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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI058150-09
Application #
8415928
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Johnson, David R
Project Start
2003-09-01
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
9
Fiscal Year
2013
Total Cost
$357,048
Indirect Cost
$98,225
Name
University of Florida
Department
Pathology
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
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
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
Duan, Biyan; Niu, Haitao; Xu, Zhiwei et al. (2008) Intrafollicular location of marginal zone/CD1d(hi) B cells is associated with autoimmune pathology in a mouse model of lupus. Lab Invest 88:1008-20
Duan, Biyan; Croker, Byron P; Morel, Laurence (2007) Lupus resistance is associated with marginal zone abnormalities in an NZM murine model. Lab Invest 87:14-28
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Blenman, Kim R M; Duan, Byian; Xu, Zhiwei et al. (2006) IL-10 regulation of lupus in the NZM2410 murine model. Lab Invest 86:1136-48