Relationship between HLA-DQA1 polymorphism and genetic susceptibility to idiopathic dilated cardiomyopathy

Background Autoimmune mechanisms are likely to participate in the pathogenesis of subgroup of idiopathic dilated cardiomyopathy (IDC), and components of the major histocompatibility complex may serve as markers for the propensity to develop immune-mediated myocardial damage. Human leukocyte antigen (HLA) class Ⅱ genes, especially highly polymorphic HLA-DQ genes, play an important role in the activation of immune responses, and thus control the predisposition for or protect from IDC. This study was conducted to investigate the HLA-DQA1 allele polymorphisms in IDC patients and to explore the underlying immunological mechanism and the hereditary susceptibility to IDC.Methods The polymerase chain reaction sequence-specific primers (PCR-SSP) technique was used to analyze the polymorphisms in the second exon of DQA1 in three groups: 72 IDC patients diagnosed according to the criteria of World Health Organization (IDC group); 100 end-stage heart failure patients suffering from a disease of known etiology (HF group); and 100 healthy subjects enrolled for the study during a routine health survey (control group). Patients in the IDC group were stratified according to ejection fraction (EF). Those with EF values were higher than 35% were placed into subgroup 1; subgroup 2 included patients with an EF value of 15%-35%; and subgroup 3 consisted of those whose EF values less than 15%. Results The frequency of HLA-DQA1＊0501 alleles was significantly higher in the IDC group (0.39) than that in the HF group (0.12) and the control group (0.09) (both P<0.05). Further analysis of the three IDC subgroups showed a higher frequency of DQA1＊0501 among patients with lower EF values (both P<0.05, compared with subgroups 1 and 2). The frequency of DQA1＊0201 was higher in the control group than that in the IDC group (P<0.05).Conclusions The HLA-DQA1＊0501 allele confers susceptibility to IDC, while the DQA1＊0201 allele confers protection against it, which indicates that genetic background involved in IDC and heart failure is different. HLA-DQA1 genes are involved in the regulation of specific immune responses by auto- or foreign anti-myocardium antibody.     

Premises for immune interventional therapy in rheumatoid arthritis

Consideration of rheumatoid arthritis (RA) as an autoimmune disease includes initiating event(s), genetic predisposition, immune regulatory derangements, and effector cycles of articular damage. The initiating event is still unknown. Collagen type 2 has good claims as a rheumatogenic autoantigen which perpetuates disease. The association of HLA DR4 with rheumatoid arthritis is in part explainable by the affinity of binding of the rheumatogenic antigen to a hypervariable portion of MHC Class II molecules with selective presentation of this complex to T cell receptors. Immune regulatory derangements include lymphokine-induced aberrant expression of MHC Class II molecules on synovial tissues, the presence of a 'resistant' subset of B cells (CD5 + ve), failure of anti-idiotypic control of autoantibodies (not well established as yet in rheumatoid arthritis), and defective immune suppression, revealed by low counts in synovial fluids of a suppressor-inducer subset of CD4 + ve T cells. The many possibilities for therapeutic immune intervention would include polyclonal or monoclonal antibody to block (a) receptors for antigen on B or T lymphocytes (but this would require knowledge of the rheumatoid arthritis-inducing antigen), (b) the CD4 complex on helper T lymphocytes, (c) MHC Class II (Ia) molecules, for which there are excellent prototypes in experimental immunopathology, or (d) lymphokines or their receptors. Induction of suppression by 'tolerogenic vaccines' is experimentally validated, but only for diseases for which an autoantigen can be identified.     

