IMMUNOPATHOGENESIS OF INFLAMMATORY VASCULAR DISEASE

炎症性血管疾病的免疫发病机制

• 批准号: 3347938
• 负责人: ELAINE ALEXANDER
• 金额: $ 19.18万
• 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/3347938
• 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.

该提案将检查炎症性疾病的免疫发作 （ivd）在人类Sjogren综合征（SS）中，一种常见的自身免疫连接 组织障碍（CTD）和自身免疫性小鼠（MRL/MP）的菌株，该菌株 与SS共享许多功能。 IVD的两个主要组织病理TGYPE 在SS中描述：嗜中性粒细胞（NIVD），组织病理学 与白细胞碎裂性血管炎和单核（MIVD）无法区分 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，其中，容器壁通过 单核细胞（主要是淋巴细胞）是主要启动 事件，随后涌入中性粒细胞。 以下特定目标 将通过免疫细胞化学技术和体外培养进行检查 系统允许解剖细胞和抗体相互作用 带有血管内皮：1）通过表型表征确定 炎症性血管浸润是否是血管炎症 T淋巴细胞通过血管早期迁移而引发 内皮。 2）评估T淋巴细胞对血管的影响 内皮细胞存活，增殖和介体释放（蛛形子 酸代谢）。 3）确定发炎中的前B细胞是否 白介素3（IL-3）合成T-Helper诱导血管壁 细胞增殖并分化为RF合成B和等离子体 细胞。 4）确定RF的本地生产和原位的生产是否 免疫复合物的沉积激活补体途径和 诱导嗜中性粒细胞趋化性或IVD浸润中的淋巴细胞 合成中性粒细胞的淋巴因子趋化剂。 这两个 机制可能是导致介导从MIVD过渡到的机制 Nivd。 5）确定自身抗体是否对内皮细胞表面 SS患者和MRL/MP小鼠存在抗原，并澄清 这种抗体对内皮细胞存活和功能的影响。 6）确定是否可以通过体内调节IVD的发展 输注涉及血管淋巴细胞亚群的抗体 针对RF的炎症抗二动抗体或类抗体 II（I-A）决定因素。 这些研究与理解 IVD在CTD中的免疫发病发生，但在其他临床环境中也是如此。