Vogt—Koyanagi—Harada综合征与人类白细胞抗原—DQA1和—DQB1基因 …

目的 探讨人类白细胞抗原－ＤＱＡ１和－ＤＱＢ１（ｈｕｍａｎ ｌｅｕｋｏｃｙｔｅ ａｎｔｉｇｅｎ－ＤＱＡ１ ａｎｄ ＤＱＢ１,ＨＬＡ－ＤＱＡ１ａｎｄＤＱＢ１）基因与沃洛特－小柳－原田综合征（Ｖｏｇｔ－Ｋｏｙａｎａｇｉ－Ｈａｒａｄａｓｙｎｄｏｍｅ,ＶＫＨ）遗传易感的相关性。方法 应用聚合酶链式反应－序列特异性引物（ｐｏｌｙｍｅｒａｓｅｃｈａｉｎｒｅａｃｔｉｏｎ－ｓｅｑｕｅｎｃｅｓｐｅｃｉｆｉｅｐｒｉｎ     

Immunogenetics of Episcleritis in Leprosy

Human leukocyte antigens (HLA) were analyzed among Japanese leprosy patients to identify any possible determinants in the development of episcleritis in leprosy patients. Seventy-nine Japanese leprosy patients (33 patients with history of episcleritis and 46 patients without episcleritis) and 114 healthy control subjects were investigated. Human leukocyte antigen-class I and class II specificities were determined serologically by the standard microcytotoxicity test. The HLA-DRB1, -DRB5, -DQA1, and -DQB1 genotypings were performed by using the polymerase chain reaction (PCR)-single strand conformation polymorphism and PCR-restriction fragment length polymorphism analyses. The frequency of HLA-Cw3 was significantly increased among the patients with episcleritis (66.7%) compared to patients without episcleritis (43.5%; odds ratio = 2.6, P < 0.05). The frequency of HLA-DR4 was significantly decreased among the patients with episcleritis (15.2%) compared to patients without episcleritis (39.1%; odds ratio = 0.28, P < 0.05) and the controls (46.5%; odds ratio = 0.21, P < 0.001). At the genomic level, frequencies of the HLA-DRB1*0405, -DQB1*0401, and -DQB1*0302 alleles were significantly decreased among the patients with episcleritis (0%, 0%, and 6.1%, respectively) compared to patients without episcleritis (15.2%, 13.0%, and 26.1%, respectively; odds ratio = 0.07, 0.09, and 0.18, P < 0.05). HLA-DRB1*0405 and -DQB1*0401 were also significantly decreased among the patients with episcleritis compared to the controls (29.8% and 29.8%; odds ratio = 0.04, P < 0.0001). Our results suggest that HLA-Cw3 antigen confers the susceptibility to the development of episcleritis among Japanese leprosy patients. Concurrently, the DRB1 (the -DBR1*0405), and/or DQB1 (the -DQB1*0401 and -DQB1*0302) alleles might provide protection against leprous episcleritis.     

T-cell recognition and cytokine profile induced by melanocyte epitopes in patients with HLA-DRB1*0405-positive and -negative Vogt-Koyanagi-Harada uveitis

PURPOSE: Vogt-Koyanagi-Harada disease (VKH), an autoimmune disease targeted against melanocytes, is associated with HLA-DRB1*0405. This study was undertaken to analyze T-cell recognition and the cytokine expression profile induced by melanocyte epitopes in HLA-DRB1*0405-positive and -negative patients with VKH uveitis. METHODS: Peripheral blood mononuclear cells (PBMC) proliferation and Th1 (IFN-gamma) and Th2 (IL-4 and IL-5) cytokine production were analyzed in HLA-DRB1*0405-positive (n = 12) and -negative (n = 22) patients with VKH and HLA-DRB1*0405-positive (n = 9) and -negative (n = 8) control subjects in response to human melanoma cell line lysate (HMCLL) and 28 synthetic peptides derived from the human melanocyte differentiation proteins TYR, TRP1, TRP2, and Pmel17. The peptides were selected using the TEPITOPE algorithm, based on their predicted binding to HLA-DRB1*0405 and to the non-disease-related HLA-DRB1*15. RESULTS: HMCLL was recognized exclusively by the patients' PBMC (44%) but not by those of the control subjects (P < 0.01). PBMC from patients with VKH recognized an increased breadth of melanocyte-derived peptides at lower peptide concentrations than in the control subjects (68% vs. 25%; P < 0.01, at 1 microM) and did not produce the Th2 cytokine IL-4 in response to disease-specific peptides (0% vs. 50%, P < 0.001). Five peptides were exclusively recognized in patients bearing HLA-DRB1*0405. Furthermore, HLA-DRB1*0405-bearing patients, but not those with HLA-DRB1*15, recognized an increased breadth of melanocyte epitopes in comparison to HLA-matched control subjects (60% vs. 28%; P < 0.05). CONCLUSIONS: These data indicate that patients with VKH are sensitized to melanocyte epitopes and display a peptide-specific Th1 cytokine response. In addition, the data indicate that patients bearing HLA-DRB1*0405 recognize a broader melanocyte-derived peptide repertoire, reinforcing the importance of this allele in susceptibility to the development of VKH disease.     

