Human lymph node stromal cells and their role in rheumatoid arthritis

Lymph node stromal cells (LNSCs) shape the lymph nodes (LNs), where adaptive immune responses are initiated. They are crucial key players in adaptive immunity and guardians of peripheral tolerance. Therefore, malfunctioning of LNSCs might lead to deregulation of adaptive immunity and potentially lead to autoimmune disease. So far, LNSCs have mainly been described in mice and this thesis presents a model to characterize human LNSCs in the context of the autoimmune disease rheumatoid arthritis (RA) by comparing LNSCs obtained from LN biopsies from three donor groups: Healthy controls, individuals which show enhanced risk of developing RA due presence of RA-specific autoantibodies (RA-risk) and RA patients. We found that human LNSCs in line with their murine counterparts expressed various immunomodulatory genes and proteins and expression was maintained in prolonged culture. Furthermore, human LNSCs preserved their capacity to influence T cell proliferation in ratio-dependent manner. In relation to autoimmunity we demonstrate disturbances of the LN microenvironment already in early stages of RA. RA-risk and RA LNSCs showed reduced induction of T cell guiding chemokines after stimulation, their contraction and proliferation ability was reduced, their regulation of T cell proliferation was disturbed and they presented a distinct expression pattern of disease-related self-antigens. Together, this might contribute to the loss of peripheral tolerance and in autoimmunity lead to attenuated function of the LN during inflammation. Overall, our approach of characterizing LNSCs during RA development has great potential to reveal new and unanticipated pathogenic processes ongoing in RA and might discover promising new therapeutic targets