肝细胞移植免疫排斥反应的机制与处理策略

一、肝细胞移植免疫排斥反应发生机制 在肝细胞移植(HCT)所致的免疫排斥反应中起主要作用的是组织相容性抗原(MHC),排斥反应发生的快慢和严重程度取决于供受体组织相容性的匹配程度。一般而言,肝细胞表面只有MHC Ⅰ类分子表达,无MHC Ⅱ类分子表达,因此肝细     

大肠癌癌组织及癌旁组织中MHC-I类分子的表达及意义

大肠癌影响预后的主要原因是肿瘤的转移及复发 ,这与肿瘤细胞逃避机体的免疫监视密切相关。机体的抗肿瘤免疫机制 ,是以细胞免疫为主导作用 ,并与体液免疫相互协调 ,协同杀伤肿瘤细胞的 ,其中主要组织相容性复合体 (MHC)在人类又称白细胞抗原系统 (HLA)起关键作用。目前国内外少见 MHC-I类分子 A、B位点在大肠癌中表达的报道。2 0 0 1年 8～ 1 2月 ,我们应用流式细胞仪检测 2 1例大肠癌患者癌组织及癌旁组织中 MHC-I类分子 A、B位点的表达 ,以探讨大肠癌逃避机体免疫监视的机制及其临床意义。现报告如下。1　资料与方法1 .1　一般资…     

HLA-DMA及DMB基因与1型糖尿病相关性的研究进展

现有研究资料表明:和经典的人主要组织相容性复合体(HLA)Ⅱ类基因一样,HLAⅡ类非经典基因DMA及DMB基因与1型糖尿病存在显著的相关性且存在一定的人种差异。HLA经典Ⅱ类分子抗原结合槽所结合肽的性质对1型糖尿病的发病有着重要影响。推测在HLA经典Ⅱ类分子所允许结合的一系列肽系中,DM易感性基因或二聚体编码的DM分子在行使其功能的过程中,更易使致糖尿病性肽复合物“得以生存”,并被呈递至细胞表面,使辅助性T细胞(Th)1/Th2比例上调,从而导致1型糖尿病的发生。对多人种进行包含DM分子在内的扩展单倍型与1型糖尿病易感相关性的研究有着重要的意义。     

同种移植大鼠心脏Ⅱ类主要组织相容性抗原表达及其机制探讨

目的　探讨同种移植心脏术后Ⅱ类主要组织相容性 (MHC)抗原表达及其影响机制。方法　建立大鼠颈部心脏移植模型 ,以同基因移植和无移植动物作为对照 ,采用免疫组化、逆转录PCR等技术测定异基因大鼠移植心脏Ⅱ类MHC抗原表达和心肌IL 2、IL 4mRNA的水平变化。结果移植心脏Ⅱ类MHC抗原表达与心肌急性免疫排斥病理学改变明显相关 (P <0 0 1 ) ,排斥早期其阳性表达细胞位于小血管内皮及周围 ,随着急性免疫排斥病变发展心肌IL 2、IL 4mRNA水平与Ⅱ类MHC抗原表达存在相关变化 (P <0 0 1 )。结论　移植心脏Ⅱ类MHC抗原表达是术后急性免疫排斥识别和效应时相的重要环节 ,急性免疫排斥早期移植心脏功能改变可能与微血管内皮损伤有关 ,受体细胞因子网络对供体Ⅱ类MHC抗原表达有调节作用     

扩张型心肌病与MHC-DR基因多态性的关联

扩张型心肌病 (DCM) ,是一种严重的心脏疾病 ,迄今为止 ,DCM的病因及发病机理仍不十分清楚 ,众多研究发现 ,DCM也具有遗传家族史等倾向 ,其发病与免疫失衡有关。人类免疫遗传基因位于MHC区域内 ,人们从免疫遗传学角度对该病进行研究 ,发现DCM与人类的免疫遗传基因 (MHC Ⅱ )的多态性有关。尤其是与MHC Ⅱ类基因的DR关系密切。新近研究表明MHC DR抗原在DNA序列上还存在着高度多态性[1]。为了分析中国汉族人MHC Ⅱ类基因在DCM病发生发展中的作用机制 ,为该病的诊断 ,治疗和预防提供依据 ,也使基因分型早日代替血清学分型 ,我们…     

