The goal of this proposal is to better understand the mechanisms by which autoreactive B cells get activated, differentiate into antigen producing cells, and participate into the autoimmune response by activating autoreactive T cells. We will use the NZM2410-derived B6.NZMSle1/Sle2/Sle3 lupus-prone strain (B6.TC), which constitutes an ideal model to analyze the immune defects responsible for lupus pathogenesis because of its simplified genetics (only ~ 6% of the NZM2410 genome). This allows co-cultures and adoptive transfer experiments between B6 and B6.TC to test the contribution of a single cell compartment in the context of a true genetic control, which has not been achieved in other lupus experimental models. We will use immunoglobulin HC transgenes, rheumatoid factor (RF) AM14, anti-DNA 56R, and anti-phosphorycholine (PC) M167 as a control, to track the fate of autoreactive B cells in the B6.TC model. Our primary focus on the AM14 model stems from its emerging significance as a generalized model for anti-nuclear autoreactivity in which the presence of the autoantigen can be controlled. To achieve these goals, we have two specific aims: 1. To define the contribution of the marginal zone B cells to autoimmunity in the B6.TC model. In vitro and in vivo experiments will define the mechanisms by which B6.TC B cells are selected to the MZ subset and participate in autoimmune pathology, and will establish whether there is a causal relationship between breach in MZB cell follicular exclusion and production of autoantibodies. 2. To define the functional mechanisms responsible for the loss of tolerance of RF AM14 B cells in the B6.TC model. B6.TC RF AM14 B cells are activated and differentiate into antibody producing cells by mechanisms that differ to what has been described in Fas-deficient strains, including a much greater role for polyclonal activation. A detailed analysis of these mechanisms will take advantage of our congenic system to systematically define the role of various cell compartments along the entire B cell developmental process. Overall, these results will provide a better understanding of how autoreactive B cells develop and contribute to autoimmune pathogenesis, and should also provide strategies to better target these cells.
B-cell depletion is the one of the most promising therapeutic strategies in autoimmune diseases, including lupus. This project proposes to investigate the mechanisms by which B cells contribute to the disease process by using a mouse model that spontaneously develops lupus. We propose to focus on two topics: 1) how a specialized subset of B cells, called marginal zone B cells, contributes to autoimmunity, and 2) to characterize the mechanism responsible for B cells to lose to tolerance to self. The results from these studies will provide a better understanding of the defining features of autoreactive B cells and will help to target therapies toward these autoreactive B cells.
|Choi, Seung-Chul; Morel, Laurence (2017) B cell contribution of the CD4+ T cell inflammatory phenotypes in systemic lupus erythematosus. Autoimmunity 50:37-41|
|Xu, Zhiwei; Morel, Laurence (2015) Contribution of B-1a cells to systemic lupus erythematosus in the NZM2410 mouse model. Ann N Y Acad Sci 1362:215-23|
|Tusi, Betsabeh Khoramian; Deng, Changwang; Salz, Tal et al. (2015) Setd1a regulates progenitor B-cell-to-precursor B-cell development through histone H3 lysine 4 trimethylation and Ig heavy-chain rearrangement. FASEB J 29:1505-15|
|Doerfler, Phillip A; Nayak, Sushrusha; Herzog, Roland W et al. (2015) BAFF blockade prevents anti-drug antibody formation in a mouse model of Pompe disease. Clin Immunol 158:140-7|
|Sang, Allison; Niu, Haitao; Cullen, Jaime et al. (2014) Activation of rheumatoid factor-specific B cells is antigen dependent and occurs preferentially outside of germinal centers in the lupus-prone NZM2410 mouse model. J Immunol 193:1609-21|
|Sang, Allison; Zheng, Ying-Yi; Morel, Laurence (2014) Contributions of B cells to lupus pathogenesis. Mol Immunol 62:329-38|
|Dozmorov, Igor; Dominguez, Nicolas; Sestak, Andrea L et al. (2013) Evidence of dynamically dysregulated gene expression pathways in hyperresponsive B cells from African American lupus patients. PLoS One 8:e71397|
|Zhou, Zhenhai; Niu, Haitao; Zheng, Ying-Yi et al. (2011) Autoreactive marginal zone B cells enter the follicles and interact with CD4+ T cells in lupus-prone mice. BMC Immunol 12:7|
|Niu, Haitao; Sobel, Eric S; Morel, Laurence (2008) Defective B-cell response to T-dependent immunization in lupus-prone mice. Eur J Immunol 38:3028-40|
|Wan, Suigui; Zhou, Zhenhai; Duan, Biyan et al. (2008) Direct B cell stimulation by dendritic cells in a mouse model of lupus. Arthritis Rheum 58:1741-50|
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