PROVIDED. Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of autoantibodies to a select group of intracellular proteins, most notably, determinants on nucleosomes and RNA-protein complexes. Autoimmune responses in human SLE and in murine models require the processing and presentation of self antigen leading to the activation of T cells. CD4 T cells provide help to autoreactive B cells, all leading to autoantibody production and pathology. The depletion of B cells in both murine SLE and in Rituximab-treated patients ameliorates disease. Our previous studies have shown that autoreactive B cells can escape peripheral tolerance, present autoantigens, and activate autoreactive T cells from the normal repertoire of lymphocytes. Indeed, this may be one mechanism by which Rituximab therapy is efficacious in human SLE. Our recent in vivo work demonstrates that unique subsets of antigen presenting cells (APCs) activate T cells at different time points in the development of immunity. In particular, B cells are the primary ARC in the early T cell responses post-immunization. Later in the autoimmune response, B cells lose the ability to present antigen while dendritic cells (DCs) gradually acquire APC function in T cell activation. Our studies demonstrate that DCs (and other APCs) can acquire antigen from the B cells by an undetermined transfer mechanism. The major goal of this proposal is to directly follow the transfer of antigen from antigen-specific B cells to other APCs and to determine if this mechanism has biological significance to the onset of autoimmunity. The success of our work will depend on the use of the In Vivo Imaging core facility. Our studies will examine the interaction of B cells, dendritic cells, and antigen T cells within the lymph node of a living mouse by intravital microscopy. In particular, we will identify the kinetics, location and mechanism of antigen transfer in vivo. Overall, our studies are designed to understand the processing and presentation of presentation of autoantigens in murine models of lupus autoimmunity.
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