人类白细胞抗原—DR4基因亚型与Vogt—Koyanagi—Harada综合征相…

研究人类白细胞抗原－ＤＲ４基因亚型与Ｖｏｇｔ－Ｋｏｙａｗｎａｇｉ－Ｈａｒａｄａ综合征的关系，从免疫遗传学角度阐明ＶＫＨ的易感性及抵抗性。方法 采用聚合酶链反应－限制性片段长度多态性分析方法，检测４例ＶＨＫ综合征患者和１０６例健康对照者的ＥＲ４－ＤＲＢ１基因亚型。结果 ５４例ＶＫＨ综合征患者中，３８例扩增出２６３ｂｐ的特异性ＤＲ－４－ＤＲＢ１基因片段，阳性检出率为７０％，对照组仅为１９％，相对危险度     

HLA typing in Vogt-Koyanagi-Harada syndrome in North Indian patients

PURPOSE: To report the HLA profile of VKH patients from India. METHOD: Forty-one patients and 50 controls were studied. Phenotyping using a lymphocytotoxicity assay was done for HLA-A and -B. DNA-based sequence-specific low resolution typing was done for HLA-DR and -DQ loci. RESULTS: HLA-A9 was over-represented in the patient population (p = 0.01), whereas HLA-A11 (p = 0.03) and HLA-DRB1*13 (p = 0.007) were found to be underrepresented. The frequency of HLA-DRB1*04 was 14.6% and 10% in the patient population and controls, respectively. The HLA-DQ frequencies did not differ significantly between patients and controls. CONCLUSION: Unlike that reported in most populations, we did not find a significant association between HLA-DRB1*04 and our patient population.     

我国汉族Vogt-Koyanagi-Harada综合征患者人类白细胞抗原DQB1等位基因多态性研究

目的探讨人类白细胞抗原（HLA）-DQB1等位基因多态性与沃格特-小柳-原田综合征（VKH）遗传易感相关性及与临床表现的关系。方法应用聚合酶链式反应-序列特异性引物（PCR—SSP）,对我国汉族VKH患者和非VKH正常对照者HLA-DQB1等位基因进行分型,分析HLA-DQB1等位基因与患者临床表现的关系。结果收集我国汉族VKH患者88例,非VKH正常对照者88例。VKH患者中男性41例（46．6％）,女性47例（53．4％）;发病年龄15—67岁,平均36岁。VKH患者HLA—DQB1各等位基因频率：HLA-DQB1＊0401为31．8％,DQB1＊0201为17．6％,DQB1＊0301／＊0304为17．1％,DQB1＊0602为12．5％,DQB1＊0303为6．8％,DQB1＊0302为6．3％,DQB1＊0402为1．7％,DQB1＊0502为1.7％,DQB1＊0601为1．7％,DQB1＊0501为1．1％,DQB1＊050为31．1％,DQB1＊0604为0．6％;DQB1＊0603未检出。VKH患者中HLA—DQB1＊0401（VKH组31．8％与对照组4．5％比较,r=44．00,P=0．000,OR=9．8,95％口为4．51—21．31）和HLA—DQB1＊0303（VKH组6．82％与对照组0．57％比较,〈=9．67,P=0．002,伽=12．81,95％CI为1.65—99．58）等位基因频率高于正常人对照组,差异有统计学意义。而VKH患者HLA—DQB1＊0601（VKH组1.7％与对照组9．7％比较,r=10．39,P=0．001,OR=0．16,95％CI为0．05—0．56）和HLA—DQB1＊0302（VKH组6．3％与对照组19．3％比较,r=13．48,P=0．000,OR=0．28,95％CI为0．14—0．57）等位基因频率显著低于正常人对照组,差异有统计学意义。HLA-DQB1＊0401阴性患者与阳性患者之间的临床表现差异无统计学意义（P〈0．01）。结论（I）HLA—DQB1＊0401和DQB1＊0303是VKH的易感等位基因,而HLA-DQB1＊0601和DQB1＊0302是抗性等位基因。HLA-DQB1＊0401基因与临床表现无明显相关性。（2）PCR-SSP可用于快速检测HLA—DQB1等位基因型别。     

