ANTIBODY DIRECTS T CELL MEDIATED AUTOIMMUNITY

在器官特异性自身免疫性疾病中，T细胞机制是关键的， 但抗体的作用尚不清楚。同样不清楚的是致病性CD 4 + T细胞归巢并靶向天然自身抗原以启动发病机制， 由于T细胞只识别抗原肽-MHC II类复合物， 抗原呈递细胞（APC）。在人类卵巢癌的小鼠模型中， 自身免疫性疾病（卵巢炎），CD 4 + T细胞，卵巢特异性 蛋白ZP 3足以诱导卵巢病理学，但抗 ZP 3不诱导任何卵巢病理学。然而，单独的T细胞靶向 在具有MHC lass II/+巨噬细胞的退化卵泡中仅降解ZP 3 浸润;具有天然ZP 3的正常卵泡得以保留。我们最近 发现抗体诱导T细胞重靶向，其中IgG结合 天然ZP 3的自身抗体完全改变了T细胞的位置 介导从退化卵泡到正常卵泡的炎症， 导致卵巢功能部分的破坏。这 这种现象不仅与临床相关，而且可以作为一种模型 研究T细胞如何靶向天然抗原，以及抗体如何在 过程根据最近的进展，我们假设一个两阶段 机制在I期中，天然ZP 3结合抗体的组合效应 与T细胞可能是细胞因子，诱导温和的抗体介导的 炎症，这导致在促炎反应， 毛囊在第二阶段，促炎性变化反过来吸引T 细胞（可能是非特异性的）和单核细胞; T细胞 介导的炎症迅速取代抗体介导的炎症。 因此，抗体引起完全T细胞介导的组织损伤， 天然抗原的位置。在具体目标1中， 级联反应将被详细研究， 将确定可能涉及第一阶段和第二阶段的问题;在具体目标2中， 我们将研究哪些细胞因子或抗体同种型能够诱导 在第一阶段的炎症;在具体目标3中，我们将研究什么是前- 炎症变化发生在卵泡中以吸引T细胞， 单核细胞，以及什么类型的T细胞参与靶向卵泡。

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.