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.
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.
