中国人群CTLA-4基因多态性与系统性红斑狼疮及类风湿性关节炎的相关性研究

系统性红斑狼疮(SLE)与类风湿性关节炎(RA)是常见的自身免疫性疾病,病因未明.研究发现,除了HLA基因的相关性以外,还可能存在其它重要的敏感基因[1].近年来发现CTLA-4基因在自身免疫性疾病发病中的作用,本文检测SLE及RA病人CTLA-4基因多态性,进一步探讨SLE及RA的发病机制.     

儿童Graves病与CTLA-4基因多态性的初步研究

Graves’病（简称GD）是一种常见的器官特异性自身免疫性甲状腺疾病,其确切病因不明,但已肯定GD是一种多基因遗传的自身免疫性疾病。近年来儿童GD与成人GD一样有发病率逐渐增加的趋势,已成为一种危害儿童健康的常见病。最新研究认为候选基因中HLA和CTLA-4两个基因位点占GD遗传易感性的50％,而CTLA-4基因作为T细胞活化的一种重要的负性调节因子,已成为导致自身免疫性内分泌疾病的一个非常重要的易感位点,也成为国内外学者研究的热点,儿童起病的GD与成人起病的GD在发病机制上截然不同,本研究对于CTLA-4基因第二外显子的多态性进行初步研究。     

自身免疫性甲状腺疾病

自身免疫性疾病是指自身免疫反应引起组织损伤的疾病,是指对自身组织具有特异性抗体或免疫活性细胞作用的结果。许多实验和临床研究认为,非特异性T抑制细胞的数目或功能下降所引起,T抑制细胞缺失被认为是自身免疫性疾病的发病原因。目前更有人提出“遗传性自身免疫性疾病的H基因理论”比T抑制细胞的全面缺失导致自身免疫性疾病更符合疾病的临床特征。此外,自身免疫性疾病具有遗传易感性,其遗传方式是有几个共显性基因一起决定其易感性,很清楚了解到某些有关基因是与MHC相关的,但非MHC基因也参与决定易感性。     

HLA-Ⅱ类基因与人类疾病相关性研究进展

通过DNA分型技术 ,已经明确了多种疾病的发生和发展与HLA Ⅱ类基因相关联。可通过计算相对危险因子 (RR)来判断HLA等位基因的频率。HLA Ⅱ类基因多态性可以改变HLA分子、抗原、T细胞之间相互作用的特性 ,并因此控制对外来抗原 (有时自身抗原 )的免疫应答。HLA Ⅱ类基因的编码的某一氨基酸序列控制着对疾病的易感性和临床性状。构成HLA基因群的各个基因是高度连锁的 ,因而与某一特定疾病关联的易感基因有可能不是单一的 ,而是一些连锁基因的组合。     

类泛素样蛋白4与1型糖尿病

1型糖尿病是一种具有多基因遗传背景的自身免疫性疾病,胰岛β细胞特异性破坏为其主要发病机制。新近发现的类泛素样蛋白4(SUMO4)基因位于IDDM5内,其编码的SUMO4蛋白通过与IκBα作用,负性调节NFκB的转录活性,从而间接参与对机体免疫应答的调控。研究发现SUMO4基因163位A→G(M55V)的单核苷酸多态性与1型糖尿病易感性有关。M55V的改变可上调NFκB的转录活性,激活自身免疫反应。     

中医体质与免疫共刺激分子CD40、CD28基因多态性的关联性研究

目的 研究中医体质与免疫共刺激分子单核苷酸多态性之间的相关性,探究中医体质分类理论与机体免疫系统功能间联系.方法 利用标准化中医体质量表结合中医四诊综合辨识,对359例志愿者进行中医体质辨识,利用聚合酶链式反应限制片段长度多态性(PCR-RFLP)方法鉴定其免疫共刺激分子CD40、CD28基因主要标签单核苷酸多态性位点(tagSNP)基因型.结果 对359例志愿者进行中医体质分类,发现CD40基因rs1883832位点基因型和等位基因在平和质和阳虚质中的分布频率存在统计学差异(P ＜0.05);CD28基因单体型GGCCTTCATAA与ACCTTTCATGA在平和质、气虚质和阳虚质三种中医体质中分布频率存在统计学差异(P＜0.05).结论 中医体质论与免疫共刺激分子基因单核苷酸多态性存在关联性,免疫共刺激分子基因单核苷酸多态性所造成的免疫功能个体差异可能是不同中医体质个体存在疾病易感性差异的理论依据之一.     

