IMMUNOPATHOGENESIS OF INFLAMMATORY VASCULAR DISEASE

炎症性血管疾病的免疫发病机制

• 批准号: 3347939
• 负责人: ELAINE ALEXANDER
• 金额: $ 21.38万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-07-01 至 1990-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3347939
• 关键词: B lymphocyte; Sjogren's syndrome; antiantibody; antiidiotype antibody; arachidonate; autoantibody; autoimmune disorder; cell migration; chemoattractants; complement pathway; disease /disorder model; enzyme linked immunosorbent assay; fatty acid metabolism; helper T lymphocyte; histochemistry /cytochemistry; histocompatibility antigens; human subject; immune complex; immunochemistry; immunofluorescence technique; interleukin 3; leukocyte activation /transformation; lymphoblast; monoclonal antibody; neutrophil; passive immunization; plasma cells; prostacyclins; rheumatoid factor; thromboxanes; tissue /cell culture; vascular endothelium; vasculitis

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.

这项提案将研究炎症性疾病的免疫发病机制。 人类干燥综合征(SS)是一种常见的自身免疫性结缔组织病 组织紊乱(CTD)，以及在一种自身免疫小鼠(MRL/MP)中，这 与党卫军有许多共同之处。IVD的两种主要组织病理类型有 已在SS中描述：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病(MIVD)无法区分 其中单个核细胞(淋巴细胞、单核细胞和浆细胞) 包括血管炎症浸润物。 提出了一种新的IVD模型，在该模型中， 单个核细胞(主要是淋巴细胞)是主要的起始物。 事件发生后，中性粒细胞大量涌入。以下是具体目标 将通过免疫细胞化学技术和体外培养进行检测 允许剖析细胞和抗体相互作用的系统 血管内皮细胞：1)通过表型特征确定 炎性血管是否渗入血管炎症 由T淋巴细胞通过血管的早期迁移启动 内皮细胞。2)评价T淋巴细胞对血管功能的影响 内皮细胞存活、增殖和介质释放(花生四烯酸 酸代谢)。3)确定前B细胞是否发炎 白介素3(IL-3)合成辅助性T细胞诱导血管壁 细胞增殖分化为RF合成B和血浆 细胞。4)确定当地生产的射频和就地 免疫复合体的沉积激活补体途径(S)和 诱导中性粒细胞趋化或IVD中的淋巴细胞是否渗入 合成一种中性粒细胞淋巴因子趋化剂。这两个中的任何一个 机制可负责调停从MIVD向 NIVD。5)确定抗内皮细胞表面的自身抗体 SS患者和MRL/MP小鼠中存在抗原，为了阐明 这些抗体对血管内皮细胞存活和功能的影响。 6)确定在体内是否可以通过以下方式调节IVD的发展 与血管有关的淋巴细胞亚群的抗体输注 针对RF的炎症性抗独特型抗体，或抗类抗体 II(I-A)行列式。这些研究对于理解 IVD在CTD中的免疫发病机制，但也在其他临床环境中。