T Cell-Independent Breach of B Cell Tolerance by Self Antigen Retention on Follicular Dendritic Cells

Follicular dendritic cell (FDC) networks supporting germinal centre (GC)-like structures and local auto-antibody production have been recognized in chronically inflamed tissues, including the synovium of rheumatoid arthritis (RA). The mechanisms by which FDCs are involved in auto-antibody production are nevertheless not fully understood. We hypothesized that auto-immune complex (IC) retention on FDCs can breach B cell tolerance and induce auto-antibody production; and we sought to investigate the mechanisms and modulation of FDC-induced auto-antibodies. To test our hypothesis, IC retention on RA synovial FDCs was examined using scanning confocal microscopy. In vitro GC reactions differentially reconstituted with T cells, complement, and ICs were set up to assess auto-antibody induction by IC-loaded FDCs. Breach of B cell tolerance with IC-retaining FDCs was investigated in sHEL-Tg mice, and modulation of FDC-IC retention and auto-antibody production by the IgG-specific Endoglycosidase- S was verified. Our results showed that fibrinogen retention can be revealed on FDCs in RA synovial follicular structures. In vitro, fibrinogen-IC-loaded FDCs induced T cellindependent (TI) fibrinogen-specific IgM, whereas noncognate T cell help was required for IgG production. Furthermore, retention of HEL-ICs on FDCs broke B cell tolerance and induced HEL-specific auto-antibodies in sHEL-Tg mice. Finally, Endoglycosidase-S interfered with FDC-IC retention and significantly inhibited FDC-induced antibody production. In conclusion, the ability of FDCs to productively present auto-antigens provides a mechanism that could help explain their pathogenic role in autoimmune disorders. Interference with FDC-IC retention using Endoglycosidase-S inhibits FDCinduced auto-antibody production, and can be potentially used to ameliorate auto-antibody-mediated autoimmune diseases.