重症肌无力单核苷酸多态性的研究进展

重症肌无力（MG）是一种由神经-肌肉接头处传递功能障碍所引起的获得性自身免疫性疾病，其发病机制目前尚未完全明确。经相关研究表明，多因素多基因的积累共同导致了重症肌无力的发生，其中遗传因素占有重要作用。单核甘酸多态性（ SNP ）是人类基因组中最常见的多态性，在已经发现的多态性中有高达90％以上是以单核苷酸多态性的形式存在的。目前研究人员已经发现大量与重症肌无力密切相关的风险单核苷酸多态性，该文将对最近几年重症肌无力发病风险与单核苷酸多态性的相关性研究进行综述。     

广东汉族正常人群TLR4基因单核苷酸多态性研究(英)

目的：人类Toll样受体4（TLR4）是先天免疫系统中一个重要的病原微生物识别受体。本研究将建立中国汉族正常人群TLR4基因座位的单核苷酸多态性图谱。方法：收集191例健康、无亲缘关系的中国广东汉族人外周血液,通过对TLR4基因的启动子区、3个外显子区以及它们周围的内含子区进行PCR扩增和测序,得到汉族正常人群TLR4基因座位单核苷酸多态性图谱及其频率分布特点。结果：共发现8个单核苷酸多态性位点,其中5个是首次发现的新位点。分布频率最高（0.283）的单核苷酸多态性位点是-1607 C/T。常见于高加索人中的2个非同义突变Asp299Gly和Thr399Ile在汉族人中没有被发现。中性检验显示汉族人群TLR4基因符合中性进化模型。结论：本研究建立了汉族正常人群TLR4基因座位的单核苷酸多态性图谱,发现了一些种族特异性的单核苷酸多态性位点,这些工作将为今后开展汉族人基因多态性与疾病相关性研究以及人群进化研究提供一定的帮助。     

慢性淋巴细胞性甲状腺炎与HLA-A、-B和-DR关联的研究

慢性淋巴细胞性甲状腺炎(CLT)是一种自身免疫性疾病,甲状腺自身抗体的产生与常染色体显性遗传有关,近年其发生率猛增.HLA是人类白细胞抗原,具有高度多态性遗传性.已有人研究CLT与HLA的相关性.为了探讨福州地区CLT患者与HLA的相关性,本文用PCR-SSP方法研究CLT患者与HLAⅠ类抗原及Ⅱ类抗原基因多态的关系.     

基质金属蛋白酶-9基因与牙周病的相关性研究进展

MMP-9即基质金属蛋白酶-9,在人体多种组织均有表达。编码该蛋白酶的基因称MMP-9基因,该基因不仅在决定个体对某些疾病的易感性上起重要作用,而且其表达与某些疾病的发生、发展密切相关。牙周病为发生在牙周支持组织（牙龈、牙周膜、牙槽骨、牙骨质）的疾病。近年研究发现MMP-9基因表达及单核苷酸多态性（SNP）在牙周病发病机制中起到重要作用。     

Non-HLA associations with autoimmune diseases

Susceptibility to autoimmune diseases (AID) has been associated with multiple combinations of genes and environmental or stochastic factors. The strongest influence on susceptibility to autoimmunity is the major histocompatibility complex (MHC), in particular HLA; however, linkage analyses among multiple affected family members have established that non-MHC chromosomal susceptibility regions also influence the susceptibility towards AID. Besides HLA, three non-HLA genes have been convincingly associated with different AID: Citotoxic T lymphocyte-associated antigen 4 (CTLA4), Protein Tyrosine Phosphatase (PTPN22) and Tumor Necrosis Factor-alpha (TNF), indicating that autoimmune phenotypes could represent pleiotropic outcomes of non-specific diseases' genes that underline similar immunogenetic mechanisms. Identification of genes that generate susceptibility will enhance our understanding of the mechanisms that mediate these complex diseases and will allow us to predict and/or prevent them as well as to discover new therapeutic interventions.     

Association of the CD226 single nucleotide polymorphism with systemic lupus erythematosus in the Chinese Han population

A novel non-synonymous (Gly307Ser) variant, rs763361, of the CD226 gene on chromosome 18q22 was recently shown to be associated with multiple autoimmune diseases. Taking into consideration that different autoimmune diseases may share some common pathogenic pathways, in this study we performed case-control studies to assess any genetic linkage with systemic lupus erythemtosus (SLE). An association between the Gly307Ser single nucleotide polymorphism (SNP) and susceptibility to SLE was identified. The TT genotype [odds ratio (OR) = 1.79, 95% confidence interval (CI) = 1.07-3.01, P = 0.025] and the T allele (OR = 1.34, 95% CI = 1.05-1.74, P = 0.018) of the rs763361 SNP were associated with the risk of SLE. This finding indicates that polymorphism of Gly307Ser (rs763361) in exon 7 of the CD226 gene may be associated with the development of SLE.     

