白介素-10基因多态性与感染性疾病的关系的研究进展

白介素-10(interluekin-10 IL-10)是一种具有抗炎和免疫调节作用的细胞因子。是同型二聚体细胞因子, 属长链细胞因子家族。现已发现B细胞、单核／巨噬细胞、肥大细胞、角化细胞、肝细胞及多种肿瘤细胞均可分泌IL-10。 IL-10通过调节其他细胞因子的作用而起到抗炎和免疫调节作用。我们在这里主要谈一下,IL-10的生物学特点及在IL- 10基因的启动子区域几个位点的基因多态性与感染性疾病的关系的研究进展。     

IL-1Ra，IL-1Ra基因多态性与溃疡性结肠炎

IL - 1Ra,IL - 1Ra基因多态性与溃疡性结肠炎 (U C)的相关性研究是从遗传基因角度探讨了 UC的发病。通过对该方面深入研究可望进一步认识到 U C发病机制 ,为其诊断及治疗开辟新途径     

白介素-10（IL-10）与乙肝易感性相关性研究

细胞因子在抗病毒免疫中发挥着重要的作用。细胞因子的基因多态性能影响个体间细胞因子水平上的差异，从而导致个体间对于乙肝病毒感染免疫应答的差异，影响个体对乙肝病毒的易感性。本文主要评述白介素-10基因多态性与乙肝病毒感染的关系     

溃疡性结肠炎的IL-1β、IL-1RA、LMP2基因多态性研究

目的研究溃疡性结肠炎(UC)病人的R-1β、IL-1RA、LMP2基因多态性,并分析其与抗中性粒细胞胞浆抗体(AN-CA)及临床分型的关系.方法用PCR-限制性片段多态性(PCR-FLP)方法和序列特异性引物-PCR(PCR-SSP)方法分别对81例UC病人和114名健康者进行IL-1β、LMP2和IL-1RA基因多态性分析.结果UC病人和健康者之间IL-1β、IL-1RA和LMP2各基因型和基因频率比较均无显著性差异(P＞0.05);当UC病人分为ANCA(+)组和ANCA(-)组后,发现ANCA(+)组IL-1RA等位基因2频率高于ANCA(-)组(13.7%对3.3%,P＜0.05),其它各基因型及基因频率比较,统计学上均无显著性差异(P＞0.05).结论中国汉族UC病人与IL-1β、IL-1RA、LMP2基因多态性无关联,但ANCA(+)UC病人IL-1RA等位基因2频率明显增加.     

白细胞介素-10 基因启动子多态性与慢性阻塞性肺疾病易感性的关系

目的　探讨中国汉族人白细胞介素 - 10基因启动子单核苷酸多态性及其与慢性阻塞性肺疾病易感性之间的关系。　方法　应用聚合酶链反应 -限制性片段长度多态性分析方法 ,检测 94名健康吸烟者和 88例吸烟慢性阻塞性肺疾病 (chronic obstructive pulmonary disease,COPD)患者白细胞介素 - 10(interleukin- 10 ,IL- 10 )基因启动子 - 10 82 G/ A、- 819C/ T、- 5 92 C/ A单核苷酸多态性位点基因型。　结果共发现 11种启动子基因型 ,以 AA·TT·AA、AA·TC· AC、AA· TC· AA基因型多见 ;通过对 11种启动子基因型进行分析 ,新发现 ATC、ACA两种单倍型 ;健康吸烟者和吸烟 COPD患者 IL- 10基因启动子- 10 82 G/ A、- 5 92 C/ A位点基因型分布频率差异无显著性 ,- 819C/ T多态性位点与中国汉族人 COPD易感性有关 ;中国汉族人 IL- 10基因启动子等位基因频率与日本人相似 ,与白种人之间差异存在显著性。　结论　中国汉族人 COPD易感性与 IL- 10基因启动子 - 819C/ T位点多态性有关 ;中国汉族人 IL- 10基因启动子至少存在 ATA、ACC、GCC、ATC、ACA5种单倍型。     

