乙型肝炎疫苗免疫不应答与HLA基因单体型的相关性研究

目的 分析接种乙型肝炎疫苗的人群中,不能产生良好的免疫应答反应的群体主要组织相容性复合性（HLA）基因单体型,为乙型肝炎疫苗免疫不应答遗传机制的破译提供有意义的结果。方法 以来自广西自治区的样本107例为研究对象,通过PCR扩增和电泳对样本个体进行HLA－DR、DQ区域的DNA分型,并对不应答家系的个体进行初步HLA－DR、DQ单体型别的确定。通过相对危险性估计、关联分析、连锁不平衡检测等统计学分析模式对不／弱应答群体与强应答群体HLA分型结果进行统计分析。结果 中国人中与乙型肝炎疫苗免疫接种不应答密切相关的HLA单体型为：HLA－DRB1＊0401－22,1122－DRB4＊01011010102／3－DQB1＊04,即HLA－DR4,1122－DQOB4。结论 乙型肝炎疫苗免疫不应答与特异的HLA等位基因单体型密切相关。     

Th1和Th2细胞因子的基因多态性与新生儿乙型肝炎疫苗低免疫应答的关联性研究北大核心

目的探讨Th1和Th2细胞因子基因多态性与新生儿乙型肝炎(乙肝)疫苗(HepB)低免疫应答的关系。方法在广西两家医院招募已完成HepB全程免疫的8-9月龄汉族儿童,采用微粒子酶联免疫测定法测定血清乙肝表面抗体(HBsAb),抗体浓度≥10mIU/L且<100mIU/L为低应答,≥1000mIU/L为高应答。采用SNPscanTM多重单核苷酸多态性(SNP)分型技术检测细胞因子,分析基因位点、基因型、等位基因与HepB免疫应答水平的关联性。结果本研究纳入HepB低应答儿童88名、高应答儿童132名;共筛选出Th1和Th2细胞因子12个基因52个位点。Logistic回归分析显示,IL18基因rs3882891位点T/T基因型、IL12A基因rs583911位点A等位基因、IFN-γ基因rs2069728位点C等位基因的低应答比例高[OR(95%CI):2.72(1.33-5.57);1.81(1.15-2.85);2.01(1.07-3.79)],IL1B基因rs16944位点A等位基因的低应答比例低[OR(95%CI):0.64(0.43-0.95)]。结论IL18基因rs3882891位点T/T基因型、IL12A基因rs583911位点A等位基因、IFN-γ基因rs2069728位点C等位基因可能与汉族儿童HepB初次免疫低应答有关,而IL1B基因rs16944位点A等位基因可能是其保护因素。     

基因多态性对疫苗免疫应答影响的研究进展

基因在免疫系统应答过程中扮演着重要的角色，不同的基因位点可能引起疫苗免疫应答率的高低差异。本文对基因多态性与疫苗免疫应答的文献进行综述，旨在探究基因多态性会对疫苗免疫应答产生的影响，从基因水平上探讨个体接种疫苗后产生免疫应答的效果，为个体化免疫发展策略提供科学依据。综述结果显示人类白细胞抗原基因、各类细胞因子及其受体基因、Toll样受体类基因的单核苷酸多态性都会影响疫苗免疫应答。     

HLA基因多态性与乙型肝炎疫苗免疫效果和安全性的研究进展

近年来,人类白细胞抗原（human leukocyte antigen,HLA）基因在乙型肝炎疫苗免疫效果相关性被诸多医疗专家所关注。本文就HLA基因在乙型肝炎疫苗免疫效果的相关研究进行总结和归纳,探讨HLA基因多态性与乙型肝炎肝疫苗免疫反应和不良反应关系,总结不同HLA基因对乙型肝炎疫苗免疫效果的相关机制,为不同HLA人群乙型肝炎疫苗的个性化疫苗接种提供科学依据,现就HLA基因概况、乙型肝炎病毒（hepatitis B virus,HBV）疫苗应答效果及其相关机制等作一综述。     

