Crosstalk between T cells and B cells in the differentiation of pathogenic plasma cells in pemphigoid diseases

The bidirectional crosstalk between B cells and T cells is crucial to generate pathogenic autoantibodies in autoimmune disorders, such as pemphigoid diseases (PDs). The mechanism how B cells modulate autoreactive T helper cells and how these feedbacks into the generation of pathogenic autoantibodies is only poorly understood. The goal of us is to elucidate the checkpoints controlling the bidirectional interaction between autoreactive B and T cells finally resulting in the generation of pathogenic autoantibodies in autoimmune diseases, such as PDs. We will particularly focus on IFN-g and RA, which we believe are crucial regulators of this crosstalk driving disease pathology. We will study the interplay between IFN-g and RA in murine models of PD employing a combined pharmacological and genetic approach. The impact of IFN-g and RA on autoreactive T cells, B cells, and plasma cells secreting pathogenic autoantibodies will be illuminated. The importance of cognate B cell help to autoreactive T cells will be probed in B cell-specific MHCII gene-deficient mice.

B cell intrinsic mechanisms of IFN-g and RA and their interactions in individual B cell subpopulations will be investigated in vitro using the advanced “Kitamura cell culture" system, which is based on BAFF/CD40L-tranfected fibroblasts in co-culture with B cells. Thus, the impact of IFN-g and RA on the differentiation, proliferation, antibody class switch, and gene expression of individual B cell populations will be profiled. The pathogenic relevance of these populations will be subsequently determined by a series of adoptive transfer experiments in our epidermolysis bullosa acquisita (EBA) mouse model. The results from our murine model systems will be validated in autoantigen-specific lymphocytes from PD patients after flow cytometric cell sorting, single cell sequencing and functional testing with focus on IFN-g and RA signaling. Collectively, we will delineate the significance and the molecular mechanisms of IFN-g and RA regulation of the bidirectional crosstalk between autoreactive T and B cells. The insights will be instrumental to develop novel therapeutic strategies targeting the generation of pathogenic autoantibodies in PDs and prospectively, in other autoimmune diseases.