IL-10RA基因多态性及其与系统性红斑狼疮关系的研究

目的:确定SLE模型小鼠IL-10RA基因变异及其与SLE表现型是否存在关联。方法:用微卫星遗传标记及数量性状位点(QTL)分析方法确定SLE模型小鼠B/W F1的SLE易感基因精确染色体定位并选取候选易感基因,对候选易感基因进行测序分析,选取有基因序列异常的候选易感基因进行PCR-SSCP分析,确定候选易感基因碱基序列变异位点与抗染色质抗体、抗DNA抗体,抗组蛋白抗体及蛋白尿等SLE表现型的相关关系。结果:QTL分析结果表明B/W F1×NZB小鼠抗染色质抗体易感基因与NZW型IL-10RA基因紧密连锁;测序分析发现IL-10RA基因编码区有18处碱基变异,其中7处碱基变异将导致编码氨基酸的变异;抗染色质抗体、抗DNA抗体,抗组蛋白抗体及蛋白尿等SLE表现型与NZW型IL-10RA基因密切相关。另一种SLE模型小鼠MRL的IL-10RA基因存在相同变异。结论:NZW小鼠IL-10RA基因编码区碱基序列存在变异,B/W F1×NZB小鼠SLE表现型与NZW小鼠第9染色体IL-10RA编码区碱基变异相关,提示IL-10RA可能是SLE模型小鼠的一个SLE易感基因。     

白介素-10与乙肝易感性相关性研究

细胞因子在抗病毒免疫中发挥着重要的作用。细胞因子的基因多态性能影响个体间细胞因子水平上的差异,从而导致个体间对于乙肝病毒感染免疫应答的差异,影响个体对乙肝病毒的易感性。该文主要评述白介素-10基因多态性与乙肝病毒感染的关系。     

IL-10RA基因多态性与SLE发病关系的临床研究

目的:研究中国北方人群白细胞介素10受体A(IL-10RA)基因多态性分布情况,探讨IL-10RA基因变异与系统性红斑狼疮发病的相关性.方法:利用基因测序、PCR扩增及单链构象多态性(Single-strand Conformation Polymorphism,SSCP)电泳技术,对IL-10RA基因多态性进行筛选及分析,比较系统性红斑狼疮病例组与健康对照组中基因型的分布频率.结果:在IL-10RA第5内含子处存在3种有意义单核苷酸多态性(SNP),即T/T型、C/C型、C/T型.其中T/T型和C/T型在病例组中的出现频率明显增加.结论:IL-10RA内含子5具有多态性并与系统性红斑狼疮的发病相关.     

IL—1Ra,IL—1Ra基因多态性与溃疡性结肠炎

IL-1Ra,IL-1Ra基因多态性与溃疡性结肠炎（UC）的相关性研究是从遗传基因角度探讨了UC的发病，通过对该方面深入研究可望进一步认识到UC发病机制，为其诊断及治疗开辟新途径。     

Association of IL-10 and TNFalpha genotypes with ANCA appearance in ulcerative colitis

The appearance of autoantibodies is a common characteristic of ulcerative colitis (UC). Specifically, anti-neutrophil cytoplasmic antibodies (ANCA) are the most prevalent in this disease and their synthesis may be genetically conditioned. The aim of the present study was to test the influence on appearance of autoantibodies of IL-10 and TNFalpha genes promoter polymorphisms, which control cytokine levels. Genetic polymorphisms of TNFalpha (-308 G/A) and IL-10 (-1082 G/A) and ANCA and anti-goblet cells antibodies (GAB) presence were determined in 99 UC patients. The -308A* allele and -308AA/AGTNFalpha genotypes (high producer), clearly correlated with ANCA positivity (p = 0.004 and p = 0.007, respectively). Additionally, homozygous carriage of the -1082A*IL-10 allele (low producer) significantly associated with ANCA presence (p = 0.007). Furthermore, combination of both genotypes (low IL-10/high TNFalpha producer genotype) had a greater influence on ANCA positivity than each individual genotype (p = 0.008). ANCA production in UC thus appears to be conditioned by IL-10 and TNFalpha genotypes.     