母亲乙型肝炎病毒感染状态对婴儿接种乙型肝炎疫苗后免疫应答的影响

161例婴儿接种乙型肝炎(简称乙肝)疫苗后免疫应答良好。接种20μg疫苗的婴儿抗-HBs阳转率为100%,几何平均滴度为1:448.9;接种10μg疫苗的婴儿抗-HBs阳转率为97.3%,滴度为1:217.8。母亲的HBV感染状态与婴儿对乙型肝炎疫苗的免疫应答有密切关系。母亲单独抗-HBs阳性的婴儿,接种乙型肝炎疫苗后的抗-HBs应答最佳(阳转率为100.0%,几何平均滴度1:670.4),依次为母亲HBV感染标记全阴性的婴儿(100.0%,1:376.4)。母亲抗-HBs和抗-HBc共阳性的婴儿(100.0%,1:218.2);而母亲为HBsAg阳性或单独抗-HBc阳性的婴儿的抗-HBs应答较差(75.0%,1:40.3;或100.0%,1:28.5)。本次研究提示机体的遗传特征以及母体HBV传染性强弱对婴儿接种乙型肝炎疫苗后的免疫应答起决定作用。     

人类白细胞抗原基因多态性与肺疾病关系

人类白细胞抗原（HLA）系统作为具有高度多态性的免疫遗传系统，与人类多种疾病的发生、发展和预后密切相关，但各国学者的研究结果不尽相同。本文对近年HLA基因多态性的相关知识及其在常见肺疾病中的应用进行了综述，提出通过选择合适的研究对象，采用精确、可靠的检测方法，进行科学的数据分析来客观地评价HLA基因多态性与临床疾病的相关性观点。     

儿童对乙型肝炎疫苗加强接种的免疫应答

观察了经乙型肝炎疫苗初免的38名儿童对乙型肝炎疫苗加强接种的免疫效果。疫苗加强接种后97.4%(37/38)儿童产生了免疫应答,接种后3周、3月及6月的抗-HBs水平由接种前的33.6IU/L,分别增至824.1、407.7及193.6IU/L,平均增高24.5、12.1和5.8倍,加强接种后3周抗-HBs水平达到高峰,3月及6月时抗-HBs水平比3周时分别下降50.5%和76.5%。加强免疫的应答效果主要由初免的免疫应答状态所决定。本文显示,儿童用10μg乙型肝炎疫苗加强接种能获得良好的免疫应答效果。     

乙型肝炎疫苗接种无,弱应答与人类白细胞抗原的关系

乙型肝炎疫苗接种无、弱应答与人类白细胞抗原的关系刘蓬勃１徐慧文２李辉１王学良２乌正赉１王小峰２张孔来１曾宪嘉１潘利１通过检测乙型肝炎（乙肝）疫苗接种后无、弱应答者和强应答者人类白细胞抗原，（ＨＬＡ）Ⅰ、Ⅱ类复合体，试图探讨无、弱应答与遗传因素的关系。...     

感染性疾病与人类白细胞抗原基因多态性

感染性疾病是世界范围的严重公共问题之一.人类白细胞抗原复合体(HLA)是决定机体免疫应答功能的重要分子基础之一,与感染性疾病转归密切相关.此文对感染性疾病与人类白细胞抗原基因多态性的相关性研究进展作了综述.     

Minimal association of alleles of human leukocyte antigen class II gene and long-term antibody response to hepatitis B vaccine vaccinated during infancy

BackgroundThe human leukocyte antigen (HLA) system plays critical roles in regulating immune responses to various vaccines. This study aimed to evaluate the association of HLA class II gene polymorphisms and the long-term duration of anti-HBs response in children vaccinated against hepatitis B during infancy.MethodsTotally 297 children 5–7 years after the completion of primary vaccination against hepatitis B in infancy, without booster immunization or natural resolved infection, were enrolled. Of them, 86 children with anti-HBs <10 mIU/ml were considered as long-term non- or hypo-responders, and 211 others with anti-HBs ≥10 mIU/ml were defined as long-term responders. Ten alleles in HLA-DR and -DQ subregions were detected by polymerase chain reaction with sequence-specific primers.ResultsThe frequency of HLA-DQB110401 was 15.1% in the long-term non- or hypo-responder group, relatively higher than 7.6% in the long-term responder group (OR = 2.17, 95% CI 1.01–4.73), however, the difference had no statistical significance after Bonferroni correction (P = 0.470). The frequencies of seven HLA-DRB1 alleles, including 101, 103, 104, 107, 108, 111, and 11301/1302, and two HLA-DQB1 alleles, including 10201 and 10501, were each similarly distributed in the long-term non- or hypo-responders and responders respectively.ConclusionNone of the ten HLA class II gene alleles previously reported to be related with short-term antibody response to hepatitis B vaccine is associated with the long-term antibody response after vaccination during infantile.     

