IMMUNOPATHOGENESIS OF INFLAMMATORY VASCULAR DISEASE

炎症性血管疾病的免疫发病机制

• 批准号: 3347937
• 负责人: ELAINE ALEXANDER
• 金额: $ 13.64万
• 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/3347937
• 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.

本提案将探讨炎症性疾病的免疫发病机制