调节性T细胞在白癜风与自身免疫性甲状腺疾病发生中的免疫机制

白癜风是一种色素脱失性自身免疫性皮肤病,常见于20岁以下的年轻人,主要影响美观和心理。白癜风发病机制尚不明确,提出多种相关发病机制学说,其中自身免疫机制学说具有最强的说服力。白癜风可能的发病机制是机体免疫耐受性被破坏,自身免疫反应中产生的有害物质影响黑色素细胞的正常代谢,最终导致黑色素大量损失而引起白癜风。调节性T细胞(Treg)抑制自身免疫反应,防止自身免疫性疾病的发生,维持机体免疫耐受的重要细胞,Treg细胞抑制正常T细胞对致病因素的过度免疫反应,避免自身组织器官在免疫反应过程的损伤。Treg是研究白癜风和自身免疫性甲状腺疾病发病机制的焦点。抗原特异性Treg细胞在机体免疫系统自身修复过程中重要细胞,Treg细胞在白癜风和自身免疫性甲状腺疾病发病过程中保护黑色素细胞和甲状腺滤泡细胞不受过度免疫反应的损伤,防止这些自身免疫性疾病的发生,正是由于这点,白癜风和有些自身免疫性疾病在病因上可能具有共同的交叉点。Treg细胞为基础的治疗方法可能对白癜风或其他自身免疫性疾病患者带来新的治疗机遇,进一步阐明Treg细胞在白癜风与其他自身免疫性疾病中免疫机制,在新的治疗方法和新药开发具有重要意义。本文探讨Treg细胞在白癜风与自身免疫性甲状腺病发生中的免疫机制,进一步阐明白癜风与自身免疫性甲状腺疾病的相关性。      

安徽汉族51例免疫性不育症中医证型与HLA-DQA1基因型的关系

目的:探讨抗精子抗体阳性的免疫性不育症患者与人类白细胞抗原-DQA1(Human LeococyteAntigen-DQA1,HLA-DQA1)基因的相关性及不同中医证型与HLA-DQAl等位基因的相关性。方法:采用聚合酶链反应序列特异性引物(polymerase chain reaction-sequence specific primer,PCR-SSP)技术,将51例抗精子抗体阳性的免疫性不育症中医分型为肾阴不足型、湿热内蕴型和瘀血阻滞型的患者与60名正常健康人的HLA-DQA1基因进行分型研究。结果:免疫性不育症组HLA-DQA1*0401等位基因频率明显高于正常对照组(χ2=29.869,P<0.01),免疫性不育症组DQA1*0301等位基因频率较正常对照组显著降低(P<0.01)。肾阴不足型免疫性不育症组HLA-DQA1*0301基因频率较正常对照组显著降低(P<0.01)。HLA-DQA1*0401基因频率较正常对照组显著升高(P<0.01)。结论:HLA-DQA1*0401等位基因可能是抗精子抗体阳性的免疫性不育症的易感基因,DQA1*0301可能是安徽汉族免疫性不育症的保护基因;免疫性不育症患者的中医证型肾阴不足型可能与DQA1*0401有关。     

人类白细胞抗原-DRβ1特异性低T细胞反应性肽对T细胞激活的抑制作用

目的　研究人类白细胞抗原 (HLA) DRβ1特异性Ⅱ型胶原 (CII)多肽的T细胞受体(TCR)结合表位改变对T细胞激活的影响。探讨通过抑制T细胞对抗原肽的识别治疗类风湿关节炎的新途径。方法　利用AutoDock3 0系统设计非T细胞结合肽 ;以激光共焦显微镜及流式细胞仪观察荧光标记的CⅡ 2 6 3 2 72修饰肽的细胞内转运及其在细胞膜上的表达 ;应用HLA DR1转基因抗原呈递细胞和特异性T细胞的激活体系 ,研究替换TCR识别氨基酸的CII修饰肽在T细胞激活中的作用。结果　计算机模拟显示CII第 2 6 3位苯丙氨酸 (F)、2 6 6位谷氨酸 (E)是与HLA DR1结合的关键位点 ,而 2 6 7位谷氨酰胺 (Q)、2 6 9位脯氨酸 (P)和 2 70位赖氨酸 (K)是T细胞识别的主要功能氨基酸。用甘氨酸 (G)、和 /或丙氨酸 (A)替换上述位点可去除功能性侧链。CⅡ修饰肽可被HLA DR1转基因抗原呈递细胞摄取并与膜表面的HLA DR1分子结合。CⅡ 2 6 3 2 72原型肽可激活T细胞 ,而用A或G单一替换 2 6 7、2 6 8、2 6 9、2 70位氨基酸或连续替换 2 6 8 2 70位氨基酸的修饰肽对T细胞的激活能力明显降低 (P <0 0 1)。低反应性修饰肽 2 70A、sub2 6 8 2 70对CⅡ诱导的T细胞激活有显著抑制作用。结论　通过替换CII中TCR特异性氨基酸可减弱或消除其对T细胞的结合能力及激     