HLA Typing in Vogt-Koyanagi-Harada Syndrome in North Indian Patients

Purpose: To report the HLA profile of VKH patients from India. Method: Forty-one patients and 50 controls were studied. Phenotyping using a lymphocytotoxicity assay was done for HLA-A and -B. DNA-based sequence-specific low resolution typing was done for HLA-DR and -DQ loci. Results: HLA-A9 was over-represented in the patient population (p = 0.01), whereas HLA-A11 (p = 0.03) and HLA-DRB1*13 (p = 0.007) were found to be underrepresented. The frequency of HLA-DRB1*04 was 14.6% and 10% in the patient population and controls, respectively. The HLA-DQ frequencies did not differ significantly between patients and controls. Conclusion: Unlike that reported in most populations, we did not find a significant association between HLA-DRB1*04 and our patient population.     

Characteristics of Vogt-Koyanagi-Harada Disease in a French Cohort: Ethnicity,Systemic Manifestations,and HLA Genotype Data

Purpose: To assess in patients followed in a French referral center the clinical spectrum of Vogt-Koyanagi-Harada (VKH) disease and the HLA-DRB1*04 genotype. Methods: Patients previously diagnosed as having VKH disease were re-evaluated in a cross-sectional study using the VKH Committee's revised criteria. High-resolution HLA-DRB1 genotyping was performed. Results: Eleven white patients satisfied ophthalmologic diagnostic criteria. All originated from Mediterranean countries. Nine and 3 patients had neurologic and/or cutaneous abnormalities, respectively. Among DRB1*04-positive patients, the HLA-DRB1*0405 subtype was 71%. Conclusion: These VKH patients predominantly had an incomplete form. The HLA-DRB1*0405 subtype allele was enriched in a group of Mediterranean stock.     

HLA-DRB1 typing of Vogt-Koyanagi-Harada's disease by PCR-RFLP and the strong association with DRB1*0405 and DRB1*0410.

Vogt-Koyanagi-Harada''s (VKH) disease is reported to be closely associated with the HLA class II antigen, HLA-DR4. Serologically defined DR4 is further divided into 11 alleles by molecular HLA genotyping. However, no study of HLA-DNA typing of VKH patients has been reported. To clarify molecular genetic mechanism underlying the susceptibility/resistance to VKH disease, HLA-DNA typing of DR antigens (DRB1 genotyping) by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was performed. It was found that DRB1*0405 showed a significant association with VKH disease compared with the healthy controls (corrected p value < 1 x 10(-5)) and that all the patients had DRB1*0405 and/or DRB1*0410. The specific amino acid residue shared only by these two alleles is Ser at position 57 which is located in the antigen binding groove and may influence the immunological function as an antigen-presenting molecule, suggesting that Ser at position 57 plays an important role in the susceptibility to VKH disease, although the possibility that the involvement of the HLA-DQ molecule, DQ4, in strong linkage disequilibrium with DRB1*0405 and DRB1*0410, cannot be excluded.     

Strong associations between specific HLA-DQ and HLA-DR alleles and the tubulointerstitial nephritis and uveitis syndrome

PURPOSE: To identify genetic markers for the tubulointerstitial nephritis and uveitis (TINU) syndrome by using human leukocyte antigen (HLA) genotyping. METHODS: Eighteen patients who had TINU syndrome were evaluated at three institutions. Typing of class I and II genes was performed by using DNA-based techniques. RESULTS: Significant associations were found with HLA-B14 (6/18 patients, 33.3%; control subjects, 5.5%; P = 0.0003; relative risk [RR] = 8.5), HLA-DQA1*01 (17/18 patients, 94.4%; control subjects, 46.6%, P = 0.0001; RR = 19.5), HLA-DQA1*0101 (14/18 patients, 77.8%; control subjects 22.2%; P < 0.0001; RR = 12.2), HLA-DQB1*05 (14/18 patients, 77.8%; control subjects 17.7%; P < 0.0001; RR = 16.3), HLA-DQB1*0501 (13/18 patients, 72.2%; control subjects 12.9%; P < 0.0001; RR = 17.6), HLA-DRB1*01 (14/18 patients, 77.8%; control subjects, 12.1%; P < 0.0001; RR = 25.5), and HLA-DRB1*0102 (13/18 patients, 72.2%; control subjects, 1.6%; P < 0.0001, RR = 167.1). The HLA haplotype most frequently identified in the study patients was HLA-DQA1*01/DQB1*05/DRB1*01 (13/18 patients, 72.2%). CONCLUSIONS: TINU syndrome is strongly associated with HLA-DQA1*01, HLA-DQB1*05, and HLA-DRB1*01. The association with HLA-DRB1*0102 is one of the highest reported for any disease. Because these genes are in linkage disequilibrium, the role of the individual alleles is difficult to assess. Based on the results of the present study and on previously reported HLA associations in patients with TINU syndrome, the alphabeta dimer encoded by HLA-DQA1*01/DQB1*05 may be particularly important in conferring risk for development of this disease.     

