Within the last decades the dogma of fibroblasts being mere structural elements with a function in tissue repair has changed by acknowledging that they dynamically interact with other cells. Fibroblasts express adhesion molecules and secrete cytokines and chemokines. Moreover, fibroblasts strongly participate in the initiation and modulation of immune responses by directly influencing the proliferation, differentiation, activation or survival of virtually all immune cells. In the pathogenesis of rheumatoid arthritis (RA), synovial fibroblasts (SF) are the effector cells of joint destruction; epigenetic and metabolic alterations contribute to their aggressive behaviour. In addition, T cells constitute about 30–50% of all cells in the RA synovium. The association of the autoimmune disease with specific HLA-DR alleles provides strong evidence for the importance of T helper cells in human RA. Despite their important role in the pathogenesis of RA, little is known about the cross-talk between these two cell types, SF and T helper cells, under normal and pathological conditions.

In this project, we aim to define mechanisms by which SF modulate the activation and the phenotype of T helper cells and vice versa. We directly compare non-inflammatory SF and T cells of healthy donors with those of patients with RA and other rheumatic diseases. Recently, we could show that SF possess the capacity to suppress B and T cell proliferation and cytokine production. This is an important finding, demonstrating that under normal, non-inflammatory conditions, SF can act as regulatory, immunosuppressive cells. Hence, SF may play an important role in preventing inappropriate inflammatory responses of lymphocyte. Cytokines secreted by lymphocytes induce immunosuppressive functions of SF, but also stimulate SF to produce matrix metalloproteinases, pro-inflammatory cytokines and chemokines and even can convert non-arthritic SF into inflammatory, cartilage-destructive RA-like SF. Interestingly, RA-SF possess a significantly weaker T cell suppressive capacity compared to non-arthritic SF. By using state-of-the-art techniques of cell biology, immunology, biochemistry, metabolomics and molecular genetics, we aim to define the phenotypes of SF and T cells under normal and pathogenic (e.g. inflammatory environment, hypoxia) conditions and to determine how their phenotype is modulated by the intercellular crosstalk. Especially we want to define signals and signalling pathways which induce an immunosuppressive and those generating a pro-inflammatory, aggressive phenotype in SF. In addition, we investigate how therapeutics used in the treatment of RA affect the crosstalk of SF and T cells and how they modulate the phenotype of these cell types. Due to our clinical environment and the close contact of scientists, clinicians and patients, our lab has direct access to cells and tissue samples of RA patients as well as of patients with other rheumatic diseases like psoriatic arthritis (PsA) and spondyloarthritis (SpA).

This project is supported by a research grant of Pfizer (Forschungsförderung “Competitive Grant Pfizer”).

Latest publications on this project

Tykocinski LO, Lauffer AM, Bohnen A, Kaul NC, Krienke S, Tretter T, Adam I, Mohapatra SR, Saikali P, Lohning M, Neidhart M, Gay S, Oezen I, Platten M, Opitz CA, Lorenz HM. 2017. Synovial Fibroblasts Selectively Suppress Th1 Cell Responses through IDO1-Mediated Tryptophan Catabolism. J Immunol 198: 3109-17

Störch H, Zimmermann B, Resch B, Tykocinski LO, Moradi B, Horn P, Kaya Z, Blank N, Rehart S, Thomsen M, Lorenz HM, Neumann E, Tretter T. 2016. Activated human B cells induce inflammatory fibroblasts with cartilage-destructive properties and become functionally suppressed in return. Ann Rheum Dis 75(5): 924-32