1型糖尿病(T1D)的细胞免疫学发病机制的研究进展

 近年来,1型糖尿病(type 1 diabetes,T1D)的发病率不断上升,其发病是遗传、环境、免疫等因素共同作用引发了胰岛β细胞为主体的自身免疫损害反应。T1D的发病机制涉及免疫应答及调节等免疫过程,其中细胞免疫在T1D的发病过程中起着重要作用,CD4+及CD8+ T淋巴细胞的浸润,B淋巴细胞、自然杀伤细胞(natural killer cells,NK)、树突状细胞(dendritic cells,DC)等免疫细胞共同参与了β细胞的损伤,最终引起T1D的发病。     

乙型肝炎肝内ICAM-1和HLA-A,B,C表达的研究

目的 研究乙型病毒性肝炎肝内ICAM－1和HLA－A,B,C表达间的关系及其在乙型肝炎免疫发病机制中的作用。方法 用免疫组化单种染色检测11例正常人和70例HBV感染者肝内ICAM－1、HLA－A,B,C表达水平,并用免疫组化双重染色检测其肝内ICAM－1和HLA－A,B,C复合表达。结果 乙型肝炎患者肝细胞ICAM－1表达水平与HLA－A,B,C表达水平之间呈显著正相关（P＜0.05）;在炎症坏死区,表达ICAM－1的肝细胞多数也同时表达HLA－A,B,C。结论 ICAM－1和HLA－A,B,C共同参与介导乙型肝炎肝细胸的免疫损伤过程;ICAM－1／HLA－A,B,C双阳性肝细胞可能是CTL发挥有效细胞毒作用的靶细胞。     

HLA基因多态性与慢性肾衰竭的相关性研究进展

人类自细胞抗原（HLA）是人类最复杂、最具多态性的遗传系统,与疾病的易患性密切相关,其功能涉及机体免疫应答和调节的各个方面。慢性肾衰竭（CRF）是各类肾脏疾病发展到晚期的共同结果,而肾脏病的发生、发展多数是由免疫介导的炎性反应所致。近年来,HLA基因的表达及其多态性与CRF可能存在的免疫遗传易患性和相对风险性引起了国内外学者的重视。该文就HLA基因多态性与CRF相关性的研究进展予以综述。     

HLA-DR抗原在自身免疫性及非自身免疫性甲状腺疾病中的表达

目的 :探讨自身免疫性及非自身免疫性甲状腺疾病中HLA DR抗原的表达方式及其与甲状腺疾病的关系。方法 :采用SABC免疫组化方法检测 2 0例自身免疫性甲状腺疾病及 18例非自身免疫性甲状腺疾病的甲状腺滤泡上皮细胞HLA DR抗原的表达。另外检测 10例正常甲状腺组织作为对照。结果 :2 0例自身免疫性甲状腺疾病中HLA DR表达阳性者 14例 ,18例非自身免疫性甲状腺疾病中HLA DR表达阳性者 11例 ,二者与正常对照组之间均存在显著差异 (P <0 .0 5 )。在自身免疫性甲状腺疾病中 ,HLA DR抗原的表达主要在细胞膜 ,而在非自身免疫性甲状腺疾病中 ,HLA DR抗原的表达多局限于细胞浆 ,二者之间存在显著差异 (P <0 .0 5 )。结论 :HLA DR的表达在自身免疫性甲状腺疾病中可能参与抗原呈递及T细胞激活 ,引起机体的免疫损伤 ;在非自身免疫性甲状腺疾病时 ,其可能与细胞增殖有关     