Ocular infiltrating CD4+ T cells from patients with Vogt-Koyanagi-Harada disease recognize human melanocyte antigens

PURPOSE: To determine whether patients with Vogt-Koyanagi-Harada (VKH) disease have immune responses specific to the melanocyte antigens tyrosinase and gp100. METHODS: T-cell clones (TCCs) were established from cells infiltrating the aqueous humor and from peripheral blood mononuclear cells (PBMCs) of patients with VKH. The target cells were LDR4-transfected cells (HLA-DRB1*0405). The TCCs were cocultured with LDR4 in the presence of tyrosinase (tyrosinase450-462: SYLQDSDPDSFQD), gp100 (gp100(44-59): WNRQLYPEWTEAQRLD), or a control peptide. The immune response was evaluated by cytokine production. The responding melanocyte peptide-specific VKH-TCCs were characterized by an immunofluorescence method with flow cytometry. A search was made for molecular mimicry among tyrosinase450-462, gp100(44-59), and exogenous antigens, such as viruses, by database screening. RESULTS: Cells infiltrating the eye and PBMCs in HLA-DR4+ (HLA-DRB1*0405, 0410) patients with VKH contained a population of CD4+ T lymphocytes that recognized tyrosinase and gp100 peptides and produced RANTES and IFN-gamma in response to the two peptides. The T cells were active memory Th1-type lymphocytes, and they recognized the tyrosinase peptide and produced IFN-gamma in response to HLA-DRB1*0405+ melanoma cells. Cytomegalovirus envelope glycoprotein H (CMV-egH290-302) had high amino acid homology with the tyrosinase peptide. In addition, some of the VKH-TCCs recognized CMV-egH290-302 peptide, as well as the tyrosinase peptides. CONCLUSIONS: In VKH there are tyrosinase and gp100 peptide-specific T cells that can mediate an inflammatory response. Such melanocyte antigen-specific T cells could be associated with the cause and pathology of VKH disease.     

我国汉族Vogt-Koyanagi-Harada综合征患者人类白细胞抗原DQB1基因多态性研究

目的 探讨人类白细胞抗原(HLA)DQB1启动子和编码子在Vogt-Koyanagi-Harada(VKH)综合征发病中的作用.方法 88例汉族VKH综合征患者和88名正常对照者纳入本研究.VKH综合征患者中,男性41例,女性47例,发病年龄15～67岁,平均年龄(36±11)岁.正常对照者中,男性42例,女性46例,年龄24～68岁,平均年龄(41±19)岁.采用聚合酶链式反应-序列特异性引物(PCR-SSP)方法进行HLA-DQB1等位基因分型,聚合酶链式反应-单链构象多态性(PCR-SSCP)-克隆-测序法检测HLA-DQB1基因启动子区(HLA-QBP)等位基因.应用x2检验或Fisher精确概率法进行统计分析.结果 VKH综合征患者中HLA-DQB1*0401(0.318比0.045,x2=44.00,P=0.000,OR=9.8)和DQB1*0303(0.068比0.006,x2=9.67,P=0.002,OR=12.81)频率明显高于正常对照者,差异有统计学意义.而HLA-DQB1*0601(0.017比0.096,x2=10.39,P=0.001,OR=0.16)和HLA-DQB1*0302(0.063比0.193,x2=13.48,P=0.000,OR=0.28)在VKH综合征患者中出现的频率显著低于正常对照者,差异有统计学意义.VKH综合征患者HLA-DQB1基因启动子区-189C/A的C等位基因频率显著高于正常对照者(0.324比0.074,x2=45.92,P=0.000),而-227G/A等位基因频率低于正常对照者(0.011比0.108,x2=15.63,P=0.000).VKH综合征患者中易感等位基因的组合(-189C和HLA-DQB1*0401)频率明显高于正常对照者,正常对照者中抗性等位基因的组合(-227G和HLA-DQB1*0601)频率显著高于VKH综合征患者.结论 VKH综合征发病可能与HLA-DQB1启动子和编码区相互作用有关.     