The genetics of complex autoimmune diseases: non-MHC susceptibility genes

Susceptibility to complex autoimmune diseases (AIDs) is a multigenic phenotype affected by a variety of genetic and environmental or stochastic factors. After over a decade of linkage analyses, the identification of non-major histocompatibility complex (non-MHC) susceptibility alleles has proved to be difficult, predominantly because of extensive genetic heterogeneity and possible epistatic interactions among the multiple genes required for disease development. Despite these difficulties, progress has been made in elucidating the genetic mechanisms that influence the inheritance of susceptibility, and the pace of gene discovery is accelerating. An intriguing new finding has been the colocalization of several AID susceptibility genes in both rodent models and human linkage studies. This may indicate that several susceptibility alleles affect multiple AIDs, or alternatively that genomic organization has resulted in the clustering of many immune system genes. The completion of the human genome sequence, coupled with the imminent completion of the mouse genome, should yield key information that will dramatically enhance the rate of gene discovery in complex conditions such as AID susceptibility.     

STAT4 gene polymorphism is associated with psoriasis in the genetically homogeneous population of Crete, Greece

Recent genome-wide association studies (GWAS) of many complex diseases have successfully identified novel susceptibility loci, with many of them being associated with more than one condition. Taking into consideration that different autoimmune diseases may share some common pathogenetic pathways, we hypothesized that STAT4, a susceptibility gene found to be associated with increased risk for systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, Sjögren's syndrome, Wegener's granulomatosis, Crohn's disease, and ulcerative colitis may also have a role in psoriasis. Psoriasis is an autoimmune, chronic inflammatory skin disease. Here we performed a case-control study in the population of island of Crete and demonstrated for the first time the association of a STAT4 single nucleotide polymorphism (SNP) with susceptibility to psoriasis, thus suggesting a putative key role of STAT4 in multiple autoimmune diseases. We found that mutated allele T of the STAT4 rs7574865 SNP, which previously was implicated in the predisposition to many autoimmune diseases, were more common in individuals with psoriasis than in controls (p = 0.045, odds ratio = 1.42, 95% confidence interval 1.01–2.00), thus concluding that the polymorphism examined is associated with the development of psoriasis in our population.     

CTLA-4 (CD152) and its involvement in autoimmune disease

Autoimmune diseases (AID) are inherited as complex genetic diseases. Different Autoimmune diseases have been found to cluster in families and are believed to share some common etiological factors. With the exception of major histocompatibility complex (MHC) genes contributing susceptibility to these diseases have been difficult to identify. CD152 has emerged as one such candidate unifying several autoimmune diseases. We here review the evidence that CD152 constitutes a general susceptibility factor for multiple autoimmune diseases and discuss how CD152 and other co-stimulatory pathways may contribute to autoimmune pathogenesis.     

CTLA-4 (CD152) and its involvement in autoimmune disease

Autoimmune diseases (AID) are inherited as complex genetic diseases. Different Autoimmune diseases have been found to cluster in families and are believed to share some common etiological factors. With the exception of major histocompatibility complex (MHC) genes contributing susceptibility to these diseases have been difficult to identify. CD152 has emerged as one such candidate unifying several autoimmune diseases. We here review the evidence that CD152 constitutes a general susceptibility factor for multiple autoimmune diseases and discuss how CD152 and other co-stimulatory pathways may contribute to autoimmune pathogenesis.     