Two sister cases of autoimmune hepatitis

Two sister cases of autoimmune hepatitis are described. Case 1 involved a 49-year-old woman who suffered from bleeding gums and general fatigue. Her laboratory data showed a marked increase in transaminase levels, an elevated IgG level with titers 1:80 or more of both antinuclear and smooth muscle antibodies and thrombocytopenia. Histology of the biopsied liver revealed chronic active hepatitis with a moderate infiltration of mononuclear cells. A complication of idiopathic thrombocytopenic purpura was determined based on higher titers of PA-IgG and a normal bone marrow findings. Case 2 involved a 54-year-old woman, an elder sister of case 1, who suffered from general fatigue with jaundice. Her laboratory data showed a severe damage of liver function and an elevated IgG level with positive antibodies to nuclear and smooth muscle antigen. Histology of the biopsied liver revealed chronic active hepatitis. Both patients were negative to markers of hepatotrophic agents. Under diagnosis of autoimmune hepatitis, they have been treated with prednisone followed by a significant clinical improvement. HLA types of two patients were Bw54-DR4 and DR4. Among 4 other siblings, the eldest sister suffered from rheumatoid arthritis. The occurrence of two sister cases of type-1 autoimmune hepatitis has rarely reported and the fact would support a role of enviromental factors besides genetic factors for the onset of this disease.     

HLA基因多态性与原发性高血压的相关性研究进展

人类白细胞抗原（HLA）由称人类主要组织相容性复合体（MHC）,它由一组具有高度多态性和连锁的不均衡性基因群体构成,其研究主要于器官移植、免疫应答、法医学、人类学和疾病相关性等领域。本文介绍了HLA的基因结构、多态性及HLA—Ⅱ类基因多态性与EH相关性等方面内容。     

Current concepts of the pathogenesis of inflammatory bowel disease

Although the cause of inflammatory bowel disease is not known, the pathogenesis involves an immune-mediated tissue damage that is the result of an interaction among genetic predisposing factors, exogenous triggers and endogenous modifying influences. Multiple genes are involved and operate at the level of the immune response and at the target organ. Exogenous triggers include the enteric microflora which might stimulate the mucosal immune system in genetically predisposed individuals. Endogenous modifying factors such as the psychoneuroendocrine system have regulatory effects on the immune system and the inflammatory response, and may influence the course of the disease. While autoimmune phenomena do occur, particularly in ulcerative colitis, there is no evidence that they are directly responsible for the tissue damage. It appears more likely, particularly in Crohn’s disease, that tissue injury may occur as an indirect or “bystander” effect of mucosal T-cell hyperactivation, perhaps in response to a normal enteric microbial antigen. Most of the immunologic and histologic features of Crohn’s disease can be explained by the effects of T-cell derived and other cytokines on the epithelium, the local immune system, the microvasculature, and the recruitment of auxilliary effector cells such as neutrophils.     