主要组织相容性复合体与控制衰老进程的关系

主要组织相容性复合体(MHC)与衰老进程有较为密切的关系。一些与衰老有关的因素诸如免疫功能的改变、DNA损伤修复、自由基的清除、某些混合功能氧化酶水平以及神经内分泌代谢变化等,均证实与MHC相关联。本文论述MHC在上述几方面的作用,认为MHC通过基因和/或其连锁位点以及基因产物来影响机体衰老的过程。研究MHC对衰老的调节有助于从基因水平上搞清衰老的机制,这对于探讨如何预防衰老和控制其进程等问题有所裨益。     

乙型和丙型肝炎病毒对主要组织相容性复合体基因的调节

众所周知，免疫学上把能引起强而迅速排斥反应者称为主要组织相容性抗原，其编码基因是一组紧密连锁的基因群，称之为主要组织相容性复合体(major histocompatibility complex，MHC)。MHC在不同的哺乳动物中有不同的命名，但是其组成、结构以及编码产物的功能等却很相似。人主要组织相容性抗原称为人白细胞抗原系统(human leucocyte antigen，HLA)。     

HLA-Ⅱ类基因多态性与肝脏疾病相关性研究进展

肝组织的免疫损伤是大部分肝脏疾病共同的发病机制.病毒性肝炎、自身免疫性肝炎、药物性肝炎等疾病的发展转归均与免疫功能密切相关.人类主要组织相容性复合体( Major histocompatibility complex,MHC)决定着机体的免疫特性,其基因位于人类6号染色体的短臂(6p21.3),全长约3 600 kb,是多态性最为复杂的基因群.人类白细胞抗原(Human leukocyte antigen,HLA)为MHC的基因产物.目前MHC基因区内已发现239个基因位点,可表达基因达130个,其中39.8％的基因与免疫系统有关,而Ⅱ类区域中几乎所有的基因均与免疫功能相关[1].     

蛋白酶体在免疫反应及自身免疫病中的作用

蛋白酶体(proteasome)是一种存在于细胞质和细胞核内的蛋白水解酶复合物，负责降解细胞内大部分蛋白质。它在主要组织相容性复合体(MHC)I类分子的抗原递呈、免疫应答和许多自身免疫病的发生发展过程中扮演重要的角色，是近年来基础及临床免疫研究的热点之一。本文就蛋白酶体在这些领域的研究进展作一综述。     

HLA—DMA及DMB基因与1型糖尿病相关性的研究进展

现有研究资料表明：和经典的人主要组织相容性复合体(HLA)Ⅱ类基因一样，HLA-Ⅱ类非经典基因DMA及DMB基因与1型糖尿病存在显著的相关性且存在一定的人种差异。HLA经典Ⅱ类分子抗原结合槽所结合肽的性质对1型糖尿病的发病有着重要影响。推测在HLA经典Ⅱ类分子所允许结合的一系列肽系中，DM易感性基因或二聚体编码的DM分子在行使其功能的过程中，更易使致糖尿病性肽一复合物“得以生存”，并被呈递至细胞表面，使辅助性T细胞(Th)1／Th2比例上调，从而导致1型糖尿病的发生。对多人种进行包含DM分子在内的扩展单倍型与1型糖尿病易感相关性的研究有着重要的意义。     

A second lineage of mammalian major histocompatibility complex class I genes.