HLA-DRB and HLA-DQB loci in the genetic susceptibility to develop glaucoma in Mexicans.

PURPOSE: Glaucoma is a clinically heterogeneous disease with a pathophysiology that may include genetic susceptibility, possibly associated with an immunologic disorder. The aim of this study was to determine whether the DNA polymorphisms located in the HLA-DRB1 and HLA-DQB1 genes show a specific association pattern in Mexican mestizo patients with primary open-angle glaucoma. METHODS: This was a cross-sectional, case-control, multicenter study. We analyzed the HLA-DRB1 and DQB1 loci of 81 Mexican mestizo nonrelated patients with primary open-angle glaucoma and 98 healthy ethnic matched control subjects. Patients were diagnosed clinically and by visual fields examination. HLA typing was performed by PCR-SSO reverse dot blot. RESULTS: We documented increased frequencies of HLA-DRB1*0301, DRB1*1101, DRB1*0701, DRB1*1402, DQB1*0302, and DQB1*0301; however, none of them were significantly different from normal control subjects. Haplotype analysis showed that the HLA-DRB1*0407-DQB1*0302 haplotype is significantly increased in patients compared with control subjects (P = .0001). CONCLUSIONS: The haplotype HLA-DRB1*0407-DQB1*0302 is common among Mexican mestizo (haplotype frequency = 0.102), and it was increased in our patients (haplotype frequency = 0.259, P = .0001). This may reflect an independent association of this haplotype with the disease as the result of linkage disequilibrium or the influence of a neighboring gene. The pathophysiology of this illness is uncertain, and further studies are needed regarding the genetic susceptibility to develop primary open-angle glaucoma.     

Eales病与人类白细胞抗原-A/B、-DRB/DQB的相关性研究

目的 26例临床确诊为Eales病的遵义市汉族患者作为研究组,选取与研究组患者年龄、性别、民族等因素无差异的100名健康人为对照组。抽取外周静脉血,提取DNA,采用聚合酶链式反应特异序列引物法（PCR-SSP）检测HLA-A/B,HLA-DRB/DQB等位基因频率分布,计算两组优势比（OR）。结果 Eales病患者HLA-A*01 （P=0.041,OR=20.5）A*02（P=0.00;OR=54.667;OR95%CI为11.837-252.473）、B*55（P=0.047;OR=4.524;OR95%CI为1.200-17.047）,HLA-DRB*01（P=0.048;OR=5.879;OR95%CI为1.227-28.169）,DQB*05（P=0.021,OR=2.769,OR95%CI为1.145-6.692）其分布频率明显高于对照组,差异有统计学意义(P＜0.05),HLA-A*11（P=0.031,OR=0.383,OR95%CI为0.158-0.930）明显低于对照组,差异有统计学意义(P＜0.05)。结论 Eales病可能存在遗传易感性,HLA-A*01,-A*02,-B*55,-DRB*01,-DQB*05可能是遵义市汉族Eales病患者的遗传易感基因,而HLA-A*11可能是该病的保护基因。     

