IMMUNOPATHOGENESIS OF INFLAMMATORY VASCULAR DISEASE

这项建议将研究炎症性疾病的免疫发病机制 (IVD)在人类干燥综合征（SS）中，一种常见的自身免疫性结缔组织病 组织疾病（CTD）和一种自身免疫小鼠（MRL/MP）， 与SS共享许多功能。 IVD的两种主要组织病理学类型 在SS中描述：嗜中性粒细胞（NIVD），组织病理学 与白细胞破碎性血管炎和单核细胞（MIVD）难以区分 其中单核细胞（淋巴细胞、单核细胞和浆细胞） 包括血管炎性浸润。 提出了一种新的IVD模型，在该模型中， 单核细胞（主要是淋巴细胞）是主要的启动细胞。 事件，随后是中性粒细胞的流入。 以下具体目标 免疫细胞化学技术和体外培养 允许剖析细胞和抗体相互作用的系统 与血管内皮细胞：1）通过表型特征确定 炎症性血管浸润的发生率， 由T淋巴细胞通过血管的早期迁移启动 内皮细胞 2)探讨T淋巴细胞对血管内皮细胞增殖的影响， 内皮细胞存活、增殖和介质释放（花生四烯酸 酸代谢）。 3)为了确定炎症细胞内的前B细胞是否 血管壁由白细胞介素3（IL-3）合成辅助性T细胞诱导 细胞增殖并分化为RF合成B和血浆 细胞 4)以确定是否在当地生产的射频和原位 免疫复合物的沉积激活补体途径， 诱导中性粒细胞趋化性或IVD浸润中淋巴细胞是否 为中性粒细胞合成淋巴因子化学引诱物。 这两 机制可以负责调解从MIVD过渡到 NIVD。 5)为了确定是否有针对内皮细胞表面的自身抗体， 抗原存在于SS患者和MRL/MP小鼠中， 这些抗体对内皮细胞存活和功能的影响。 6)为了确定IVD的发展是否可以通过以下方式在体内调节： 将抗体输注到参与血管内皮细胞的淋巴细胞亚群， 抗RF的炎症抗独特型抗体，或类 II（I-A）行列式。 这些研究有助于理解 在CTD中IVD的免疫发病机制，但也在其他临床设置。

This proposal will examine the immunopathogenesis of inflammatory disease (IVD) in human Sjogren's Syndrome (SS), a common autoimmune connective tissue disorder (CTD), and in a strain of autoimmune mice (MRL/MP), which shares many features with SS. Two main histopathologic tgypes of IVD have been described in SS: neutrophilic (NIVD), histopathologically indistinguishable from leukocytoclastic vasculitis, and mononuclear (MIVD) in which mononuclear cells (lymphocytes, monocytes, and plasma cells) comprise the vascular inflammatory infiltrates. A new model of IVD is proposed in which the infiltration of vessel walls by mononuclear cells (principally lymphocytes) is the primary initiating event, followed by an influx of neutrophils. The following specific aims will be examined by immunocytochemical techniques and in vitro culture systems permitting the dissection of cellular and antibody interactions with vascular endothelium: 1) To determine by phenotypic characterization of inflammatory vascular infiltrates whether vascular inflammation is initiated by early migration of T lymphocytes through vascular endothelium. 2) To assess the effects of T lymphocytes on vascular endothelial cell survival, proliferation, and mediator release (arachidonic acid metabolism). 3) To determine whether pre-B cells within inflamed vessel walls are induced by interleukin 3 (IL-3) synthesizing T-helper cells to proliferate and differentiate into RF synthesizing B and plasma cells. 4) To determine whether the local production of RF and in situ deposition of immune complexes activate the complement pathway(s) and induce neutrophil chemotaxis or whether lymphocytes in IVD infiltrates synthesize a lymphokine chemoattractant for neutrophils. Either of these mechanisms could be responsible for mediating the transition from MIVD to NIVD. 5) To determine whether autoantibodies to endothelial cell surface antigens are present in SS patients and MRL/MP mice and to clarify the effects of such antibodies on endothelial cell survival and function. 6) To determine whether the development of IVD can be modulated in vivo by infusion of antibodies to subsets of lymphocytes involved in the vascular inflammation anti-idiotypic antibodies against RF, or antibodies to Class II (I-A) determinants. These studies have relevance to understanding the immunopathogenesis of IVD in CTD, but also in other clinical settings.