Association of the RAVER2 gene with increased susceptibility for ulcerative colitis

Crohn's disease (CD), ulcerative colitis (UC), systemic lupus erythematosus (SLE) and autoimmune polyglandular syndromes (APS) are autoimmune diseases (ADs) that may share common susceptibility pathways. We examined ribonucleo-protein, polypyrimidine tract-binding protein (PTB)-binding 2 (RAVER2) loci for these diseases in a cohort of 39 CD cases, 67 UC cases, 93 SLE cases, 60 APS cases and 162 healthy control subjects of Tunisian origin. We genotyped 3 SNPs of RAVER2 (rs2780814, rs1333739 and rs2780889) and evaluated it genetic association with each ADs, using X2-test. For each association, odds ratio (OR) and 95% CI were calculated. We show that rs2780814 is significantly associated with UC (P = 0.00016, P(corr) = 0.00048, OR = 3.66 (1.82; 7.34)). We also observed a trend of possible association to SLE (P = 0.023, P(corr) = 0.69, OR = 2.19 (1.1; 4.36)). None of these RAVER2 SNPs were associated with CD and APS susceptibility. These findings establish RAVER2 as a new UC genetic susceptibility factor and reveal a genetic heterogeneity of the associated polymorphisms and risk alleles between ADs suggesting different immunopathological roles of RAVER2 in these diseases.     

IL-10 gene polymorphism and herpesvirus infections

Genetics has an important role in resistance to various infections and it also may modify the clinical picture of an infectious disease. Here, we briefly review our recent data demonstrating that the polymorphism of the IL-10 gene is associated with resistance to some common herpesviruses and, additionally, that this same gene is involved in the regulation of the severity of the infection and in the reactivation process.     

IL-10基因多态性与特应性皮炎发生的相关性

目的 研究白细胞介素-10（IL-10）基因启动子区域的单核苷酸多态性与特应性皮炎发生的相关性。方法 门诊特应性皮炎患儿174名和健康儿童130名,利用Taqman方法分析IL-10基因启动子区域 -1082（G/A）, -819（C/T）, -592(C/A) 单核苷酸多态性和单核苷酸组合成的单倍型和基因型。分析特定基因型保留和血液中嗜酸性粒细胞总数或血浆中IgE浓度之间的关联性。结果 健康组儿童ACC单倍型频率显著高于特应性皮炎儿童（p﹤0.05）。而血液中嗜酸性粒细胞总数和血浆中IgE浓度,ATA/ATA基因型的儿童显著高于ATA/ACC基因型儿童（p﹤0.05）。结论 IL-10基因启动子区域的单核苷酸多态性与特应性皮炎发生有关。     

HLA基因多态性与溃疡性结肠炎遗传易感关系的研究

目的:研究HLA-DRB1等位基因多态性与我国汉族溃疡性结肠炎遗传易感的相关性,并分析其与疾病临床分型的相关性。方法:应用基因芯片技术分析了本地区汉族溃疡性结肠炎60例患者和健康对照者DRB1的基因分型,采用Fisher’s精确概率法比较了两组各位点等位基因频率分布的差异。结果:溃疡性结肠炎患者DR2和DRB1*15基因表达频率分别为45%和41.7%,较对照组(23.3%和21.7%)明显升高,OR分别为2.688和2.582(均P<0.05)。慢性持续型UC的DRB1*15等位基因频率较相应其他型升高更为显著(P<0.05)。结论:DR2或DRB1*15等位基因可能是我国汉族人群UC的易感基因。HLA-DR基因多态性与UC的临床分型密切相关。     