Major histocompatibility complex (MHC) class I genes typically encode polymorphic peptide-binding chains which are ubiquitously expressed and mediate the recognition of intracellular antigens by cytotoxic T cells. They constitute diverse gene families in different species and include the numerous so-called nonclassical genes in the mouse H-2 complex, of which some have been adapted to variously modified functions. We have identified a distinct family of five related sequences in the human MHC which are distantly homologous to class I chains. These MIC genes (MHC class I chain-related genes) evolved in parallel with the human class I genes and with those of most if not all mammalian orders. The MICA gene in this family is located near HLA-B and is by far the most divergent mammalian MHC class I gene known. It is further distinguished by its unusual exon-intron organization and preferential expression in fibroblasts and epithelial cells. However, the presence of diagnostic residues in the MICA amino acid sequence translated from cDNA suggests that the putative MICA chain folds similarly to typical class I chains and may have the capacity to bind peptide or other short ligands. These results define a second lineage of evolutionarily conserved MHC class I genes. This implies that MICA and possibly other members in this family have been selected for specialized functions that are either ancient or derived from those of typical MHC class I genes, in analogy to some of the nonclassical mouse H-2 genes.     

Regulation of cytotoxic T lymphocyte triggering by PIR-B on dendritic cells

Priming of cytotoxic T lymphocytes (CTLs) by dendritic cells (DCs) is crucial for elimination of pathogens and malignant cells. To activate CTLs, DCs present antigenic peptide-complexed MHC class I molecules (MHC-I) that will be recognized by the CTLs with T cell receptors and CD8 molecules. Here we show that paired Ig-like receptor (PIR)-B, an MHC-I receptor expressed on antigen-presenting cells, can regulate CTL triggering by blocking the access of CD8 molecules to MHC-I. PIR-B-deficient DCs evoked CTLs more efficiently, leading to accelerated graft and tumor rejection. PIR-B(+) non-DC transfectant cells served as less efficient stimulators and targets for CTLs than PIR-B(-) cells at the effector phase in vitro. On surface plasmon resonance analysis, PIR-B and CD8alpha alpha were revealed to compete in binding to MHC-I. Our results may provide a novel strategy for regulating CTL-mediated immunity and diseases in a sterical manner.     

Takayasu's arteritis: An update on physiopathology

Takayasu's arteritis (TA) is a chronic large vessel vasculitis. The physiopathology of TA has not been completely elucidated, but it appears to be multifactorial and to mainly involve cellular immunity. The pathologic sequence could implicate stimulation from an antigen that triggers heat shock protein (HSP)-65 expression in aortic tissue which, in turn, induces MHC class I-related chain A (MICA). T-cells and natural killer (NK) cells expressing NKG2D receptors could recognize MICA, resulting in acute inflammation. Pro-inflammatory cytokines released from these infiltrating cells induce matrix metalloproteinases and amplify the inflammatory response, inducing more MHC antigen and costimulatory molecule expression on vascular cells and, thus, recruiting more mononuclear cells. Alpha-beta T-cells then infiltrate and specifically recognize one or a few autoantigens presented by a shared epitope associated with specific MHC on the dendritic cells (DC). These DC simultaneously cooperate to some extent with B-cells and determine a humoral immunity mainly constituted by anti-endothelial cell autoantibodies that could trigger complement-dependent cytotoxicity against endothelial cells. The use of corticosteroids and of other immunosuppressive agents can bring TA into remission in most patients. A better understanding of the immunological mechanisms responsible for the vascular injury has led to trials of anti-TNF-alpha agents with encouraging results. In the near future, new drugs specifically designed to target some of the mechanisms described above may be able to expand the physician's therapeutic arsenal in TA.     

Expression of costimulatory molecules (4-1BBL and Fas) and major histocompatibility class I chain-related A (MICA) in aortic tissue with Takayasu's arteritis

