CRU 303 Subproject 06: The Role of Lymphocyte-derived Factors in the Effector Phase of Pemphigoid Diseases

Activation of autoreactive B and T cells is part of the loss of self-tolerance in the afferent phase of PD and results in the production of autoantibodies, that later initiate tissue inflammation. Although T and B cells are also part of the inflammatory infiltrate of PD skin lesions, their role in the effector phase of PDs is largely unknown, and the effector phase has been thought to be solely driven by the actions of myeloid cells. Intriguingly, we have recently found evidence that individual B and T cell subsets do significantly modulate the course of the PD effector phase and, dependent on the specific lymphocyte subset, promote or contain skin inflammation by actions on the effector cell level. Herein, NKT cells and gamma delta T cells apparently contribute to the onset of disease in the AAb transfer EBA mouse model, while, in contrast, regulatory T cells and IL-10 producing B cells/plasma cells counteract skin inflammation on the effector cell level, consequently containing and resolving skin inflammation. However, the contribution of many other subsets, including antigen-specific lymphocytes as well as the temporal dynamics and mechanisms of lymphocyte recruitment and their mode of action to modulate skin inflammation are still largely elusive. Project 6 will therefore set out to further differentiate and elucidate the role of different lymphocyte subsets in the effector phase of PD. To this end, it will profile the recruitment of the individual lymphocyte subsets in inflamed PD skin and its draining lymph nodes throughout the course of disease and will use this information to unravel the molecular mechanisms, these subsets apply to modulate the course of disease. The results will highlight the previously unappreciated role of lymphocytes in the effector phase of PD and will provide new insights into the mechanism orchestrating the effector phase of PDs. This will be instrumental to develop new therapeutic strategies and biomarkers for the treatment of PD targeting lymphocytes and their products in PDs.