Systemic lupus erythematosus (SLE) is a complex autoimmune disease with no effective cure. The major clinical manifestation of SLE is the production of a variety of autoantibodies affecting multiple organ systems. Although almost all immune components could be involved at different stages of SLE development, antibody-producing B cells have been the focus of blame. Several therapeutic interventions aimed to deplete B cells have been under clinical trials. Recently, the phase II/III clinical trial of Rituximab, a depleting anti-CD20 monoclonal antibody, failed to demonstrate clinical efficacy in treating SLE patients. Together with other controversial B cell- depleting trials, a better understanding of B cell immunology in SLE is urgently needed for future therapeutics design. Studies have shown that B cells are not always pathogenic in autoimmune diseases. In some animal models, depleting B cells not only failed to alleviate symptoms, but also prevented prompt recovery from diseases. Others have reported that B cells can even suppress autoimmunity through various mechanisms. However, the true identity of such "suppressive" or regulatory B cells is still elusive. Our preliminary data suggested that B1 B cells have previously unknown regulatory functions. Moreover, we found a new subpopulation of B1 B cells that is highly auto-reactive with promiscuity in recognition SLE related autoantigens and can be detected in both murine lupus and human autoimmune patients. In the murine lupus model, we have shown that this B cell subset is elevated in the peripheral blood and most importantly infiltrates into the thymus. Based on our preliminary results, we hypothesize that in SLE the increase of B1 cells in the thymus may reflect a feedback effort of the immune system to reinforce central tolerance, which might be breached by the overwhelming inflammatory environment that counters the regulatory functions of B1 B cells. In this RO3 grant, we propose to obtain preliminary data on the in vitro and in vivo regulatory functions of the novel subpopulation of B1 B cells, particularly, its effects on thymic T cell development in healthy and SLE mice. The results of the study will allow us to apply for RO1 grant support for further investigation of the regulatory arm of B cells and how "Breg" themselves are regulated in SLE.
Project narrative Although B cells are thought to contribute to systemic lupus erythematosus (SLE) by producing self-attacking antibodies that leads to multi-organ failure, recent clinical studies suggest that pan-depletion of B cells may not be the optimal solution. We believe that not all B cells are villains in autoimmune diseases, and particularly we suspect a novel subset of B1 B cells could be the "guardian angels" that may be called upon during systemic autoimmune crisis like SLE and can enter the thymus to re-establish central immune tolerance. Our study will provide new knowledge for redesigning future immune therapy for SLE.
|Zhong, Xuemei; Rothstein, Thomas L (2011) L2pB1: a new player in autoimmunity. Mol Immunol 48:1292-300|