To further investigate the immunological mechanisms involved, we analyzed the expression of costimulatory molecules in aortic tissue and their counterpart molecules on infiltrating cells of patients with Takayasu's arteritis. We also examined the expression of major histocompatibility complex (MHC) class I chain-related (MIC) A in aortic tissue, which is known to be induced by external stress, and its counterpart NKG2D receptors on infiltrating cells. Among these costimulatory molecules, strong expression of 4-1BBL and Fas was induced in the aortic tissue, and most of the infiltrating cells expressed 4-1BB and FasL, suggesting these pathways play critical roles in T-cell-mediated vascular injury. We also found that MICA was strongly induced in the aortic tissue and that at least part of the infiltrating cells expressed NKG2D receptors. Some infiltrating cells - but not vascular smooth muscle cells - seemed to have undergone apoptosis. Our findings strongly suggest that 4-1BB/4-1BBL and Fas/FasL pathways play important roles in vascular injury in Takayasu's arteritis. We assume that gammadelta T cells infiltrated aortic tissue recognizing MICA, resulting in the induction of MHC antigens and costimulatory molecules, and then alphabeta T-cells infiltrated recognizing some auto-antigens presented by MHC antigens, leading to chronic inflammation.     

Immunogenetic biomarkers in inflammatory bowel diseases: Role of the IBD3 region

Many studies have demonstrated the linkage between the IBD3 region (6p21.1-23), an area which encompasses the famous human leukocyte antigen (HLA) complex, and Crohn’s disease (CD) or ulcerative colitis (UC). IBD3 is the only region that meets genome-wide significance, and provides stronger evidence of the linkage than 16p13.1-16q12.2 (IBD1), the locus that contains the susceptibility gene CARD15. However, despite these findings, IBD3 susceptibility genes remain elusive and unclear due to the strong linkage disequilibrium, extensive polymorphism, and high gene density that characterize this area and also due to varying allele frequencies in populations around the world. This area presents an extremely high abundance of genes, including the classical and non-classical major histocompatibility complex (MHC) class I and II genes, and other genes, namely MHC class III genes tumor necrosis factor (TNF)-α and -β, and Hsp, whose proteins play key functions in immunological processes. To date, it is not clear which genes within the MHC family contribute to the IBD pathogenesis, although certain HLA alleles have been associated with IBD. Recent insights into the biological function of other genes encoded within the IBD3 region, such as the MHC class I chain-related (MIC) genes, have led investigators to a more comprehensive exploration of this region. MHC class I chain-related molecule A (MICA) is highly polymorphic and interacts with NKG2D, its receptor on the surface of NK, Tγδ and T CD8⁺ cells. Increased expression of MICA in intestinal epithelial cells and increased expression of NKG2D in CD4⁺ T cells (lamina propria) in patients with CD have also been reported. MICA alleles have also been associated with IBD, and a variation at amino acid position 129 of the α2-heavy chain domain seems to categorize MICA alleles into strong and weak binders of NKG2D receptor, thereby influencing the effector cells’ function. In this regard, a relevant role of MICA-129-Val/Met single nucleotide polymorphism has recently been implicated in the pathogenesis of IBD. TNF-α and -β also play an important role in inflammatory response. In fact, IBD is commonly treated with TNF-α inhibitors. Additionally, polymorphisms of TNF-α gene are known to affect the gene expression level and particular TNF-α genotypes may influence the response of IBD patients treated with TNF-α inhibitors.     

Cell stress-regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium.

Conventional major histocompatibility complex (MHC) class I genes encode molecules that present intracellular peptide antigens to T cells. They are ubiquitously expressed and regulated by interferon gamma. Two highly divergent human MHC class I genes, MICA and MICB, are regulated by promoter heat shock elements similar to those of HSP70 genes. MICA encodes a cell surface glycoprotein, which is not associated with beta 2-microglobulin, is conformationally stable independent of conventional class I peptide ligands, and almost exclusively expressed in gastrointestinal epithelium. Thus, this MHC class I molecule may function as an indicator of cell stress and may be recognized by a subset of gut mucosal T cells in an unusual interaction.     