遵义市汉族居民Eales病人类白细胞抗原基因多态性和结核感染的相关性研究

目的 探讨遵义市汉族Eales病与人类白细胞抗原(HLA)-A/B、HLA-DRB/DQB基因多态性和结核感染的相关性.方法 采用聚合酶链反应序列特异引物法(PCR-SSP)检测Eales病组、肺结核组、正常对照组HLA-A/B、HLA-DRB/DQB共59个等位基因分布频率,计算各组间优势比(OR)及95%可信区间(CI);对Eales病组与肺结核组的HLA-A*02基因分布频率做相关分析.Eales病组为临床确诊的Eales病患者47例;肺结核组为痰结核菌培养确诊肺结核并排除眼部疾病的患者36例;正常对照组为与研究组患者年龄、性别、民族等因素无差异的100名健康人.Easle病组中,资料完整的39例Eales病患者根据病史及纯结核菌素试验(PPD)检查结果分为4组,a组为既往或现在患肺结核患者,12例;b组为无结核感染患者,27例;c组为PPD检查阳性者,27例;d组为PPD阴性者,12例.结果 Eales病组HLA-A*02(OR=9.719,OR 95%CI为4.377～21.580,P=0.000)、HLA-B*07(OR=11.605,OR 95%CI为2.397～56.191,P=0.001)基因分布频率高于正常对照组,差异有统计学意义,HLA-A*11基因分布频率低于正常对照组,差异有统计学意义(OR=0.495,OR 95%CI为0.245～1.000,P=0.048).肺结核组HLA-DRB*16(OR=5.215,P=0.049)、HLA-A*02(OR=18.87,P=0.000)基因分布频率高于正常对照组,差异有统计学意义,HLA-A*24基因分布频率低于正常对照组,差异有统计学意义(OR=5.690,P=0.015).a组与b组,c组与d组比较:HLA-A*02、HLA-A*11、HLA-B*07基因分布频率差异无统计学意义.在Eales病组、肺结核组、正常对照组间,HLA-A*02、HLA-A*24、HLA-B*07、HLA-DRB*16基因总体分布频率比较,差异均有统计学意义,进一步行x2分割法在Eales病组、肺结核组间两两比较,肺结核组HLA-A*24基因分布频率低于Eales病组,差异有统计学意义(x2=7.289,P=0.007),而HLA-A*02基因分布频率无统计学意义(OR=0.515,P=0.202).Eales病组与肺结核组HLA-A*02基因相关性比较,差异无统计学意义(列联系数0.412,P=0.064).结论 Eales病可能存在遗传易感性,HLA-A*02和HLA-B*07可能是遵义市汉族Eales病患者的遗传易感基因,而HLA-A*11可能是保护基因;HLA-DRB*16和HLA-A*02可能是遵义市汉族肺结核病的易感基因,而HLA-A*24可能是保护基因.HLA-A*02可能是遵义市汉族人群中Eales病和肺结核病共同的易感基因.

Abstract：

Objective To analyze the relationship of human leukocyte antigen alleles (HLA-A/B,HLA-DRB/DQB) polymorphism and Eales disease, tuberculosis infection in a Han population in Zunyi city of China. Methods The subjects were analyzed by case-control study, which consisted of three groups including Eales disease group (47 patients), pulmonary tuberculosis group (36 patients) and normal control group (100 healthy people). Thirty-nine patients in Eales disease group who had complete history were divided into 4 subgroups according to the history and tuberculin PPD test. Twelve patients with past or present pulmonary tuberculosis were in group A, 27 patients without pulmonary tuberculosis were in group B, 27 patients with positive PPD test were in group C, and 12 patients with negative PPD test were in group D. Fifty-nine alleles of HLA-A/B and HLA-DRB/DQB were analyzed by polymerase chain reaction with sequence-specific primers (PCR-SSP) in all subjects. Odds ratios between each group (OR) and 95%confidence interval (CI) were calculated; Frequency distribution of HLA-A * 02 gene were analyzed for the group A and the TB group. Results The frequency distribution of HLA-A* 02 (OR=9. 719, OR 95% CI:4. 377-21. 580, P=0. 000) and HLA-B* 07 (OR= 11. 605, OR 95% CI: 2. 397-56. 191, P=0. 001) alleles in Eales disease group were obviously higher than that in normal control group, but frequency distribution of HLA-A * 11 (OR = 0. 495, OR 95% CI: 0. 245-1. 000, P= 0. 048) in Eales disease group was obviously lower than that in normal control group. There was no significant difference in frequency distribution of HLA-A * 02, HLA-A * 11 and HLA-B* 07 alleles between groups A and B, and between groups C and D (P＞0. 05). The distribution frequency of HLA-A * 02, HLA-A * 24, HLA-B * 07 and HLA-DRB * 16alleles among Eales disease group, pulmonary tuberculosis group and control group was statistically different (P＜0. 05). The frequency distribution of HLA-A * 24 alleles in pulmonary tuberculosis group was lower than that in Eales disease group (x2 = 7. 289, P = 0. 007), but the frequency distribution of HLA-A * 02 alleles had no significant difference (OR=0. 515, P=0. 202) between two groups. Conclusions The alleles of HLA-A * 02 and HLA-B * 07 may be genetic predisposing genes of Eales disease, but HLA-A * 11 alleles may be protective gene in population of Han nationality from Zunyi city. The alleles of HLA-DRB * 16 and HLA-A * 02 may be genetic predisposing genes of pulmonay tuberculosis. The alleles of HLA-A * 02 may be a common susceptible gene for Eales disease and pulmonary tuberculosis. HLA-A * 11 and HLA-A * 24 alleles were protective genes of Eales disease and pulmonary tuberculosis respectively.     

