In organ specific autoimmune diseases, the T cell mechanism is pivotal, but the role of antibody is unclear. Also unclear is how pathogenic CD4+ T cells home to and target native autoantigens to initiate pathogenesis, since T cells only recognized antigenic peptide-MHC class II complexes on the antigen presenting cells (APC). In a murine model for human ovarian autoimmune disease (oophoritis), CD4+ T cells, specific to an ovarian protein ZP3, are sufficient to induce ovarian pathology, but antibody to ZP3 does not induce any ovarian pathology. T cells alone, however, targets only degraded ZP3 in degenerated follicles with MHC lass II/+ macrophage infiltration; normal follicles with native ZP3 are spared. We recently discovered antibody induced T cell retargeting, in which binding of IgG autoantibody to native ZP3 completely alters the location of T cell mediated inflammation from degenerated follicles to normal follicles, leading to destruction of the functional part of the ovary. This phenomenon is not only clinically relevant, but also may serve as a model to study how T cells target native antigen, and how antibody functions in the process. Based on recent progress, we hypothesize a two-phase mechanism. In Phase I, the combined effect of native ZP3-bound antibody with T cells probably cytokine(s), induces a mild antibody mediated inflammation, which results in a pro-inflammatory response in the follicles. In Phase II, the pro-inflammatory changes in turn attract T cells (maybe non-specific) and monocyte to the follicles; a T cell mediated inflammation rapidly replaces antibody-mediated inflammation. Thus, antibody brings about a full T cell mediated tissue injury in the location of native antigen.
In Specific Aim 1, cellular and molecular cascades will be investigated in detail, and inflammatory molecules possibly involved in Phase I and II will be identified;
in Specific Aim 2, we will study which cytokines or antibody isotypes are able to induce inflammation in Phase I;
in Specific Aim 3, we will investigate what pro- inflammatory changes occur in the follicles to attract T cells and monocytes, and what type of T cells are involved in targeting follicles.
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