Sex differences and genomics in autoimmune diseases

Autoimmune diseases (AIDs) are believed to be multifactorial diseases that commonly involve multiple organ systems. About three fourth of the patients afflicted with AIDs are women suggesting that sex differences impact the incidence of AID. However, the proportion of females to males suffering from AID varies depending on the disease. The response to some AID therapeutics also differs in females versus males, suggesting that enrollment of adequate numbers of women and men is important in clinical trials for development of AID drugs. It is known for a long time that genetic factors are important contributors to AID susceptibility. Currently available information suggests that multiple genes with modest association to AID contribute to susceptibility to AID. Also, the associations may differ for the various ethnicities. The major histocompatibility (MHC) locus appears to be a major genetic factor that confers susceptibility to multiple AIDs, even though the locus is complex and has the highest density of genes in the human genome. Thus, the association of different AIDs could be with different genes in the MHC locus. Among the non-MHC genes, some of the risk alleles are shared between different AIDs, but may not be common to all AIDs. For example, genetic polymorphisms in the Protein Tyrosine Phosphatase-22 (PTPN22) gene have reproducibly shown to have association with systemic lupus erythematosus (SLE), Graves' disease (GD), rheumatoid arthritis (RA) and multiple sclerosis (MS), but not with psoriasis. Identification of factors responsible for risk for developing AID and the of the pathways underlying these diseases are likely to help understand subsets of disease, identify responders to a specific treatment and develop better therapeutics for AID.     

Copy number variation in the human genome and its implication in autoimmunity

The causes of autoimmune disease remain poorly defined. However, it is known that genetic factors contribute to disease susceptibility. Hitherto, studies have focused upon single nucleotide polymorphisms as both tools for mapping and as probable causal variants. Recent studies, using genome‐wide analytical techniques, have revealed that, in the genome, segments of DNA ranging in size from kilobases to megabases can vary in copy number. These changes of DNA copy number represent an important element of genomic polymorphism in humans and in other species and may therefore make a substantial contribution to phenotypic variation and population differentiation. Furthermore, copy number variation (CNV) in genomic regions harbouring dosage‐sensitive genes may cause or predispose to a variety of human genetic diseases. Several recent studies have reported an association between CNV and autoimmunity in humans such as systemic lupus, psoriasis, Crohn's disease, rheumatoid arthritis and type 1 diabetes. The use of novel analytical techniques facilitates the study of complex human genomic structures such as CNV, and allows new susceptibility loci for autoimmunity to be found that are not readily mappable by single nucleotide polymorphism‐based association analyses alone.     

Polymorphisms of interleukin 4 receptor gene and interleukin 10 gene are not associated with Graves' disease in the UK

Graves' disease (GD) is an autoimmune disorder of the thyroid gland and both environmental and genetic factors contribute to disease aetiology. Cytokines, such as interleukin 4 (IL-4) and interleukin 10 (IL-10), are involved in the immune response and may be implicated in the autoimmune disease process. Associations have been reported between single nucleotide polymorphisms (SNPs) of IL-10 and the Ile50Val polymorphism of the IL-4 receptor gene (IL-4R) gene and atopy and autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. The autoimmune diseases cluster within families and susceptibility genes may overlap between the different disorders. Therefore, we investigated 5 SNPs (-592C/A, -657G/A, - 819C/T, -1349A/G, and -2013G/A) in the promoter region of the IL-10 and the Ile50Val polymorphism (A/G) in the IL-4R in a large UK population based case-control dataset with GD. No association was found between the polymorphisms studied and GD and no significant differences were found in genotype or allele frequencies between the patients and control subjects. We conclude these polymorphisms of IL-10 and IL-4R previously associated with other immune mediated diseases, do not confer susceptibility to GD in white Caucasians in the United Kingdom.     

A possible mechanism for non-replication of allelic association between a single nucleotide polymorphism of the human beta T-cell receptor and autoimmune diseases

Gene polymorphisms, in particular single nucleotide polymorphisms (SNPs), have been associated to multifactorial diseases such as cancer, inflammation and autoimmunity. Indeed for some autoimmune diseases, it has been possible to identify critical residues that play a major role in susceptibility to diseases. The association of a common T/C polymorphism in the promoter region of the beta 2 constant chain of the T-cell receptor with autoimmune diseases, such as insulin-dependent diabetes, autoimmune hepatitis, IgA nephropathy, membranous nephropathy, Graves' disease and Hashimoto's thyroiditis, was described in the 1990 s. These reports have not been confirmed in the last few years. We also failed in a previous study to detect any difference between 70 normal subjects and 70 patients with primary biliary cirrhosis; however, we found a difference in allelic frequency between males and females. This finding led us to make an allele frequency study of this single nucleotide polymorphism between sexes in a new series of patients. We studied 165 subjects, 80 males and 85 females, and we found a significant difference between sexes especially for the CC homozygous genotype: 34% of females vs. 14% of males (P = 0.008). If the higher frequency of CC homozygous genotype (that is associated with an increased risk of autoimmune diseases) in females would be confirmed in normal population, this could be an explanation of the controversial results obtained by association studies made between this SNP and autoimmune diseases.