IMMUNOLOGIC STUDIES IN PRIMARY BILIARY CIRRHOSIS

原发性胆汁性肝硬化的免疫学研究

• 批准号: 4690017
• 负责人: E ANTHONY JONES
• 金额: --
• 依托单位: NAT INST OF ARTHRITIS, DIABETES, DIGESTIVE & KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/4690017
• 关键词: B lymphocyte; T lymphocyte; affinity chromatography; biopsy; cellular pathology; complement pathway; computer simulation; cytotoxicity; density gradient ultracentrifugation; erythrocytes; gel filtration chromatography; haptens; helper T lymphocyte; human subject; human tissue; humoral immunity; hypersensitivity; immune adherence reaction; immunofluorescence technique; immunoglobulin G; immunoglobulin M; immunohematology; immunologic assay /test; immunopathology; immunosuppression; leukocyte activation /transformation; liver cirrhosis; liver disorder diagnosis; liver function; mixed lymphocyte reaction test; monocyte; orphan disease /drug; phagocytosis; radiation immunosuppression; radioimmunoassay; radiotracer; reticuloendothelial system; suppressor T lymphocyte; surface antigens; tissue /cell culture

Abnormal immune mechanisms are being studied in patients with primary biliary cirrhosis (PBC). T cell mediated help and suppression of pokeweed mitogen-induced immunoglobulin synthesis by B cells has been studied using radioimmunoassays to measure IgG and IgM synthesized by cultures containing appropriate mixtures of different lymphocyte subpopulations in vitro. The ability of T cells to proliferate when cultured with either autologous or allogeneic irradiated B cells (mixed lymphocyte reactions) or with hapten-modified autologous irradiated B cells has been assessed. Results of these studies include the demonstration in PBC of (i) a diminished capacity of T cells to inhibit immunoglobulin synthesis in vitro, (ii) a deficiency of the autologous but not the allogeneic mixed lymphocyte reaction and (iii) a deficiency in the primary but not the secondary proliferative response of T cells to hapten-modified cells. These findings suggest that in PBC there is a fundamental defect in the interaction between autoreactive T cells and surface antigens on autologous non-T cells which leads to diminished activation of suppressor T cells and, hence, predisposes to a state of immune hyperresponsiveness. The coexistence of IgA deficiency and PBC has been documented. Thus, while it is possible that IgA deficiency may contribute to the development of PBC, the pathogenesis of PBC does not require IgA-dependent mechanisms. Sera from patients with PBC has been shown to contain a factor, probably an abnormally immunoreactive IgM, which blocks the binding of C3b-opsonized erythrocytes by monocytes; this finding affords a potential explanation for the C3b-receptor specific clearance defect by fixed macrophages in PBC. Patients with PBC have been shown to have diminished natural killer cell activity due to a functional defect of cytolytic effector cells. Defects of humoral immunity in PBC appear to be due to activation of small subpopulations of B cells. For example, in PBC there is evidence compatible with an expanded clone of B cells that synthesize mitochondrial antibodies with different antigenic specificities from those synthesized by normal B cells. A disease-specific immunologic defect has yet to be defined in PBC.

正在对原发性癌症患者的异常免疫机制进行研究 胆汁性肝硬化（PBC）。 T 细胞介导的商陆帮助和抑制 已使用 B 细胞研究了有丝分裂原诱导的免疫球蛋白合成 放射免疫测定法测量含有以下成分的培养物合成的 IgG 和 IgM 体外不同淋巴细胞亚群的适当混合物。 这 T 细胞与自体或自体培养物一起培养时的增殖能力 同种异体辐照 B 细胞（混合淋巴细胞反应）或 已对半抗原修饰的自体照射 B 细胞进行了评估。 结果 这些研究包括在 PBC 中证明 (i) T 细胞在体外抑制免疫球蛋白合成的能力，(ii) 自体混合淋巴细胞缺乏，同种异体混合淋巴细胞不缺乏 反应和（iii）主要缺陷而不是次要缺陷 T 细胞对半抗原修饰细胞的增殖反应。 这些发现 表明 PBC 的相互作用存在根本性缺陷 自身反应性 T 细胞与自体非 T 细胞表面抗原之间的关系 这会导致抑制性 T 细胞的激活减少，因此， 容易进入免疫高反应状态。 共存 IgA 缺乏症和 PBC 已被记录。 因此，虽然有可能 IgA 缺乏可能会导致 PBC 的发生 PBC的发病机制并不需要IgA依赖性机制。 血清来自 PBC 患者已被证明含有一个因素，可能是 异常免疫反应性 IgM，可阻断 C3b 调理素的结合 红细胞由单核细胞组成；这一发现提供了一个潜在的解释 PBC 中固定巨噬细胞的 C3b 受体特异性清除缺陷。 PBC 患者的自然杀伤细胞数量减少 由于溶细胞效应细胞的功能缺陷而导致的活性。 缺陷 PBC 中体液免疫的减弱似乎是由于小 B 细胞亚群。 例如，PBC 有证据表明 与合成线粒体的 B 细胞扩增克隆相容 与合成的抗体具有不同的抗原特异性 正常B细胞​​。 疾病特异性免疫缺陷尚未确定 在 PBC 中定义。