MICA基因多态性与1型糖尿病

1型糖尿病(T1DM)是一种具有多基因遗传背景的自身免疫性疾病。目前研究发现主要组织相容性复合物Ⅰ类链相关基因A(MICA)多态性与T1DM及其发病年龄和进展缓急相关,但在不同的种族其易感性和保护性基因型不完全一致。并且这种作用是独立于其他T1DM易感基因如人类白细胞抗原(HLA)DR/DQ的。新近发现柯萨奇病毒抗体在含有MICA易感基因型的T1DM患者中多见,提示该基因的表达产物可能通过参与针对柯萨奇病毒感染的免疫,以分子模拟机制导致胰岛β细胞的损伤及T1DM。     

MICA基因多态性与1型糖尿病

1型糖尿病(T1DM)是一种具有多基因遗传背景的自身免疫性疾病。目前研究发现主要组织相容性复合物Ⅰ类链相关基因A(MⅠCA)多态性与T1DM及其发病年龄和进展缓急相关，但在不同的种族其易感性和保护性基因型不完全一致。并且这种作用是独立于其他T1DM易感基因如人类白细胞抗原(HLA)-DR／DQ的。新近发现柯萨奇病毒抗体在含有MⅠCA易感基因型的T1DM患者中多见，提示该基因的表达产物可能通过参与针对柯萨奇病毒感染的免疫，以分子模拟机制导致胰岛β细胞的损伤及T1DM。     

MICA基因多态性、巨细胞病毒感染与溃疡性结肠炎的相关性

炎症性肠病(IBD),包括克罗恩病(CD)和溃疡性结肠炎(UC),是病因不明确的慢性肠道炎症,多在中青年轻发病,呈慢性反复发作过程,以黏血便、腹泻、腹痛、消瘦和贫血为主要表现,严重时可发生中毒性巨结肠、肠穿孔、肠梗阻、肠出血及     

GTLA—4基因多态性与内分泌性自身免疫疾病

ＣＴＬＡ－４是激活的Ｔ细胞表达的一种膜蛋白，对Ｔ细胞增生起负性调节作用，引起Ｔ细胞凋亡，阻断免疫反应的发生。１型糖尿病，Ｇｒａｖｅｓ病与桥本甲状腺炎等是Ｔ细胞介导的内分泌性自身免疫疾病，近年来研究发现，ＣＴＬＡ－４基因的多态性与上述疾病有关，ＣＴＬＡ－４基因的多态性是一种自身免疫性疾病的易感因素。     

功能性主要组织相容性复合体Ⅰ类相关基因A(MICA)-129多态性和血清可溶性MICA水平与溃疡性结肠炎的关系

目的 探讨人类主要组织相容性复合体I类相关基因A(MICA)-129位点多态性及血清可溶性MICA(sMICA)水平与溃疡性结肠炎(UC)的关系.方法 采用聚合酶链反应-直接测序分型(PCR-SBT)方法 检测256例UC患者和460例正常对照者MICA-129的基因多态性;随机选取80例UC患者和90例正常对照者,采用ELISA法测定并比较血清sMICA的浓度差异.结果 UC组的MICA-129的G等位基因和GG基因型频率明显高于正常对照组(76.8%比72.2%,P=0.060;55.9%比46.3%,P=0.016);UC组sMICA水平明显高于正常对照组[(576.47±279.02)ng/L比(182.17±73.11)ng/L,P＜0.001].此外,携带GG基因型的UC患者的sMICA水平明显高于(GA+AA)基因型携带者[(638.87±347.15)ng/L比(507.51±152.87)ng/L,P=0.035].结论 MICA129基因多态性及sMICA水平与UC明显相关,MICA-129基因可能在UC的发病机制中发挥作用.

Abstract：

Objective To investigate the association of the major histocompatibility complex class Ⅰ chain-related antigens A (MICA)-129 gene polymorphism and soluble MICA (sMICA) levels with ulcerative colitis (UC) in Hubei Han nationality. Methods The genetic polymorphism of MICA-129 was examined using a polymerase chain reaction-sequence based test (PCR-SBT) in 256 UC patients and 460 healthy controls. From the above subjects, 80 patients and 90 healthy individuals were randomly selected for determining serum sMICA concentrations by ELISA. Results The frequencies of variant allele (G) and genotype (GG) in MICA-129 gene were significantly higher in the UC patients than in the controls(76. 8%vs 72. 2%, P =0. 060; 55.9% vs 46. 3% ,P =0. 016). Serum sMICA levels were significantly elevated in the patients compared to the controls[(576. 47 ±279. 02) ng/L vs( 182. 17 ±73. 11 ) ng/L,P ＜0. 001]. In addition, the sMICA levels were higher in the patients carrying MICA-129 GG genotypes than in those carrying ( GA + AA) genotypes [( 638. 87 ± 347. 15 ) ng/L vs ( 507. 51 ± 152. 87 ) ng/L, P = 0. 035].Conclusions The genetic polymorphism of MICA-129 and sMICA levels are correlated with the UC patients in Hubei Han nationality. Our findings demonstrate that MICA-129 gene may contribute to the pathogenesis of UC.     

