Autoimmune diseases are associated with a loss of immunological tolerance, a failure of an organism's adaptive immune cells to distinguish between 'self'and 'non-self'. While the existence of B cell central tolerance (in the bone marrow) is now well-established, our knowledge about the cellular and molecular mechanisms of peripheral tolerance (in peripheral lymphoid organs) and their perturbation in autoimmune diseases such as 'lupus'is limited. Understanding peripheral B cell tolerance is important as perturbed regulation of these tolerance mechanisms may allow for the development of autoreactive B cells and pathogenic IgG autoantibodies that contribute to autoimmune diseases such as systemic lupus erythematosus (SLE). Here, we have used a B cell antigen receptor (BCR) knock-in mouse model (HKIR) that yields dual-reactive {Arsonate (Ars) and DNA-chromatin-self-antigen- reactive} B cells. We previously showed that dual-reactive HKIR B cells can develop into follicular B cells and differentiate into antibody forming cells (AFCs) upon immunization with Ars-conjugated foreign antigen. These dual-reactive cells also can enter germinal centers (GCs), but due to their autoreactivity are negatively regulated or prevented from expanding in GCs by a GC tolerance mechanism and do not efficiently become memory B cells. Therefore, in contrast to other autoreactive transgenic mouse models in which B cells are excluded from the peripheral lymphoid follicles including AFC and GC pathways, the HKIR model is well suited to study AFC and GC-mediated B cell tolerance pathways of nuclear-Ag-specific HKIR B cells that regulate autoantibody production. Our published and preliminary data indicate that peripheral B cell tolerance operative in the AFC and GC pathways can be altered in the presence of lupus susceptibility locus Sle1. However, the influence of Sle1 on the AFC and GC-memory tolerance appeared to be incompletely penetrant indicating the possible requirement of defects in T and/or myeloid compartments for such loss of peripheral B cell tolerance leading to production of IgG ANAs and development of lupus. Here, we propose to identify the susceptibility gene(s) within the Sle1 locus that drive B cell development into AFC and GC pathways leading to loss of peripheral B cell tolerance (Aim-1).
In Aim -2, we will determine the cell type (T and/or DCs) affected by the susceptibility gene(s) within the Sle3 interval that provides B cell help and thus promotes a break in GC tolerance.
In Aim -3, we will study how type I IFNs (IFN-1) may accelerate the process of a break in GC-memory tolerance and permits robust autoantibody production in lupus-prone mice.

Public Health Relevance

Completion of the proposed studies will provide important new insights into the role of peripheral self-tolerance operative during the AFC and GC-memory pathways in silencing autoantibody production. These studies will also facilitate our understanding of how perturbations in these pathways due to the presence of lupus susceptibility loci lead to the development of autoantibody production and autoimmune disease lupus.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI091670-01A1
Application #
8183980
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Johnson, David R
Project Start
2011-08-15
Project End
2016-07-31
Budget Start
2011-08-15
Budget End
2012-07-31
Support Year
1
Fiscal Year
2011
Total Cost
$387,500
Indirect Cost
Name
Thomas Jefferson University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
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Soni, Chetna; Domeier, Phillip P; Wong, Eric B et al. (2015) Distinct and synergistic roles of Fc?RIIB deficiency and 129 strain-derived SLAM family proteins in the development of spontaneous germinal centers and autoimmunity. J Autoimmun 63:31-46
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Soni, Chetna; Wong, Eric B; Domeier, Phillip P et al. (2014) B cell-intrinsic TLR7 signaling is essential for the development of spontaneous germinal centers. J Immunol 193:4400-14
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