人类白细胞抗原DQ基因多态性与三氯乙烯药疹样皮炎易感性的关系

目的研究人类白细胞抗原DQ（HLA-DQ）基因多态性与三氯乙烯药疹样皮炎易感性的关系。方法应用聚合酶链反应产物直接测序方法,比较112例三氯乙烯药疹样皮炎病例和142例健康三氯乙烯接触工人HLA—DQA1和HLA—DQBl基因第2外显子氨基酸密码子多态性及等位基因型频率分布。结果病例组DQA1等位基因0201和060101／0602的分布频率[7．6％（17／224）和16．1％（36／224）]显著高于对照组[3．5％（10／284）和7．0％（20／284）],而病例组DQAl等位基因0103和050101／0503／0505的分布频率[5．8％（13／224）和8．9％（20／224）]显著低于对照组[10．9％（31／284）和17．3％（49／284）]。此外,病例组与对照组之间差异有统计学意义的氨基酸密码子多态性位点见于DQA1的5个密码子（25、41、52、54和69）。病例组与对照组HLA-DQB1等位基因的分布频率差异无统计学意义。结论HLA-DQA1基因多态性可能是导致三氯乙烯药疹样皮炎个体易感性差异的原因之一。     

Influence of maternal antibody against hepatitis B surface antigen on active immune response to hepatitis B vaccine in infants

Transplacentally acquired maternal antibodies in infants may inhibit active immune responses to vaccines. In this study, we compared the immunogenicity of the recombinant hepatitis B vaccine, which was intramuscularly injected at 0, 1, and 6 months of age, in 71 infants born to mothers with positive or negative antibody against hepatitis B surface antigen (anti-HBs). Forty-one infants born to anti-HBs positive mothers were all positive at birth. At 2 months after the second injection, anti-HBs in 30 infants with negative maternal antibody was significantly higher than that in 41 infants with positive maternal anti-HBs (191.1mIU/ml vs. 96.2mIU/ml, P=0.018). At one month after the full immunization, the anti-HBs levels had no statistical difference between maternal anti-HBs negative and positive groups, but the antibody response in infants with high maternal anti-HBs (>1000mIU/ml) was significantly inhibited. Nevertheless, all infants had anti-HBs higher than the protective level. In conclusion, passively acquired maternal anti-HBs in infants may to some extent impair the antibody response to hepatitis B vaccine. The long-term efficacy of hepatitis B vaccine in infants with high titers of maternal anti-HBs remains to be further evaluated.     

Toll-like receptors and cytokines/cytokine receptors polymorphisms associate with non-response to hepatitis B vaccine

It is well documented that 5-10% hepatitis B adult vaccinees are non- and hypo-responders and probably are not adequately protected against hepatitis B virus (HBV) infection. The sequence variations of genes involved in processes such as pathogen recognition, antigen processing and presentation, and differentiation/maturation of lymphocytes may affect the duration and intensity of protective humoral immune response to the hepatitis B vaccine. In this study, frequencies of 53 known SNPs within 21 candidate genes were analyzed among 46 responders and 24 non-responders. Four SNPs (rs2243248, rs1805015, rs1295686 and rs3804100) in IL-4, IL-4RA, IL-13 and TLR2 genes were found significantly associated with the vaccinees’ status of serum anti-HBV response triggered by the vaccine (P < 0.05). Two SNPs (rs1295686 and rs1805015) also showed significant association with the vaccine-induced immune response when analyzed together with risk factors such as age and gender, by multivariable logistic regression analysis (P < 0.05). Further, haplotype analysis showed that the AG haplotype defined by SNPs rs1143633 (IL-1B; intron) and rs1143627 (IL-1B; intron) was present more frequently in non-responders than in responders (P = 0.035). Thus, specific SNPs in genes of cytokines/cytokine receptors and TLR2 were associated with status of the hepatitis B vaccine-induced protective humoral immune response.     