CTLA-4基因多态性与内分泌性自身免疫疾病

CTLA 4是激活的T细胞表达的一种膜蛋白 ,对T细胞增生起负性调节作用 ,引起T细胞凋亡 ,阻断免疫反应的发生。 1型糖尿病、Graves病与桥本甲状腺炎等是T细胞介导的内分泌性自身免疫疾病 ,近年来研究发现 ,CTLA 4基因的多态性与上述疾病有关 ,CTLA 4基因的多态性是一种自身免疫性疾病的易感因素。     

DNA甲基转移酶基因多态性与自身免疫性疾病关系的研究进展

DNA甲基化是最常见的表观遗传修饰形式,在调控基因表达、维持基因组稳定中起着极其重要的作用。DNA甲基转移酶是催化并维持这一过程的一类酶,其单核苷酸多态性可导致DNA甲基转移酶构型、功能异常,进而影响基因组DNA甲基化水平,并通过多种机制导致自身免疫性疾病的发生、发展。本文以系统性红斑狼疮、类风湿关节炎、免疫性血小板减少症等常见自身免疫性疾病为例,重点阐述DNA甲基转移酶单核苷酸多态性与免疫性疾病易感性的关系。     

抗原肽运载体基因多态性与Graves病关联性的初步探讨

目的　探讨抗原肽运载体 (TAP)基因在华南地区一组汉族人中的分布及其与Graves病的关联性。方法　采用扩增阻滞突变体系 (ARMS)检测TAP1及TAP2基因各多态性位点在 67例Graves病患者及 69例正常对照组中的分布。结果　TAP基因各多态性位点在本组华南地区健康汉族人中的分布与国内外其他组资料基本一致 ,但存在一定程度的差异 ,提示TAP1及TAP2基因可能有民族、地区分布的差异。TAP1基因的单倍体型TAP1D在正常人群中的分布频率显著高于Graves病组(RR =0 1 7,P <0 0 1 ) ,TAP1C在正常人群中的分布频率显著低于Graves病组 (RR =2 0 5 ,P <0 0 5) ;而TAP2基因的单倍体型TAP2A在正常人群中的分布频率显著高于Graves病组 (RR =0 46 ,P <0 0 5) ,TAP2F在正常人群中的分布频率显著低于Graves病组 (RR =9 95 ,P <0 0 5)。结论　TAP1D及TAP2A与Graves病的保护性相关 ,可能是Graves病的保护基因 ;TAP1C及TAP2F与Graves病的易感性相关 ,可能是Graves病的易感基因     

腺苷代谢途径中基因多态性与类风湿关节炎甲氨蝶呤治疗反应的研究进展

类风湿关节炎（RA）是一种以慢性、对称性、多关节炎为主要表现的自身免疫性疾病，病程迁延，如不及早合理治疗，3年内关节破坏达70％，最终导致关节畸形和功能丧失。一直以来，甲氨蝶呤（MTX）作为RA患者改善病情的抗风湿药物的首选，即使是与其他抗风湿药物、生物制剂联用，MTX在RA治疗过程中的地位不可动摇。但其疗效个体差异很大，仅35％～65％的患者可达临床疗效，病情改善，     

载脂蛋白B基因多态性分析及其临床意义

载脂蛋白（ａｐｏ）是脂蛋白的组成成分,它们在胆固醇酯和甘油三酯的代谢过程中具有重要作用。主要的载脂蛋白有ａｐｏＡ、ａｐｏＢ、ａｐｏＣ、ａｐｏＤ和ａｐｏＥ。ａｐｏＡ主要存在于高密度脂蛋白（ＨＤＬ）中,ａｐｏＡＩ可激活卵磷脂－胆固醇酰基转移酶（ＬＣＡＴ）,ａｐｏＡⅡ可激活肝酯酶。ａｐｏＣ主要存在于极低密度脂蛋白（ＶＬＤＬ）中,ａｐｏＣⅠ也可激活ＬＣＡＴ,ａｐｏＣⅡ激活脂蛋白脂酶,ａｐｏＣⅢ作用不清。ａｐｏＤ仅见于ＨＤＬ中,其作用也不清楚。ａｐｏＥ主要存在于ＶＬＤＬ和乳糜微粒（ＣＭ）中,与组织间胆固醇…     