特发性肌炎与HLA基因的相关性研究进展

特发性肌炎(IIM)是以肌肉炎症为特征的罕见的自身免疫病及结缔组织病,包括皮肌炎、多发性肌炎、包涵体肌炎及儿童皮肌炎,此类疾病常与人类白细胞抗原(HLA)系统相关。HLA-Ⅱ类基因HLA-DRB1*0301和与它连锁的等位基因DQA1*0501以及单体型AH8.1已被许多研究证实是IIM的主要遗传危险因素,在白种人中表达最为显著。相同HLA等位基因在不同种族及表型中可为IIM遗传危险因素或保护因素。现就HLA等位基因与IIM的相关性进行综述。     

外伤性持续植物状态病人非特异性免疫功能的损害及意义

目的通过检测HLA-DR在外周血单核细胞表面的表达水平,了解脑外伤后持续植物状态(PVS)病人的免疫功能变化情况.方法应用密度梯度离心法将实验组即PVS病人及正常对照组的外周血单核细胞分离出来,然后应用酶联免疫法检测外周血单核细胞受IFN-r或LPS刺激后,其所表达的HLA-DR的变化水平.结果和正常对照组相比,脑外伤后PVS病人外周单核细胞表面HLA-DR的表达水平明显下降(P＜0.001).实验组及对照组的外周血单核细胞经IFN-r或LPS共孵育刺激后,其HLA-DR的表达水平皆有显著升高(P＜0.01),但对脑外伤后PVS病人来说,其HLA-DR的表达仍难以恢复到正常水平(P＜0.05).结论脑外伤后持续性植物状态病人的免疫功能明显受到抑制.     

1型糖尿病与成人隐匿性自身免疫糖尿病

主要探讨自身免疫糖尿病（包括1型糖尿病和LADA）的临床以及致病谱。遗传易感因素影响了自身免疫糖尿病的发病年龄。1型糖尿病和LADA的最主要的易感基因位于HLA区域。由于年龄相关的遗传影响因素,目前还不能用遗传学的方法来区分LADA和1型糖尿病。非遗传因素在1型糖尿病中有很大的作用,但关于LADA还知之甚少。在低龄儿童中就可有糖尿病相关的免疫过程,这可预测β细胞毁损过程。对于LADA的治疗和预防还需进一步研究以确定最佳方案。     

肾移植术后新生HLA抗体和MICA抗体对移植肾功能的损伤作用

目的研究肾移植术后新生人类白细胞抗原(HLA) 抗体及主要组织相容性I类相关链A抗原（MICA）抗体的产生对移植肾功能的损伤作用。方法采用免疫磁珠流式细胞仪液相芯片技术检测96例肾移植患者HLA及MICA抗体。根据检测结果,将患者分为HLA抗体阳性组（HLA+）、MICA抗体阳性组（MICA+）、以及HLA、MICA抗体阴性组（HLA /MICA ）,观察并比较各组不良免疫事件的发生率。再根据有无急性排斥（AR）,将患者分为排斥组（AR+）和非排斥（AR ）组,观察HLA抗体、MICA抗体对移植肾功能的影响。结果HLA+组急性排 斥反应发生率高于HLA /MICA 组(43．5％ vs 11.7％,P＜0.05);MICA+组急性排斥反应发生率与HLA /MICA 组比较差异无统计学意义(15．3％ vs 11．7％,P＞0．05);AR+组中,HLA+患者术后1、3、6和12个月时血清肌酐水平高于HLA /MICA 患者, MICA+患者在术后1、3月时血肌酐水平高于抗体阴性患者;AR 组中,HLA+患者术后6、12个月血肌酐水平高于HLA /MICA 患者;MICA+组在术后6个月及12个月的尿蛋白定量均值高于150?mg,并随时间逐渐升高。结论HLA抗体对移植肾功能的损伤作用表现为血清肌酐的升高以及与急性排斥反应的发生有关;MICA抗体对移植肾功能的损伤主要表现为尿蛋白定量的升高。     

