The Role of B Cell Maturation Antigen in Controlling Tolerance The establishment of long-lived plasma cells (PC) is a hallmark of the adaptive immune response and is critical for host protection against pathogens. In autoimmune diseases, such as systemic lupus erythematosus (SLE), this process is disrupted to generate self-reactive long- lived PCs (LL-PCs) that produce pathogenic auto-antibodies. LL-PCs arise from germinal center (GC) responses which are initiated by follicular B and T cells. The formation and maintenance of GCs is dependent on a subset of T helper cells known as T follicular helper (TFH) cells, which provide costimulatory molecules and cytokines to drive proliferation and differentiation of PCs. Given the requirement for TFH cells in GC responses, signals that control TFH development and activity are likely to also be important in maintaining self-tolerance. These fundamental issues are not only relevant to autoimmunity, but may also lead to new insights into vaccine design where a robust B cell response is valuable. B Cell Maturation Antigen (BCMA) is an important receptor that binds two ligands: BAFF and APRIL. Although BCMA was reported to be important in maintaining the long-lived PC compartment in immunized B6 mice, our lab has previously demonstrated that the spontaneous development of long-lived PCs, autoantibody production, and lethality in two autoimmune-prone mouse models were significantly worsened in the absence of BCMA. These observations suggest that, in autoimmune-prone mice, signals through BCMA on B cells help control GC B cell homeostasis and the stringent elimination of autoreactive GC B cells. However, signaling through BCMA could also affect other cell types within the context of autoimmunity that impacts GC responses. I have recently determined that TFH cells from autoimmune-prone mice express BCMA. In the absence of BCMA, the frequency of TFH cells dramatically increases in autoimmune-prone mice and the frequency of the T follicular helper regulatory cell subset decreases. These preliminary findings suggest that signaling through BCMA on TFH cells or their progenitors controls TFH cell homeostasis and functionality that, in turn, influences the development of GC B cells and their differentiation int autoantibody-secreting long-lived PCs. Based on these observations, I hypothesize that BCMA is a critical regulator of TFH cells in autoimmunity and that signaling through BCMA on TFH cells can modulate their cytokine production, proliferation, and survival. The overall goal of this project is to define the qualities of TFH cells in autoimmune-prone mice in the presence and absence of BCMA, and to determine their role in the development of long-lived PCs in order to understand the role of BCMA in mediating tolerance.
Lupus Erythematosus is an autoimmune disease that affects more than 1 million individuals in the United States alone. This disease is characterized by the persistence of long-lived cells that produce antibodies reactive against self-proteins, which is thought to contribute to disease progression. The proposed work serves to establish how these long-lived cells are maintained in these patients and identify novel factors that mediate this process in order to develop more effective therapeutics.
|Coquery, Christine M; Wade, Nekeithia S; Loo, William M et al. (2014) Neutrophils contribute to excess serum BAFF levels and promote CD4+ T cell and B cell responses in lupus-prone mice. PLoS One 9:e102284|