Functional MICA-129 polymorphism and serum levels of soluble MICA are correlated with ulcerative colitis in Chinese patients

Background and Aim: The aim of the present study was to evaluate the contribution of the dimorphism (MICA‐129 val and met) to the genetic susceptibility and functions of ulcerative colitis (UC) in patients in central China. Methods: Genotyping of MICA‐129 was performed in 272 consecutive UC patients and 560 age‐ and sex‐matched healthy individuals by using a polymerase chain reaction‐sequencing based typing (PCR‐SBT) method. A total of 93 patients and 98 healthy individuals serum soluble MICA (sMICA) concentrations were detected by enzyme‐linked immunosorbent assay. Results: Both the frequencies of the variant allele (val) and genotype (val/val) in the MICA‐129 gene were significantly higher in UC patients than in the controls (77.4% vs 71.7%, P = 0.015, 95% confidence interval [CI]: 1.064–1.716; 56.9% vs 46.4%, P = 0.005, 95% CI: 1.142–2.047). Serum sMICA levels were significantly higher in UC patients than in the controls (560 ± 140 pg/mL vs 157 ± 67 pg/mL, P < 0.0001). The genotype also affected the extent and the activity of UC. Furthermore, patients with the MICA‐129 val/val genotype had higher serum sMICA levels than those with the val/met + met/met genotype (661 ± 352 SD pg/mL vs 523 ± 245 SD pg/mL, 95% CI: 13.47–265.35, P = 0.03). In addition, patients with severe colitis were more susceptible to higher levels of sMICA than those with mild colitis. Conclusions: Our findings showed that the MICA‐129 gene polymorphism as a functionally relevant gene was associated with UC and seems to play a potential role in the development of UC in patients in central China.     

MICA基因第2、3和4外显子多态性与血清阴性脊柱关节病关联研究

目的：探讨MICA基因外显子2，3和4的多态性与血清阴性脊柱关节病（SpA)的发生是否存在关联。方法：采用地高辛标记的寡核苷酸探针杂交技术（PCR－SSOP），调查上海地区199例B27（＋）SpA患者MICA外显子2，3和4的多态性，结果：SpA病例组中MICA*007的频率比随机对照组显著升高（RR＝3．04，Pc＝0.000045），但比较B27（＋）病例组与B27（＋）正常对照组差异无显著性（P＞0．05），结论：MICA*007等位基因与SpA的发生可能无直接的关联，MICA＊007的频率在SpA病例组中显著升高可能由于和HLA－B27基因存在连锁不平衡所致。     

Increased prevalence of celiac disease without gastrointestinal symptoms in adults MICA 5.1 homozygous subjects from the Campania area

OBJECTIVES: Polymorphisms in the major histocompatibility complex class I chain-related gene A may influence its binding to the Natural Killer Cell Receptor G2D (NKG2D). We looked for polymorphisms in major histocompatibility complex class I chain-related gene A exon 5 and in Human Leukocyte Antigen (HLA)-DQ/DR in adult coeliac disease patients to determine whether they affected coeliac disease phenotypes. METHODS: Adult coeliac disease patients with (n=98) and without (n=93) gastrointestinal symptoms (gastrointestinal symptoms+/gastrointestinal symptoms-) and 108 control subjects from Campania (Italy) were characterized by Polymerase Chain Reaction (PCR) sequence specific oligonucleotide followed by PCR sequence specific primer assays for HLA DQ/DR, and by PCR followed by capillary electrophoresis for major histocompatibility complex class I chain-related gene A exon 5 polymorphisms. Immunoglobulin A (IgA) anti-transglutaminase antibodies were also evaluated by immunosorbent assay. RESULTS: Five different major histocompatibility complex class I chain-related gene A alleles were detected in both coeliac disease patients and control subjects. The major histocompatibility complex class I chain-related gene A 5.1 allele occurred more frequently in patients than in controls (p<0.05), and the major histocompatibility complex class I chain-related gene A 5.1/5.1 homozygous genotype increased the risk of gastrointestinal symptoms- coeliac disease (OR=2.79, 95% CI 1.15-6.79). Gastrointestinal symptoms- coeliac disease patients bearing major histocompatibility complex class I chain-related gene A 5.1/5.1 alleles showed lower anti-transglutaminase levels (18U/L) than the gastrointestinal symptoms+ coeliac disease patients (35U/L). HLA-DQ2/DQ8 genotypes did not differ between gastrointestinal symptoms+ and gastrointestinal symptoms- coeliac disease, although DQ8 tended to be more frequent in gastrointestinal symptoms- coeliac disease (11.7%) than in gastrointestinal symptoms+ coeliac disease (6%). CONCLUSIONS: Our study shows that a double dose of the major histocompatibility complex class I chain-related gene A 5.1 allele could predispose to the onset of gastrointestinal symptoms- coeliac disease. We can hypothesize that a lower level of immunological involvement in gastrointestinal symptoms- coeliac disease patients is associated with absence of gastrointestinal symptoms. This test could represent a second step in the genetic typing of high-risk subjects such as first-degree relatives of coeliac disease patients positive for the DQ2/DQ8 molecule.     

