Study of a peptide -induced lupus model

Abstract

Systemic lupus erythematosus (SLE) is a disease of unknown etiology. It is characterized by the production of autoreactive antibodies, especially anti-nuclear antibodies (ANA). The induction of the ANA is T cell dependent and is thought to be an antigen driven process. Although several antigens have been implicated in murine lupus models, it is still not known what is the responsible antigen in lupus patients. Using an anti-dsDNA antibody to screen a phage peptide display library, we previously identified a peptide DWEYS, which is a mimetope of double stranded (ds) DNA. Immunization of BALB/c mice with this peptide induced an anti-dsDNA antibody response.;My thesis work mainly focuses on studying the regulation of autoreactive B cells and the genetic factors that may contribute to the development of SLE in the peptide-induced SLE model. In contrast to BALB/c mice, DBA/2 mice did not develop an anti-dsDNA response after peptide immunization. We demonstrate that DBA/2 mice are able to generate a peptide specific T cell response similar to that of BALB/c mice. However, DBA/2 mice possess a less autoreactive naive B cell repertoire, which results in non-responsiveness in DBA/2 mice. We further showed that B cell receptor (BCR) crosslinking could induce more cell death and a stronger calcium flux in B cells from DBA/2 mice. Therefore, DBA/2 mice appear to regulate their autoreactive B cells more stringently than BALB/c mice and display more severe central tolerance.;Fc receptors have been shown linked to the development of SLE in murine models and SLE patients. We tested the function of the activating Fc receptors in the peptide-induced model of SLE. We observed that following peptide immunization Fcgamma-/- BALB/c mice developed a stronger autoantibody response and showed more profound glomerular immunoglobulin deposition compared to wild type mice. We further showed that the Fcgamma-/- mice mounted a stronger peptide specific Th1 type T cell response. Consistent with these observations, bone marrow derived dendritic cells (BMDCs) from the Fcgamma-/- mice display elevated expression of MHC class II and co-stimulatory molecules and they produce more interleukin 12. These data suggest that the absence of the common gamma chain predispose mice to autoimmunity and that molecules associated with the gamma chain may have an "inhibitory" role in the development of autoimmune diseases.;Anti-dsDNA antibody correlates best with disease activity in SLE patients. Tolerizing the anti-dsDNA response, therefore, may potentially benefit SLE patients. We took advantage of the defined antigen in our peptide induced-lupus model and asked whether we can induce tolerance to the DWEYSVWLSN peptide in non-spontaneously autoimmune mice. We show treatment of BALB/c mice with soluble peptide twice prior to immunization reduced the in vivo activation of peptide-specific T cells and altered their cytokine profile. The BALB/c mice treated with soluble peptide displayed a lower serum anti-dsDNA response and less immunoglobulin deposition in the kidney. This effect was not dependent on tolerogenic properties of B cells since we were able to tolerize T cells from BALB/c B cell deficient (mu) mice. Thus, it is possible to diminish the autoimmunity that arises by molecular mimicry by tolerizing to foreign antigen.