It has been estimated that nearly 50% of newly produced B cells in the bone marrow are autoreactive and therefore must be eliminated or tolerized to prevent autoimmunity. During the maturation, B cells undergo consecutive ?checkpoints? to induce and preserve immune tolerance in the developing B cell repertoire. First, early in the development, the classic Burnet's clonal deletion eliminates B cells expressing highly autoreactive BCR through FAS-mediated apoptosis or impediment of BCL-2 survival pathways. At later developmental stages, the second mechanism - receptor editing further reduces the affinity of autoreactive BCR through additional V(D)J genetic recombinations or somatic hypermutations. The third tolerogenic mechanism, which takes place in na??ve mature B cells that still retain a degree of autoreactivity after receptor editing, is receptor tuning (also known as anergy or peripherally induced immune tolerance). This mechanism relies on the intrinsic inhibition of BCR signaling pathways and down- regulation of BCR expression to prevent autoreactive B cells from activation. B cells with induced immune tolerance can recognize chronically present antigens but are immunologically silenced due to the BCR signaling inhibition. These B cells are vulnerable to autoimmune activation by crossreactive autoantigens. Anergic immune tolerance is a signaling phenomenon, and the tolerogenic balance between activatory and inhibitory BCR signaling inputs is reversible. Studies in patients with Rheumatoid arthritis and in the mouse arthritis model indicate that BCR signal inhibitory pathways that maintain induced B cell tolerance are altered in RA. Our recent findings demonstrated that complement receptor 2 (CR2) and CD19-mediated BCR signaling co-stimulation bypasses the inhibitory mechanism maintaining induced immune tolerance in autoreactive in B cells and induces antibody production, and that this mechanism omits BCR inhibitory phosphatases. This project will investigate the pathogenic role of the loss of induced B cell immune tolerance in experimentally induced arthritis and address the involvement of CR2/CD19-mediated BCR signaling augmentation in this process. We hypothesize that complement-opsonized antigens disrupt the anergic tolerance to crossreactive autoantigens. This study focuses on the following Aims: (1) Use the mouse model of collagen-induced arthritis (CIA) to demonstrate a more severe loss of peripherally induced B cell tolerance in animals immunized with collagen/complement conjugates vs. collagen only. (2) Demonstrate a protective effect of CR2 deletion on B cell tolerance in CIA in CR2-deficient animals. (3) Confirm the loss of BCR signaling features associated with induced immune tolerance in normal B cells stimulated via BCR & CR2/CD19 co-receptors in vitro.
The goal of this study is to investigate the role of Complement Receptor 2 (CR2; CD21) in the activation of autoreactive B cells in experimentally induced arthritis in mice. Upon complement-mediated activation, these B cells produce cross-reactive antibodies that attack the body's own tissue and this process leads to the joint damage. Data from this study will provide valuable insights into the development of new treatments to control arthritis and offer important new information about the interaction of innate (complement) and adaptive immune responses.