HLA-DRB1 alleles influence clinical phenotypes in Japanese patients with ulcerative colitis

The human leukocyte antigen (HLA) region has been implicated in the disease susceptibility of inflammatory bowel disease by several linkage and association studies. In Caucasians, HLA-DRB1 has been reported to determine the clinical phenotypes of ulcerative colitis (UC). Others and we previously reported that HLA-DRB1*1502 was strongly associated with UC in the Japanese population. However, the contribution of HLA-DRB1 to the clinical phenotypes in Japanese UC has not been elucidated yet. The aim of this study was to determine whether HLA-DRB1 alleles were associated with the clinical phenotypes in Japanese patients with UC. A total of 353 patients with UC were recruited. Patients were classified into subgroups by sex, age at diagnosis, disease extent, need for steroid therapy or need for surgical treatment. The allele frequency of HLA-DRB1*08 was significantly higher in patients whose disease extended beyond the rectum (left-sided and extensive UC) than in those with proctitis [odds ratio (OR)=2.20, Pc=0.043). The allele frequency of HLA-DRB1*09 was significantly higher in patients with UC diagnosed at the age of 40 years or older than in those with UC diagnosed before the age of 40 years (OR=2.31, Pc=0.022). Besides these positive associations, no significant differences were found in the allele frequencies between the other subgroups. We conclude that HLA-DRB1*09 is associated with the age at diagnosis and HLA-DRB1*08 is associated with the disease extent of UC in Japanese. These results indicate that HLA-DRB1 is not only associated with the overall UC susceptibility but also associated with the clinical phenotypes in Japanese.     

溃疡性结肠炎患者血清IL-23和IL-17的水平变化及意义

目的:探讨溃疡性结肠炎(UC)血清IL-23和IL-17的水平变化及其临床意义。方法:收集经临床明确诊断的UC患者54例,并选择同期健康体检者30例作为对照组。采用酶联免疫吸附法(ELISA)检测两组血清IL-23和IL-17的水平。结果:UC组患者血清IL-23和IL-17水平明显高于对照组,差异有显著统计学意义(t=18.76,21.48,P<0.01)。在轻度、中度、重度UC患者血清中,IL-23和IL-17的浓度水平均呈逐渐升高趋势,重度患者高于中度患者,中度患者高于轻度患者,三组间比较存在显著差异(P<0.05或0.01)。IL-23和IL-17在溃疡性结肠炎患者血清中的表达呈正相关(r=0.548,P<0.01)。结论:IL-23与IL-17的高表达可能参与了UC的慢性炎症形成过程;两者表达水平有密切相关性,IL-23可能通过诱导IL-17的产生而使后者在UC的发病中发挥作用。     

The IL-10R1 S138G loss-of-function allele and ulcerative colitis

Genetic predisposition is a risk factor for the development of inflammatory bowel diseases (IBDs). Disruption of the interleukin (IL)-10 pathway in mice causes intestinal inflammation similar to human IBD. Two common non-synonymous IL-10R1 variants, S138G and G330R, were cloned and expressed in HeLa and Ba/F3. A reduction in IL-10-induced STAT1 and STAT3 activation was seen for IL-10R1-S138G (but not IL-10R1-G330R) by phosphospecific western blotting in both cell types. When analyzing 52 world populations for the presence of IL-10R1 variants, a strong dissimilarity was found between major geographical regions. In addition, when 182 IBD-parent trios were genotyped for both variants, a reduced transmission of haplotype -7 (carrying the S138G variant allele) to offspring with ulcerative colitis (UC) was observed. This UC-protective effect of S138G was confirmed in a Hungarian cohort (n=185, allele frequency 11.6 versus 17.5%; P=0.017) but not in an independent Belgian cohort (n=666, allele frequency 15.9 versus 15.5%; P=0.8). In conclusion, the IL-10R1 S138G variant is a loss-of-function allele for IL-10-induced STAT1 and STAT3 activation but does not protect from UC susceptibility.