Systemic lupus erythematosus is an autoimmune disease characterized by the production of nephritogenic anti-double stranded (ds) DNA antibodies. We have identified a peptide mimetope of dsDNA that can induce anti-DNA antibodies in non-spontaneously autoimmune BALB/c mice and have devised a novel methodology to stain and sort peptide-reactive B cells. In this model, crossreactive anti-peptide, anti-DNA B cells break tolerance, while T cell tolerance is maintained at the initiation of the response. We propose to study the initiation and progression of autoreactivity and renal pathology in this model. We will identify whether the B cells producing crossreactive anti-peptide, anti-DNA antibodies belong to the marginal zone, follicular or B1 subset (s). We will determine if progression of the response involves the activation of autoreactive T cells, and if the cytokine profile of the peptide reactive T cells changes during progression of the response. Since the peptide-reactive T cells are uniquely of the TH1 type at initiation of the response, we will immunize with protocols that induce TH2 type T cells to ask whether either the antibody response or renal pathology is altered by immune deviation. Finally, we have shown that both the autoantibody response and the T cell response to peptide are enhanced in mice with a targeted disruption of the FcR gamma chain. We will determine if an enhanced T cell response alters the repertoire of activated B cells. These studies, in composite, will help us understand how autoreactive B cells can be activated in vivo by antigen exposure.
| Kim, Sun Jung; Zou, Yong Rui; Goldstein, Jordan et al. (2011) Tolerogenic function of Blimp-1 in dendritic cells. J Exp Med 208:2193-9 |
