RasGRP1 is a key-signaling molecule. Deficiency of RasGRP1 results in lupus-like autoimmune disease in mice. Aberrant RasGRP1 expression is exclusively associated with SLE patients. However, the underlying mechanism remains elusive. Our preliminary results showed for the first time that B1 cells uniquely express RasGRP1. Deficiency of RasGRP1 leads to impaired B1 cell development, especially of the autoreactive PD-L2+ B1 cell subset, and impaired natural IgM secretion. B1 cells are the major source of autoreactive, natural IgM facilitating apoptotic cell clearance. Inefficient apoptotic cell clearane is considered a critical cause of lupus autoimmune disease. Thus, we hypothesize that impaired B1 cell development, especially of the autoreactive PD-L2+ B1 cell subset, results in impaired natural IgM, particularly of autoreactive natural IgM, secretion which impairs phagocytosis of apoptotic cells. Therefore, an autoantigen accumulation-lymphocyte activation-autoantibody expression axis is activated in RasGRP1 deficient mice. This hypothesis is validated by our findings that reconstitution of WT B1 cells significantly eliminates expression of spontaneous germinal center B cells and anti-nuclear autoantibodies.
The specific aims of this proposal are to: 1) characterize the nature of wild-type B1 cells that counteract lupus-like autoimmune disease in RasGRP1 deficient mice; and, 2) determine autoreactivity of natural IgM and phagocytosis of apoptotic cells in RasGRP1 deficient mice. This proposal will elucidate the etiopathogenesis of SLE initiated by aberrant expression of RasGRP1 and provide novel insights into further understanding of autoimmune diseases. The results of these studies will provide the foundation for accurate classification, early diagnosis, and improved therapy of lupus autoimmune diseases.
Systemic lupus erythematosus (SLE) is a complex autoimmune disease in which the immune system becomes hyperreactive and attacks normal, healthy tissues. RasGRP1 is a key signaling molecule implicated in lupus-like autoimmune disease in mice and humans. This proposal will elucidate the etiopathogenesis of lupus-like autoimmune disease initiated by aberrant RasGRP1 expression, and the results of these studies will provide the foundation for better classification, earlier diagnosis, and improved therapy of SLE patients.
| Guo, Benchang; Zhang, Lu; Chiorazzi, Nicholas et al. (2016) IL-4 rescues surface IgM expression in chronic lymphocytic leukemia. Blood 128:553-62 |
| Guo, Benchang; Rothstein, Thomas L (2016) RasGRP1 Is an Essential Signaling Molecule for Development of B1a Cells with Autoantigen Receptors. J Immunol 196:2583-90 |
