Genotyping of HLA-I and HLA-II alleles in Chinese patients with paraneoplastic pemphigus

BACKGROUND: Class I and class II HLA genes are thought to play a role in the immunopathogenesis of bullous dermatoses such as pemphigus vulgaris and pemphigus foliaceus, but we know little about the genetic background of paraneoplastic pemphigus (PNP) in Chinese patients. OBJECTIVES: To identify class I and class II HLA alleles by genotyping in Chinese patients with PNP, and to find out the possible association between HLA alleles and disease susceptibility. METHODS: Nineteen Chinese patients with PNP were enrolled in this study. HLA-A, B, C, DRB1 and DQB1 alleles were typed by polymerase chain reaction and a colour-coded sequence-specific oligonucleotide probes method. RESULTS: The frequencies of HLA-B*4002/B*4004, B*51, B*52, Cw*14, DQB1*0301, DRB1*08 and DRB1*11 were relatively prevalent in Chinese Han patients with PNP in comparison with normal controls. After correction for multiple comparisons, Cw*14 remained statistically significant, and the other alleles were unremarkable in these patients. CONCLUSIONS: The genetic background predisposing to PNP may be different in patients from various races and areas. HLA-Cw*14 may be the predisposing allele to PNP in Chinese patients, which is different from the predisposing allele in French patients with PNP and the alleles predisposing to pemphigus vulgaris and pemphigus foliaceus.     

Tunisian endemic pemphigus foliaceus is associated with the HLA-DR3 gene: anti-desmoglein 1 antibody-positive healthy subjects bear protective alleles

Background  Pemphigus foliaceus is an autoimmune blistering skin disease that partly results from genetic factors, especially human leucocyte antigen (HLA) class II genes.
Objectives  The aim of the study was to determine the HLA DR/DQ markers of susceptibility and protection in the Tunisian endemic form.
Methods  Genomic DNA from 90 patients with pemphigus foliaceus recruited from all parts of the country and matched by age, sex and geographical origin with 270 healthy individuals, was genotyped.
Results  Firstly, when the whole patient population was studied, DRB1*03 , DQB1*0302 and DRB1*04 alleles were significantly associated with the disease while a significant decrease of, in particular, DRB1*11 and DQB1*0301 was observed in patients compared with controls. DRB1*0301 was the dominant allele in DR3-positive patients and controls, while DRB1*0402 was found in 42% of DR4-positive patients. Secondly, when the HLA DR/DQ allele distribution was studied after dividing patients according to their geographical origin, the southern group, which consisted exclusively of patients with the endemic form of the disease, showed the same associations as the whole pemphigus foliaceus population, particularly with DRB1*03 . In the northern group, only the DRB1*04 and DQB1*0301 alleles were found to be associated. Interestingly, anti-desmoglein 1 antibody-positive healthy controls did not carry susceptibility alleles but, in contrast, most carried negatively associated alleles.
Conclusions  These observations indicate that a particular genetic background characterizes the Tunisian endemic form of pemphigus foliaceus and that HLA class II genes control the pathogenic properties of the autoimmune response rather than the initial breakage of B-cell tolerance.     

Molecular analysis of HLA DP and DQ genes associated with dermatitis herpetiformis

HLA class II DQ and DP genes from dermatitis herpetiformis patients were amplified and analyzed using molecular probes and compared to those from celiac disease patients and to an HLA and ethnically matched control group. In dermatitis herpetiformis, as in celiac disease, the strongest association of disease was with the DQ subregion alleles DQB1*0201 and DQA1*0501 that are linked to the DRB1*0301 allele. DQB1*0201 determines the DQw2 serologic marker whereas DRB1*0301 determines the DRw17 serologic marker (formerly termed DR3). A DP subregion allele DPB1*0301 was increased and a constellation of DPB1 alleles that included DPB1*0202, *0901, and *1301 was decreased in dermatitis herpetiformis. DPB1*0101, an allele reported to be increased in celiac disease, was not increased in dermatitis herpetiformis. DP beta chains that lack a negatively charged amino acid residue at position 69 of the DP beta chain are significantly over-represented both in dermatitis herpetiformis and celiac disease patients with the DRw17, DQw2 haplotype, compared to healthy controls with that haplotype. These data favor a multigenic model for the contribution of HLA class II D region genes to dermatitis herpetiformis susceptibility. Further, they indicate that a specific DQ molecule, when present in combination with the product of one of several different DPB1 alleles, may contribute to susceptibility to the intestinal lesion, which is common to dermatitis herpetiformis and celiac disease.     

Molecular genetic analysis of HLA-DR and -DQ alleles in Spanish patients with melanoma

Controversial data have been reported about HLA alleles and susceptibility to melanoma. The relationship between distribution of HLA alleles in patients with melanoma and susceptibility to tumour was analysed, to study the possible correlation between HLA class II DQA1, DQB1 and DRBI genes and melanoma in a Spanish population. Genomic DNA from 82 patients with melanoma and 367 random healthy donors, from the same geographic area, were typed by PCR-SSP (sequence specific primers). The patients were also divided into different groups according to the age and presence of cancer relatives, and compared with the controls. None of these HLA class II alleles showed significant positive or negative associations with either the overall population of patients with melanoma or the considered subgroups. Moreover, values for relative risk of DQB1*0301, DQB1*0302, DQB1*0303, DQB*05, DQA1*0401, DQA1*0101/0104 and DRB*08, which have been reported to be increased or decreased in patients with melanoma, were very low and of no statistical significance. Our results indicate that HLA class II alleles may not contribute to a strong susceptibility to melanoma in the Spanish population, although further studies on larger series are needed to corroborate this. Key words:     