Human leukocyte antigen serologic and DNA typing of Beh?et's disease and its primary association with B51.

Ninety Japanese patients with Beh?et's disease (BD) were typed for human leukocyte antigen (HLA)-DRB1, -DQA1-, -DQB1, and -DPB1 alleles by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method and for HLA-A, -B, -C, -DR, and -DQ antigens by conventional serologic typing. Serologic HLA typing showed a remarkably significant increase of HLA-B51 and a significant decrease of HLA-DQw1 in the patients with BD, especially those with ocular lesions including complete type, as compared with the control group (for B51, chi-squared = 46.75, P corrected < 0.001, relative risk [RR] = 7.9; for DQw1, chi-squared = 12.10, P corrected < 0.01, RR = 0.4). By PCR-RFLP genotyping, no significant difference was revealed in any class II alleles between the patient and the control groups in the corrected P value test, but P value analysis showed the significantly high frequency of DRB1*0802 and the significantly low frequencies of DQA1*0103, DQB1*0601, and DQB1*0501. No significant difference was observed in any DPB1 alleles by either P value analysis. These results indicated that the primary and primordial gene(s) responsible for the susceptibility to BD, especially related to ocular lesions, were not located in the HLA class II gene region but were in or very close to the HLA-B locus in the class I region. They also suggested the possibility that BD was a symptom complex associated with some independent diseases.     

Immunogenetics and clinical phenotype of sympathetic ophthalmia in British and Irish patients

BACKGROUND/AIMS: Sympathetic ophthalmia (SO) is a classic example of autoimmune disease where human leucocyte antigen (HLA) genomic associations could provide further understanding of mechanisms of disease. This study sought to assess HLA genetic polymorphism in British and Irish patients with SO, and to assess whether HLA gene variants are associated with clinical phenotype or disease severity. METHODS: High resolution DNA based HLA typing using polymerase chain reaction sequence specific primers was performed in 27 patients with SO and 51 matched healthy controls. Clinical phenotype and markers of disease severity were determined prospectively in 17 newly diagnosed patients and from medical record review and repeat clinical examination in 10 previously diagnosed patients. RESULTS: HLA-Cw*03 (p=0.008), DRB1*04 (p=0.017), and DQA1*03 (p=0.014) were significantly associated with SO. For class II alleles at higher resolution, only HLA-DRB1*0404 (relative risk (RR) = 5.6, p = 0.045) was significantly associated with SO. The highest relative risk for any of the associated haplotypes was with HLA-DRB1*0404-DQA1*0301 (RR=10.9, p=0.019). Patients with the DRB1*04-DQA1*03 associated haplotype were significantly more likely to develop SO earlier, with fewer inciting ocular trauma events, and to require more systemic steroid therapy to control inflammatory activity. CONCLUSIONS: Sympathetic ophthalmia is associated with HLA-DRB1*04 and DQA1*03 genotypes in white patients, similar to Japanese patients. Differences in DRB1*04 gene variant associations (-0404 in Britain and Ireland and -0405 in Japan) may have implications for HLA peptide binding in disease initiation. The DRB1*04-DQA1*03 haplotype is a marker of increased SO susceptibility and severity, as in Vogt-Koyanagi-Harada disease, which also has similar clinicopathological and HLA associations.     

Frequent immune response to a melanocyte specific protein KU-MEL-1 in patients with Vogt-Koyanagi-Harada disease

AIM: To isolate autoantigens possibly involved in the pathogenesis of Vogt-Koyanagi-Harada (VKH) disease. METHODS: Autoantigens recognised by immunoglobulin G antibodies (IgG Ab) in sera from VKH patients were isolated by screening the lambda phage cDNA libraries made from melanocytes and a highly pigmented melanoma cell line with the patients' sera. Presence of IgG specific for the autoantigens in sera from patients with various panuveitis and healthy individuals was evaluated. Relation between the specific IgG and various clinicopathological features was examined. RESULTS: KU-MEL-1 was found to be one of the 81 isolated positive clones representing 35 distinct genes, which is a previously isolated melanoma antigen preferentially expressed in melanocytes. The IgG Ab specific for KU-MEL-1 was detected in sera from patients with VKH in significantly higher amounts than in sera from patients with Beh?et's disease, sarcoidosis, and from healthy individuals. Positive serum KU-MEL-1 Ab was significantly associated with HLA-DRB1*0405 and male VKH patients. CONCLUSION: KU-MEL-1 was identified as a new autoantigen for VKH. The highly frequent induction of IgG Ab for KU-MEL-1 in HLA-DRB1*0405 positive VKH patients may suggest the possible involvement of KU-MEL-1 specific CD4(+) T cells in the pathogenesis of VKH, suggesting the possible use in the development of diagnostic and therapeutic treatments for VKH patients.     

