ANTIBODY DIRECTS T CELL MEDIATED AUTOIMMUNITY

在器官特异性自身免疫性疾病中，T细胞机制是关键， 但抗体的作用尚不清楚。同样不清楚的是CD4+是如何致病的 T细胞与天然自身抗原结合并以其为靶点启动发病机制， 由于T细胞仅识别抗原肽-MHC-II类复合体 抗原提呈细胞(APC)。在人类卵巢的小鼠模型中 自身免疫性疾病(卵巢炎)，卵巢特有的CD4+T细胞 蛋白ZP3，足以诱导卵巢病理，但抗体 ZP3不会引起任何卵巢病变。然而，T细胞本身就是靶点 MHC LASS II/+巨噬细胞仅降解变性卵泡中的ZP3 正常卵泡不受ZP3的侵袭。我们最近 发现抗体诱导T细胞重定向，其中结合免疫球蛋白 天然ZP3自身抗体完全改变T细胞的位置 从退化卵泡到正常卵泡的介导性炎症， 导致卵巢的功能部分被破坏。这 这一现象不仅具有临床意义，而且可以作为一种模式。 为了研究T细胞如何靶向天然抗原，以及抗体如何在 这一过程。根据最近的进展，我们假设有两个阶段 机制。在第一阶段，天然ZP3结合抗体的联合作用 与T细胞可能的细胞因子(S)，诱导温和的抗体介导 炎症，这会导致体内的促炎反应 毛囊。在第二阶段，促炎变化反过来吸引T 毛囊的细胞(可能是非特异性的)和单核细胞；T细胞 介导性炎症迅速取代抗体介导性炎症。 因此，抗体可导致完全T细胞介导的组织损伤。 本地抗原的位置。在特定目标1中，细胞和分子 将对级联反应进行详细研究，炎症分子 将确定可能参与第一和第二阶段；在具体目标2中， 我们将研究哪些细胞因子或抗体同种类型能够诱导 炎症处于I期；在特定的目标3中，我们将调查哪些促进 炎症变化发生在滤泡中，以吸引T细胞和 单核细胞，以及哪种类型的T细胞参与靶向毛囊。

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.