Col VII). Although Col VII has wide tissue expression, DEB pathology has so far almost exclusively been attributed to its deficiency in skin. However, Col VII is also present in immune organs. Recently, we were the first to describe an innate immune deficiency in DEB. The innate immune defect is due to loss of Col VII – cochlin interactions in the extracellular matrix of secondary lymphoid organs, which systemically regulate antibacterial surveillance by activating inflammatory cells.
Our proposed work for this funding period has the following objectives: I) Delineate the role of Col VII in B cell development and homeostasis using patient material and transgenic mice. II) Elucidate the cause of an altered immunization response in DEB. III) Characterize and elucidate the cause of autoreactive antibodies in DEB and their implication for disease progression. IV) Explore the impact of autoimmunity on the skin phenotype in DEB patients. Collectively, by addressing paradox immune reactions occurring in a genetic extracellular matrix disease, we will start to unravel the previously largely underappreciated active involvement of the extracellular matrix in immunity.