HLA genotypes and rubella vaccine immune response: Additional evidence

Recent population-based studies have demonstrated the genetic heritability of rubella vaccine response and assessed that the HLA system may explain about 20% of the inter-individual variance in humoral immune response to this vaccine. Our earlier studies compared HLA allelic associations with rubella vaccine-specific antibodies between two smaller cohorts of healthy Rochester, MN, children (346 and 396 subjects) after two doses of rubella-containing vaccine. This study found that specific HLA alleles were consistently associated with rubella-specific antibody titers (B*27:05, DPA1*02:01, and DPB1*04:01 alleles). The current study examined HLA associations in an independent larger cohort of 1012 healthy San Diego, CA, subjects (age 19–40 years) after rubella vaccine in order to replicate our previous findings in the Rochester subjects. Two HLA associations of comparable magnitudes were consistently observed between B*27:05 (median NT₅₀ Rochester cohort 48.9, p = 0.067; San Diego cohort 54.8, p = 0.047) and DPB1*04:01 (median NT₅₀ Rochester cohort 61.6, p < 0.001; San Diego cohort 70.8, p = 0.084) alleles and rubella virus-neutralizing antibody titers. Additional HLA alleles resulted in consistent effects on IL-6 production in both cohorts, but did not meet criteria for statistical significance. Our data suggest these HLA alleles play a role in rubella vaccine-induced immunity and provide the basis for future studies that may explain the mechanism(s) by which these HLA polymorphisms affect immune responses to rubella vaccine.     

抗—HBs不同水平者接种乙型肝炎疫苗的初探

After hepatitis B vaccine immunization, serum antibody response was of primary type in 33 cases with anti-HBs less than 2.1 S/N (S/N Ratio Unit) at T0, the anti-HBs positive rate was 39.4%, 84.8%, 96.7% and 96.7% in T1, T2, T0 and T12 respectively. Anti-HBs S/N rose gradually month by month, the antibody response in younger children was better than that in adult. Anamnestic type in 38 cases with anti-HBs greater than 2.1 S/N at T0, the antibody levels rose rapidly in T1, T2 and began to fall in T8. The children were negative for HBsAg, anti-HBs and anti-HBc in sera by RPHA, PHA and ELISA respectively, most (100% in 1-4 age group and 63.2% in 5-9 age group) of them were also negative for HBV serological markers by SPRIA repeatedly, thus they were susceptible and need for hepatitis B vaccine immunization. Indication of hepatitis B vaccination for adult population was also discussed.     

Strong influence of human leukocyte antigen-DP variants on response to hepatitis B vaccine in a Japanese population

Genome-wide association studies (GWASs) have reported that human leukocyte antigen (HLA) variants are associated with chronic hepatitis B, spontaneous hepatitis B virus (HBV) clearance, and response to hepatitis B vaccine. Single nucleotide polymorphisms (SNPs) in HLA-DP (rs9277535 and rs3077) and HLA-DQ (rs2856718 and rs7453920) have been repeatedly associated with chronic hepatitis B and spontaneous HBV clearance. However, the data on the SNPs associated with response to hepatitis B vaccine are inconclusive. The objective of this study was to determine whether these four HLA SNPs that have been identified as risk loci for chronic HBV infection are associated with response to hepatitis B vaccine in a Japanese population. We enrolled 278 medical students who received hepatitis B vaccination and measured anti-hepatitis B surface (HBs) antibody titers 1 month after a three-dose vaccination series. We found that rs9277535 and rs3077 in HLA-DP were strongly associated with response to hepatitis B vaccine (odds ratio [OR] = 0.31 and 0.32, P = 0.004 and 0.010, respectively). These two SNPs were significantly associated with anti-HBs titers in an allele-dependent manner. On the other hand, rs2856718 and rs7453920 in HLA-DQ were not associated with response to hepatitis B vaccine. These results indicate that rs9277535 and rs3077 in HLA-DP are the major determinants of response to hepatitis B vaccine, whereas rs2856718 and rs7453920 in HLA-DQ have little effect on the immune response to hepatitis B vaccine.     