血吸虫抗原基因的多态性及其对免疫保护的影响

抗原多态性对传染病疫苗研发的影响已引起研究者们的广泛重视.针对某一变异类型的重组蛋白疫苗,其诱导的免疫力往往小能产生对其他变异类型的保护效果.血吸虫基因组研究显示血吸虫存在大量抗原基因的变异,特别是一些与免疫保护相关的抗原基因,其变异程度和频率更高.该文综述了血吸虫重要抗原的多态性及其变异机制和对免疫保护的影响.     

MICA polymorphism identified by whole genome array associated with NKG2D-mediated cytotoxicity in T-cell large granular lymphocyte leukemia

Background

Large granular lymphocyte leukemia is a semi-autonomous clonal proliferation of cytotoxic T cells accompanied by immune cytopenias and various autoimmune conditions. Due to the rarity of this disease and its association with autoimmune diseases, a theoretical germline or somatic mutation might have significant penetrance, thus enabling detection, even from samples of suboptimal size, through genome-wide association studies.

Design and Methods

To investigate a non-mendelian genetic predisposition to large granular lymphocyte leukemia, we used a step-wise method for gene discovery. First, a modified ‘random forests’ technique was used for candidate gene identification: this was followed by traditional allele-specific polymerase chain reaction, sequencing modalities, and mechanistic assays.

Results

Our analysis found an association with MICA, a non-peptide-presenting, tightly regulated, stress-induced MHC-like molecule and cognate receptor for NKG2D, found abundantly on large granular lymphocyte leukemia cells. Sequencing of germline DNA revealed a higher frequency of MICA*00801/A5.1 in patients with large granular lymphocyte leukemia than in matched controls (64% versus 41%, P<0.001, homozygous 40% versus 15%, P<0.001). Flow cytometry was employed to determine the expression of MICA within hematologic compartments, showing that the signal intensity of MICA was increased in granulocytes from neutropenic patients with large granular lymphocyte leukemia in comparison with that in controls (P=0.033). Furthermore, neutrophil counts were inversely correlated with MICA expression (R²=0.50, P=0.035). Finally, large granular lymphocyte leukemia cells were able to selectively kill MICA⁺ Ba/F3 lymphocytes transfected with human MICA*019 in a dose-dependent manner compared to naïve cells (P<0.001), an effect mitigated by administration of an anti-NKG2D antibody (P=0.033).

Conclusions

Our results illustrate that MICA-NKG2D played a role in disease pathogenesis in the majority of patients in our cohort of cases of large granular lymphocyte leukemia and further investigation into this signaling axis may provide potent therapeutic targets.     

Aqueous Humor and Serum Concentrations of Soluble MICA and MICB in Glaucoma Patients

Background: Immune reactions have been reported to be involved in the destruction of retinal ganglion cells (RGCs) in glaucoma. Objective: To investigate the role of major histocompatibility complex class I-related chain A and B (MICA and MICB) molecules in the pathogenesis of glaucoma. Methods: Aqueous humor and serum samples from 15 glaucoma patients and 45 patients with cataract, undergoing ocular surgery, were obtained. The concentrations of MICA and MICB molecules in all samples were measured using ELISA. Results: Both MICA and MICB concentrations were higher in the aqueous humor of patients with glaucoma compared to those with cataract (p=0.013 and p=0.004, respectively); however, in the serum samples, no significant differences were observed. Conclusions: Increased intraocular pressure may be associated with increased expression of the MICA and MICB molecules, which could initiate the destruction of RGCs and consequent development of glaucoma.     

细胞色素P450基因多态性对他克莫司临床应用的影响

肝移植是终末期肝病患者最有效的治疗手段,而免疫抑制剂的应用是影响患者移植术后长期存活的关键。本文介绍了最常用的免疫抑制剂——他克莫司的作用机制,以及细胞色素P450基因多态性对他克莫司应用影响的最新研究进展。为临床上合理使用他克莫司,减少相关并发症的发生,提高肝移植患者的长期生存率提供参考。