IMMUNOGENETICS OF THE MAJOR HISTOCOMPATIBILITY COMPLEX

本项目研究人类免疫遗传学的主要组织相容性 复合体是免疫学、遗传学和 生物化学方面的HLA复合体和紧密相连的基因。 的 本项目的总体目标是更好地了解 负责同种异体移植反应的遗传因素，以确定 免疫机制参与这种反应，并了解 HLA复合体与遗传因素之间的关系 疾病 这些研究分为四个项目。 (1)细胞表面 人同种异体活化淋巴细胞的表型和功能。 这个项目 利用T淋巴细胞克隆技术分析 淋巴细胞多样性 (2)人B淋巴细胞体外产生 检测细胞表面抗体的人单克隆抗体正在 研究了 (3)血清学、生物化学和遗传学分析 进行胸腺-白血病（TL）抗原的人等效物， 与鼠的对应物相比。 (4)之间的关系 致病基因和HLA正在研究使用先天性肾上腺皮质激素， 由于21-羟化酶缺乏引起的增生作为模型。 这个项目 利用分子遗传学工具分析HLA基因， 地区 近年来同种异体反应性研究的重点是 T淋巴细胞分化抗原与 MHC基因产物。 这些研究涉及同种细胞毒性，人类T细胞 克隆这些结论是基于生化指标的综合分析。 使用鼠抗HLA单克隆抗体的MHC抗原的研究， 用单克隆抗体分析T淋巴细胞分化抗原 抗体和阻断研究的同种细胞毒性与这两套 抗体的调查揭示了一个独特而复杂的 格局 已经证明，多种HLA-D相关的II类 抗原都携带同种异型决定簇， 细胞毒性T细胞 其他研究涉及T细胞的研究， 通过细胞表面抗原T3和T11活化。 的关系 目前，这两种T细胞活化途径之间的联系 调查 我们在人类免疫遗传学项目中取得了重大进展， 先天性肾上腺皮质增生症的分子遗传学分析 21-羟化酶缺乏症（21-OH-Def.）。去年，我们 克隆并测序了肾上腺21-羟化酶， 细胞色素P450 该cDNA已被用于定位两个21-OH-基因内， 鼠H-2复合物。这些基因位于H-2的S区， 非常接近H-2D。 相同的cDNA探针已被用于表征 HLA复合体中的两个21-OH基因。 这两个基因中至少有一个 在一些患者中发现的HLA-Bw 47阳性HLA单倍型中缺失 与严重的，盐浪费形式的21-OH-DEF。这些研究表明， 21-OH-Def.引起的CAH是肾上腺结构基因的缺陷， 细胞色素P450 21-羟化酶。 （简体中文）

This project on human immunogenetics of the major histocompatibility complex is an integrated investigation of immunological, genetic, and biochemical aspects of the HLA complex and closely linked genes. The overall objectives for this project are to obtain a better understanding of the genetic factors responsible for allograft reactions, to identify the immunological mechanisms involved in such reactions, and to understand the relationship between the HLA complex and genetic factors predisposing to diseases. The studies are divided into four projects. (1) Cell surface phenotype and function of human alloactivated lymphocytes. This project utilizes the techniques of T-lymphocyte cloning for the analysis of lymphocyte diversity. (2) In vitro production by human B lymphocytes of human monoclonal antibodies detecting cell surface antibodies is being investigated. (3) Serological, biochemical, and genetic analysis of the human equivalent of the thymus-leukemia (TL) antigen is undertaken and compared with the murine counterparts. (4) The relationship between a disease-causing gene and HLA is being investigated using congenital adrenal hyperplasia due to 21-hydroxylase deficiency as a model. This project utilizes molecular genetic tools for the analysis of the genes in the HLA region. The major emphasis in the studies of alloreactivity during the last year has been the relationship between T lymphocyte differentiation antigens and MHC gene products. These studies have involved allocytotoxic, human T-cell clones. The conclusions are based upon the combined analysis of biochemical studies of MHC antigens using murine anti-HLA monoclonal antibodies, analysis of T-lymphocyte differentiation antigens with monoclonal antibodies and blocking studies of allocytotoxicity with these two sets of antibodies. The investigations have revealed a distinct but complex pattern. It has been demonstrated that multiple HLA-D-related class II antigens all carry allotypic determinants which can be recognized by cytotoxic T cells. Other studies have involved the investigation of T cell activation via the cell surface antigens T3 and T11. The relationship between these two T cell activation pathways is presently under investigation. We have achieved major progress in this project on human immunogenetics in the molecular genetic analysis of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OH-Def.). During the last year, we have cloned and sequenced a full length cDNA for adrenal 21-hydroxylase, a cytochrome P450. This cDNA has been used to map two 21-OH-genes within the murine H-2 complex. These genes are located within the S-Region of H-2 and very close to H-2D. The same cDNA probe has been used to characterize the two 21-OH genes within the HLA complex. At least one of these two genes are deleted in the HLA-Bw47 positive HLA haplotypes found in some patients with the severe, salt-wasting form of 21-OH-Def. These studies indicate that CAH due to 21-OH-Def. is a defect in the structural gene for adrenal cytochrome P450 21-hydroxylase. (CS)