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 is now well-established, our knowledge about the cellular and molecular mechanisms of peripheral tolerance and how they may be altered in autoimmunity are 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 targeted B cell antigen receptor (BCR) knock-in mouse model (HKIR) that yields dual-reactive {Arsonate (Ars) and DNA-chromatin-reactive} B cells. HKIR dual- reactive B cells escape central tolerance and develop into mature follicular B cells. These B cells can be recruited into the antibody forming cell (AFC) and germinal center (GC) pathways with Ars-conjugated foreign Ag. In contrast to other autoreactive transgenic mouse models in which B cells are excluded from the peripheral lymphoid follicles, the HKIR model is ideal to study peripheral B cell tolerance mechanisms operative in the AFC and GC-memory pathways or checkpoints that regulate autoantibody production. Our published data show that due to their autoreactivity, HKIR dual-reactive B cells differentiate into primary AFCs but are prevented from expanding in the GC response and do not efficiently become memory B cells. Our published and preliminary data indicate that peripheral B cell tolerance checkpoints operative at antibody forming cell (AFC) and germinal center (GC) pathways can be altered in the presence of lupus susceptibility locu Sle1. However, the influence of Sle1 on the AFC and GC-memory checkpoints 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 confer a B cell autonomous break in the AFC and GC tolerance checkpoints (Aim-1).
In Aim -2, we will determine the cell type (T and/or DCs) that provides B cell help and thus promotes a break in GC tolerance. Data generated from these studies will reveal how these two mechanisms permit autoantibody production in lupus and thus have both diagnostic and therapeutic implications.

Public Health Relevance

Completion of the proposed studies will provide important new insights into whether and how peripheral tolerance checkpoints operative during GC and AFC pathways silence 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 SLE.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
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Johnson, David R
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Pennsylvania State University
Schools of Medicine
United States
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Domeier, Phillip P; Chodisetti, Sathi Babu; Schell, Stephanie L et al. (2018) B-Cell-Intrinsic Type 1 Interferon Signaling Is Crucial for Loss of Tolerance and the Development of Autoreactive B Cells. Cell Rep 24:406-418
Domeier, Phillip P; Schell, Stephanie L; Rahman, Ziaur S M (2017) Spontaneous germinal centers and autoimmunity. Autoimmunity 50:4-18
Domeier, Phillip P; Chodisetti, Sathi Babu; Soni, Chetna et al. (2016) IFN-? receptor and STAT1 signaling in B cells are central to spontaneous germinal center formation and autoimmunity. J Exp Med 213:715-32
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
Wong, Eric B; Soni, Chetna; Chan, Alice Y et al. (2015) B cell-intrinsic CD84 and Ly108 maintain germinal center B cell tolerance. J Immunol 194:4130-43
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
Khan, Tahsin N; Wong, Eric B; Soni, Chetna et al. (2013) Prolonged apoptotic cell accumulation in germinal centers of Mer-deficient mice causes elevated B cell and CD4+ Th cell responses leading to autoantibody production. J Immunol 190:1433-46
Wong, Eric B; Khan, Tahsin N; Mohan, Chandra et al. (2012) The lupus-prone NZM2410/NZW strain-derived Sle1b sublocus alters the germinal center checkpoint in female mice in a B cell-intrinsic manner. J Immunol 189:5667-81