重型颅脑损伤患者单核细胞人类白细胞抗原DR表达及意义

目的 研究重型颅脑损伤患者伤后外周血单核细胞人类白细胞抗原DR(HLA-DR)表达变化规律,探讨HLA-DR表达与感染和预后的关系.方法 选取颅脑损伤患者90例(试验组),按入院时格拉斯哥昏迷量表(GCS)评分将试验组分为试验1组(GCS评分13～15分)、试验2组(GCS评分9～12分)、试验3组(GCS评分3～8分),每组30例,分别为轻、中、重型颅脑损伤患者.选择同期健康体检者30例作为对照组.采用流式细胞仪检测试验各组入院后1、3、7、14d及对照组体检当天外周血单核细胞HLA-DR表达情况,入院后30 d统计试验组患者感染率、治愈率、残疾率、植物状态率、病死率.结果 试验1组、试验2组入院后1、3、7、14d外周血单核细胞HLA-DR表达[分别为(28.11±2.37)、(26.45±1.63)、(27.75±1.83)、(27.15±2.17) MCF,(29.34±2.07)、(27.55±1.63)、(28.42±1.94)、(29.46±2.12) MCF]与对照组体检当天[(29.18±1.91) MCF]比较差异无统计学意义(P＞0.05),试验1组、试验2组入院后1、3、7d及对照组体检当天HLA-DR表达与试验3组入院后1、3、7d[分别为(18.02±1.78)、( 16.05±1.97)、( 20.76±1.65) MCF]比较差异有统计学意义(P＜0.05),但试验1组、试验2组入院后14d及对照组体检当天与试验3组入院后14d[(26.13±2.15) MCF]比较差异无统计学意义(P＞0.05).试验1组、试验2组、试验3组感染率分别为0、3.6％( 1/28)、82.8％(24/29),治愈率分别为100.0％(30/30)、100.0％(28/28)、10.3％(3/29),残疾率分别为0、0、41.4％(12/29),植物状态率分别为0、0、20.7％(6/29),病死率分别为0、0、27.6％(8/29),试验1组与试验2组感染率、治愈率、残疾率、植物状态率、病死率比较差异无统计学意义(P＞0.05),但试验1组、试验2组与试验3组比较差异均有统计学意义(P＜0.05).结论 轻、中型颅脑损伤患者入院后1、3、7、14d外周血单核细胞HLA-DR表达变化不明显,重型颅脑损伤患者HLA-DR表达伤后1d开始下降、3d明显下降、7d开始升高、14d恢复到正常水平,重型颅脑损伤患者HLA-DR表达下降与感染有相关性,并预示预后不良.     

在校大学生乙肝疫苗普种效果对比观察

目的 分析北京市农村居民乙肝疫苗接种状况及影响因素,为提高农村居民乙肝疫苗接种率和乙肝防控政策的制定提供参考依据。 方法 本研究数据采集于2011年1月 — 2012年4月,应用随机抽样的方法和结构式访谈问卷调查的方式在北京大兴区3个自然村进行入户调查 ≥ 16岁成年人,并采用方差分析、二元logistic回归模型进行统计分析。 结果 本研究共调查2 006人,总接种率29.86 %。其中男性1 004人（50.05 %）,接种率30.38 %,女性1 002人（49.95 %）,接种率29.34 %;平均年龄39.8岁。多因素分析中,结合回归系数和OR值分析可得,随着年龄的下降、家庭人均年收入的增加、乙肝认知水平的增加,乙肝疫苗的接种概率逐渐上升（P < 0.01）。职业分组中,接种率由高到低依次是学生、固定工作者、个体工商业者、打工者、农民（P < 0.01）。到达最近的医疗机构花费的时间越短,乙肝疫苗接种概率越高（P < 0.01）。 结论 高年龄、低收入、认知水平低都是阻碍乙肝疫苗接种的重要因素,农民和打工者群体接种率最低,医疗服务的可及性也会影响乙肝疫苗接种率。