The interaction of mesenchymal stromal cells and activated B cells in the context of fibrosis-associated autoimmune diseases, under special consideration of systemic sclerosis and CREST syndrome

• Applicant: Theresa Tretter, Ph.D.
• Subject Area: Rheumatology
• Term: from 2018 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 394518511

Systemic Sclerosis (SSc) is a rare autoimmune disease, belonging to the group of collagenoses. SSc is characterized by progressive fibrosis of skin and internal organs and - in a subgroup of patients- additionally by increased calcifications (CREST syndrome). Current medications can delay fibrosis, however not really stop it. Fibrosis is the main determinant for mortality in SSc. Therefore a better basic understanding of SSc-associated fibrosis is of utmost importance to improve treatment options. The bidirectional cross-talk of activated immune cells and stromal cells, such as fibroblasts is considered a central mechanism in pathophysiology of SSc and other matrix remodeling autoimmune diseases. However, so far this interaction has not been sufficiently investigated. Specifically the participation of B cells in this process has long been considered to merely encompass production of pathological auto-antibodies, thereby supporting fibrosis in a direct or indirect manner. However several hints indicate that B cells can actively take part in the disease by other properties, such as their ability to secrete cytokines. For example improvement of the SSc symptoms upon B cell depleting therapy in patients is not necessarily paralleled by a reduction of antibody titers. And in vitro experiments from our own lab demonstrate that human B cells can activate fibroblasts from a non-inflammatory environment via secretion of soluble factors such as TNF-alpha and IL-1ß. Such activated fibroblasts increase their own cytokine production, including IL-8, IL-6 and TGFß up to 100fold above baseline concentration.Moreover our unpublished preliminary work to this project also revealed that B cells can modulate functions of multipotent mesenchymal stromal cells (MSC), including their differentiation capacity.These results together with additional observations, led us to the hypothesis that activated B cells may also contribute to pathogenesis and/or progression of SSc via their secretion of cytokines.The testing of this hypothesis includes: 1) the detailed elaboration of the bidirectional interaction of B cells and dermal fibroblasts (of healthy individuals and SSc lesions) under special consideration of SSc-specific conditions. 2) the investigation in how far activated B cells influence the differentiation of fibroblasts and MSC, - thereby contributing to aberrant fibrosis and calcification (CREST-syndrome), 3) the analysis of the B cell- mediated signaling pathways in fibroblasts and MSC and potential options for intervention, 4) the confirmation for antibody-independent influence of activated B cells on SSc-associated fibrosis by means of a 3-dimensional skin model. Our aim is to better elucidate the concept of B cells as modulators of fibrosis in SSc, as an autoimmune disease that is hardly understood, often aggressive and with few therapeutic options.

• DFG Programme: Research Grants