三种常见肝细胞系免疫相关分子的表达

目的探讨三种常见肝细胞系Huh7、HepG2、HepG2.2.15免疫相关分子的表达。方法提取三种细胞的RNA并逆转录合成cDNA,用PCR方法检测细胞因子及其受体、MHC分子的表达情况。结果三种细胞均能表达Ⅰ型干扰素及干扰素受体、IL-7、IL-15等细胞因子,也能表达HLA-A、HLA-B、HLA-DP、HLA-DR及非经典的CD1d、MICB等MHC分子及其相关基因,HepG2、HepG2.2.15表达MICA。三种细胞均不表达IL-4、IL-5、IL-6、IFN-γ等细胞因子。与内参相比,IL-7及IL-15、HLA-A等的表达在HepG2和HepG2.2.15之间存在一定的差异。结论三种肝细胞系能表达Ⅰ型干扰素及干扰素受体、IL-7、IL-15、HLA等一系列的免疫相关分子。     

Prevalent expression of MHC class I chain-related molecule A in human osteosarcoma

MHC class I chain-related molecule A (MICA) is one of the major ligands for activating immune-receptor NKG2D which is expressed on NK cells and cytotoxic T lymphocytes. The release and sustained expression of MICA protein can impair NKG2D-mediated cytotoxic activity by reducing NKG2D receptor on immune effector cells. The aim of the study was to investigate the expression and release of MICA in human osteosarcoma. RT-PCR, immunohistochemistry, western blotting and flow cytometry were used in analyzing the expression of MICA. Serum level of soluble MICA was quantitated by ELISA. Our data showed that MICA is prevalently expressed in osteosarcoma both in mRNA and protein level. Upregulation of MICA was found in osteosarcoma compared with benign tumors and normal bone tissues. Higher level of soluble MICA in serum can be detected in osteosarcoma patients. In conclusion, prevalent expression of MICA and higher serum level of soluble MICA may suggest a deficiency of MICA-NKG2D mediated immunosurveillance in osteosarcoma patients. Restoring the expression of NKG2D receptor on immune effector cells may contribute to a therapeutic strategy for human osteosarcoma.     

HLA class I, NKG2D, and natural cytotoxicity receptors regulate multiple myeloma cell recognition by natural killer cells

The role of natural killer (NK) cells in multiple myeloma is not fully understood. Here, NK susceptibility of myeloma cells derived from distinct disease stages was evaluated in relation to major histocompatibility complex (MHC) class I, MHC class I chain-related protein A (MICA), MHC class I chain-related protein B (MICB), and UL16 binding protein (ULBP) expression. MHC class I molecules were hardly detectable on bone marrow cells of early-stage myeloma, while late-stage pleural effusion-derived cell lines showed a strong MHC class I expression. Conversely, a high MICA level was found on bone marrow myeloma cells, while it was low or not measurable on pleural effusion myeloma cells. The reciprocal surface expression of these molecules on bone marrow- and pleural effusion-derived cell was confirmed at mRNA levels. While bone marrow-derived myeloma cells were readily recognized by NK cells, pleural effusion-derived lines were resistant. NK protection of pleural effusion cells was MHC class I dependent. Receptor blocking experiments demonstrated that natural cytotoxicity receptor (NCR) and NK receptor member D of the lectin-like receptor family (NKG2D) were the key NK activating receptors for bone marrow-derived myeloma cell recognition. In ex vivo experiments patient's autologous fresh NK cells recognized bone marrow-derived myeloma cells. Our data support the hypothesis that NK cell cytotoxicity could sculpture myeloma and represents an important immune effector mechanism in controlling its intramedullary stages.     

MICB gene expression on peripheral blood mononuclear cells and susceptibility to multiple sclerosis in north of Iran

Multiple sclerosis (MS) is an autoimmune multifactorial degenerative disease with detrimental affliction on central nervous system. MHC class I chain- related geneA,B(MICA and MICB) are nonclassical human leukocyte antigens that can affect on some diseases and also on transplantation. The purpose of this study was to evaluate the MICA and MICB MRNA expression in multiple sclerosis patients. In this study, we evaluated MICA and MICB MRNA expression in the peripheral blood mononuclear cells by reverse transcryptase-polymerase chain reaction(RT-PCR) in MS patients and normal controls. The results of this study showed that 32.6% of patients with progressive clinical outcome over expressed MICB genes in comparison with controls ( p=0.002). It is concluded that the high expression of MICB gene in MS patients is an important criterion of MS disease that it may be due to the interaction between MICB and its receptor on CD8+T or NK cells.