Recent evidence increasingly points to the importance of antibodies specific for RNA antigens in the pathogenesis of SLE. Using a novel mouse model in which RNA-specific B cells are generated and easily tracked, and in which clinical SLE pathologies are recapitulated, new and critical information on the pathogenesis of SLE will be obtained. The mouse line to be used, 564Igi, was generated in our laboratory and has already made an important contribution to the emerging understanding of the role played by TLRs, in particular TLR7, in the development of SLE. In this system, on the non-autoimmune C57BL/6 background, most RNA-reactive B cells undergo receptor editing, while those that retain their RNA-specificity become anergic by multiple criteria. Yet class-switched pathogenic autoantibodies are produced by a T-independent, but TLR7-dependent mechanism. Thus, either anergic RNA-specific IgM+ B cells are capable of activation and differentiation into IgG producing cells in response to self-antigen, or a subpopulation of these cells is able to evade anergy, namely those that have undergone CSR in the bone marrow during B cell development in response to self-antigen encounter. In the current proposal, these two models will be tested in detail. In either case, the signals required for differentiation into antibody producing cells and the extent to which there are contributions from non-B cells will be determined. Finally, the effect of autoimmune-prone backgrounds on the regulation of RNA-specific B cells in the 564Igi system will be studied. These experiments will help unravel the mechanisms by which RNA-specific B cells become activated and produce pathogenic autoantibodies in SLE.

Public Health Relevance

B cell recognition of endogenous ligands for Toll like receptors such as nuclear antigens present in apoptotic cell bodies probably have a crucial role in sensing and repairing various forms of tissue injury. The understanding of how, when and where this recognition is taking place and are regulated will provide the means to treat a broad range of chronic inflammatory conditions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI076409-01A2
Application #
7785270
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Ferguson, Stacy E
Project Start
2010-07-02
Project End
2014-06-30
Budget Start
2010-07-02
Budget End
2011-06-30
Support Year
1
Fiscal Year
2010
Total Cost
$412,500
Indirect Cost
Name
Tufts University
Department
Pathology
Type
Schools of Medicine
DUNS #
039318308
City
Boston
State
MA
Country
United States
Zip Code
02111
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Han, Jin-Hwan; Umiker, Benjamin R; Kazimirova, Anastasia A et al. (2014) Expression of an anti-RNA autoantibody in a mouse model of SLE increases neutrophil and monocyte numbers as well as IFN-I expression. Eur J Immunol 44:215-26
Umiker, Benjamin R; McDonald, Gabrielle; Larbi, Amma et al. (2014) Production of IgG autoantibody requires expression of activation-induced deaminase in early-developing B cells in a mouse model of SLE. Eur J Immunol 44:3093-108
Umiker, Benjamin R; Andersson, Shauna; Fernandez, Luis et al. (2014) Dosage of X-linked Toll-like receptor 8 determines gender differences in the development of systemic lupus erythematosus. Eur J Immunol 44:1503-16