Vogt-Koyanagi-Harada syndrome in patients of Vietnamese ancestry

Background: Vogt-Koyanagi-Harada syndrome (VKH), is an idiopathic, multisystem inflammatory disorder primarily involving the eye. HLA typing has shown a strong association between the HLA-DR4 antigen and people of Japanese, Han Chinese and Hispanic ancestry with VKH. This study reviewed the clinical features and HLA typing of Vietnamese patients with VKH.
Patients and methods: A retrospective review of four unrelated Vietnamese patients with VKH seen in private practice and hospital clinic. The American Uveitis Society (1978) criteria for VKH diagnosis were satisfied. Standard microcytotoxic assays for Class I antigens and HLA-DNA typing of Class II DR antigens (DRB1 genotyping) by the PCR-SSO method were performed.
Results: The clinical features of VKH in Vietnamese were comparable to those seen in other Asian races. HLA-DR4 was present in three of the four VKH patients. Two of these patients also expressed the allele DRB1*0405.
Discussion: The strong association betlNeen HLA-DR4 and the DRB1*0405 allele and VKH seen in Japanese people, may well also exist in Vietnamese people. The HLA association suggests an immunogenetic predisposition to VKH.     

Profiling of human leukocyte antigens in Eales disease and tuberculosis

To analyze the association between Eales disease, histocompatibility leukocyte antigen alleles (HLA-A/B, HLA-DRB/DQB) and tuberculosis infection, and to explore susceptible genes and protective genes associated with Eales disease and tuberculosis infection in a population of Han nationals from Zunyi City in Guizhou Province, China. The subjects were analyzed by a case–control study consisting of three groups—Eales disease group (47 cases), pulmonary tuberculosis group (36 cases) and normal control group (100 cases). The Eales disease group was divided into four parts. Part one consisted of 12 patients who had suffered from pulmonary tuberculosis. Part two consisted of 27 patients who had not suffered from pulmonary tuberculosis. Parts three and four consisted of 27 patients with a positive purified protein derivative test and 12 patients with a negative test, respectively. DNA samples from 47 patients with Eales disease, 36 patients with pulmonary tuberculosis and 100 healthy people were detected by polymerase chain reaction with sequence-specific primers. The 59 HLA-A/B and HLA-DRB/DQB alleles from Eales disease were compared with those from tuberculosis and normal control, and a correlativity test of common susceptible genes was performed to analyze the potential relationship between Eales disease and pulmonary tuberculosis. The frequency distribution of HLA-A*02 alleles (OR 9.719, OR 95 % CI 4.377–21.580, P = 0.000) and HLA-B*07 (OR 11.605, OR 95 % CI 2.397–56.191, P = 0.001) in the Eales disease group was higher than in the normal control group, but the HLA-A*11 alleles (OR 0.495, OR 95 % CI 0.245–1.000, P = 0.048) were lower than in the normal control group, showing a significant difference. Compared with parts two and four, the frequency distribution of HLA-A*02, HLA-A*11 and HLA-B*07 alleles in parts one and three showed no significant difference (P > 0.05). HLA-A*A02, HLA-A*24, HLA-B*07 and HLA-DRB*16 alleles between the Eales disease, pulmonary tuberculosis and normal control group showed statistical significance (P < 0.05). HLA-A*24 alleles in the pulmonary tuberculosis group were lower than the Eales disease group (χ² 7.289, P = 0.007), but HLA-A*02 alleles showed no significant difference (P > 0.05) between the two groups. The results show that HLA-A*02 and HLA-B*07 may be genetic predisposing genes, but HLA-A*11 alleles may be protective genes of Eales disease, the HLA-A*02 allele may be a common susceptible gene of Eales disease and pulmonary tuberculosis. HLA-A*11 and HLA-A24 alleles are protective genes of Eales disease and pulmonary tuberculosis, respectively. In summary, the frequency distribution of susceptible genes of Eales disease and pulmonary tuberculosis in a population of Han nationals from Zunyi City in Guizhou Province, China showed no significant difference.