The genetic basis of hyperreactive malarious splenomegaly

Hyperreactive malarious splenomegaly (HMS) represents an abnormal immune response to recurrent malaria, characterized by excessive production of both IgM and IgG antibodies. It has both a racial and a familial distribution in various parts of the world. Immune responses to many foreign antigens, including those of malaria, are under genetic control of the major histocompatibility locus (MHC), through the influence of HLA antigens on regulatory T-lymphocyte activity. It is therefore likely that this region also contains the genetic determinants for HMS, which would be reflected in associations between HMS and particular HLA antigens or haplotypes. Genetic studies of the Watut people of Papua New Guinea have not shown any association between HMS and a wide range of red cell and serum polymorphisms. However, HMS in this group is associated with the class II HLA antigen DR2, and with high levels of HLA heterozygosity. Formal genetic analysis of family data also points to a sex-linked gene as a further determinant of overresponsiveness to malaria in the Anga. These findings suggest that more than one genetic system may be involved in the development of HMS, and that the combined effects of several genetic determinants may be responsible for the extraordinarily high frequency of HMS found in the Upper Watut Valley.     

HLA-DRB1和HLA-DQB1基因多态性与天疱疮的相关性

目的探讨人白细胞抗原(HLA)-DRB1和HLA-DQB1等位基因多态性与天疱疮的遗传相关性。方法以上海地区的58例天疱疮患者(病例组)和89名正常对照者(对照组)作为研究对象。采用聚合酶链反应-序列特异性引物分型技术(PCR-SSP)对两组HLA-DRB1和HLA-DQB1等位基因进行分型,直接计数法计算等位基因频率并进行组间比较,以等位基因频率的比值比(OR)评价基因与疾病的关联性。结果病例组和对照组共检测到13种HLA-DRB1等位基因和5种HLA-DQB1等位基因。统计学分析结果表明:病例组HLA-DRB1*14和HLA-DQB1*05等位基因频率分别为17.24%和18.97%,显著高于对照组的1.69%(P=0.000,P值的校正值Pc<0.05,OR=12.150)和6.74%(P=0.001,Pc<0.05,OR=3.238);病例组HLA-DQB1*06等位基因频率为15.52%,显著低于对照组的30.90%(P=0.003,Pc<0.05,OR=0.411)。结论 HLA-DRB1*14和HLA-DQB1*05可能是上海地区天疱疮患者的易感基因,而HLA-DQB1*06则可能是保护基因。     

HLA alleles in patients with Guillain-Barre syndrome

ＧｕｉｌｌａｉｎＢａｒｒｅｓｙｎｄｒｏｍｅ(ＧＢＳ)ｉｓａｃｏｍｍｏｎｎｅｕｒｏｌｏｇｉｃａｌｄｉｓｅａｓｅｗｉｔｈｃｈａｒａｃｔｅｒｉｓｔｉｃｓｏｆｆｌａｃｃｉｄｐａｒａｌｙｓｉｓＴｈｅｅｔｉｏｌｏｇｙｏｆＧＢＳｉｓｔｈｏｕｇｈｔｔｏｂｅｄｅｍｙｅｌｉｎａｔｉｏｎａｎｄａｘｏｎａｌｄａｍａｇｅｓａｆｔｅｒｉｎｆｅｃｔｉｏｎＴｈｅｅｘａｃｔｍｅｃｈａｎｉｓｍｉｓｓｔｉｌｌｕｎｃｌｅａｒＭｏｌｅｃｕｌａｒｍｉｍｉｃｒｙｈｙｐｏｔｈｅｓｉｓｏｆＧＢＳｉｓｔｈｅｍｏｓｔｃｉｔｅｄｅｘｐｌａｎａｔｉｏｎＴ…     

人类白细胞抗原与乙型肝炎病毒感染相关性研究进展

乙型肝炎病毒(HBV)感染与机体的免疫功能状态密切相关,而人体免疫状态主要取决于人类白细胞抗原(HLA)基因复合体。HLA分子在抗原识别、免疫应答和免疫调控,破坏外来抗原靶细胞方面与抗HBV免疫反应有着密切的关系。HLA基因的多态性可能导致机体免疫功能状态的差异,因而决定HBV感染的易感性和发生、发展与转归。现就HLA基因的多态性与乙型肝炎病毒感染的相关性进行综述。