TITLE: FDC regulation of self-reactive B cells Abstract: Systemic lupus erythematosus (lupus) is a B cell disease characterized by secretion of pathogenic autoantibody specific for nuclear antigens or DAMPS. A hallmark of the disease is spontaneous formation of germinal centers (GC) in spleen and lymph nodes and development of pathogenic long- lived memory B cells. Follicular dendritic cells (FDC) which are stromal derived and important in maintaining the architecture of B cell follicles are essential to formation and maintenance of GC as they are a major source of B cell antigen and survival factors. We propose FDC play a critical role in the regulation of tolerance of autoreactive B cells and their differentiation and secretion of pathogenic antibodies. Using a lupus-prone mouse model, we found that FDC uptake of nuclear antigens via CD21 triggers endosomal TLR promoting B cell loss of tolerance and differentiation. Thus, FDC are not only a critical source of self-antigen; but they are an important source of signals that can ?drive? self-reactive B cells to differentiate into autoantibody producing cells and memory B cells. These findings suggest FDC may be a novel target for therapy in lupus patients. To test this possibility in a pre-clinical model, lupus mice will be treated over a period of 1 month with a blocking antibody to the CD21 receptor expressed by FDC. Our hypothesis will take advantage of several novel murine models such as a human-mouse CD21 chimeric lupus mouse where the FDC express murine CD21 and the B cells express human CD21. Using this novel system, we will test the efficacy of anti-mouse CD21 therapy in the elimination of retention of nuclear antigens by FDC and turning-off TLR signaling and cytokine secretion.
Three aims are proposed:
Aim 1. Test the hypothesis that the tolerance of self-reactive B cells is regulated by FDCs Aim 2. Test the hypothesis that the maintenance of self-reactive memory B cells is FDC-dependent Aim 3. Test the efficacy of blocking CD21 in lupus mouse models Summary: The successful completion of this study will not only provide valuable reagents and novel tools to push the field forward but it could lead to development of novel strategies and/or blocking therapies for systemic autoimmunity such as lupus.
A hallmark of systemic lupus erythematosus, an incurable autoimmune disease, is escape of tolerance by self- reactive B cells that become activated, form germinal centers where they differentiate into autoantibody producing cells and long term memory B cells. In the current proposal, we will test the hypothesis that follicular dendritic cells are crucial to regulation of B cell tolerance through their secretion of interferon alpha in response to uptake of nuclear antigens. We propose that blockade of FDC uptake of self-antigen complexes can reverse autoimmunity and reduce autoantibody secretion.
| Degn, Søren E; van der Poel, Cees E; Firl, Daniel J et al. (2017) Clonal Evolution of Autoreactive Germinal Centers. Cell 170:913-926.e19 |