HLA-DR and DQ polymorphisms in bullous pemphigoid from northern China

Bullous pemphigoid (BP) is an autoimmune disease mediated by autoantibodies against hemidesmosome components. This study used PCR-sequence-specific primers to genotype polymorphisms in HLA-DR and DQ in 25 BP patients and 57 normal controls from northern China. We found lower frequencies of DRB1*08 (DR8) and DRB1*08/DQB1*06 (DR8/DQ6) haplotypes in BP patients than in controls (4.08% vs. 15.19% and 1.54% vs. 13.82%, respectively; P < 0.05), suggesting a protective role for DR8 and DR8/DQ6 haplotypes in BP patients from northern China; there were no statistical differences among other alleles tested. This result is strikingly different from previous reports that DQB1*0301 is associated with BP in Caucasian patients and DRB1*1101, DQB1*0302, DRB1*04/DQA1*0301/DQB1*0302 and DRB1*1101/ DQA1*0505/DQB1*0302 with Japanese BP patients. Ethnic differences in the polymorphic composition of the HLA-DR and DQ genes may influence genetic susceptibility to BP.     

Common human leukocyte antigen alleles in pemphigus vulgaris and pemphigus foliaceus Italian patients.

Pemphigus refers to a group of autoimmune blistering skin diseases, mainly identified as pemphigus vulgaris and pemphigus foliaceus, both characterized by the presence of autoantibodies against keratinocyte adhesion molecules, leading to loss of cell-cell adhesion with consequent blister formation. Pemphigus vulgaris is reported to be associated with human leukocyte antigen DR4 and/or DR6 whereas no data are available on pemphigus foliaceus, except for the endemic Brazilian form (fogo selvagem), which is reported to be associated with DR1 and DR4. We here report human leukocyte antigen molecular typing on a total of 87 patients, 61 with pemphigus vulgaris and 26 with pemphigus foliaceus, versus 128 healthy matched controls. Generic typing showed an increase of DRB1*04 and DRB1*14 and a decrease of DRB1*07 in both pemphigus vulgaris and pemphigus foliaceus patients. Molecular subtyping of DR4+ and DR14+ subjects showed a highly significant association between the DRB1*1401 and both pemphigus vulgaris (p < 0.0001) and pemphigus foliaceus patients (p < 0.0001) together with a significant increase of the linked DQB1*0503 (pemphigus vulgaris p < 0.0001; pemphigus foliaceus p < 0.0001). Moreover, whereas the association between DRB1*0402 and pemphigus vulgaris (p < 0.0001) has been confirmed, no significant association between a specific allele of the DR4 group and pemphigus foliaceus, has been found. Therefore, at least in Italian patients, pemphigus vulgaris and pemphigus foliaceus share DRB1*1401 and DQB1*0503, as susceptible human leukocyte antigen alleles, whereas DRB1*0402 is only found associated with pemphigus vulgaris. The observation that both diseases, pemphigus vulgaris and pemphigus foliaceus, carry the same susceptible human leukocyte antigen alleles has been interpreted as a common genetic background predisposing to pemphigus as, like in other autoimmune disorders, it is not sufficient to explain the onset of the disease on the basis of the sole aforementioned alleles. Other linked genes and/or environmental factors should play a facilitating role in the outbreak of pemphigus, either pemphigus vulgaris or pemphigus foliaceus.     

Mycosis fungoides: HLA class II associations among Ashkenazi and non-Ashkenazi Jewish patients

BACKGROUND: An immunogenetic mechanism has been suggested to play a role in the pathogenesis of mycosis fungoides (MF). While results of studies on HLA class I associations haveproved inconsistent, two previous studies showed that certain HLA class II alleles were significantly increased among North American caucasian patients with MF: HLA-DRB1*11 and DQB1*03. OBJECTIVES: To investigate the possible HLA class I and class II associations with MF among Jewish patients. METHODS: The patient group comprised 68 Jewish patients with MF: 38 Ashkenazi and 30 non-Ashkenazi. The control group comprised 252 healthy Jewish volunteers: 132 Ashkenazi and 120 non-Ashkenazi. Tissue typing for HLA class I (A and B) was performed using the National Institutes of Health microlymphocytotoxicity technique. DNA-based low-medium resolution analysis for DRB1* and DQB1* alleles was performed using polymerase chain reaction (PCR) amplification with sequence-specific primers. For those alleles found to have significantly increased frequency, high-resolution analysis was done by means of PCR sequence-specific oligotyping. RESULTS: The allele frequency of HLA-DRB1*11 was found to be significantly increased but only among Ashkenazi patients with MF (30% vs. 19% in the controls; P = 0.034). High-resolution analysis for DRB1*11, not previously performed, suggested that its greater frequency is due to the increased number of Ashkenazi MF patients with the DRB1*1104 allele (P corrected = 0.036). Analysed together, DQB1*03 alleles (DQB1*0301-0304) had a significantly greater frequency in MF as a group as compared with controls (47% vs. 33%, P = 0.003). DQB1*0301 was demonstrated to be the specific allele associated with MF in Jewish patients (allele frequency of 36% vs. 23% in controls; P corrected = 0.0068), which was not the case for North American caucasian patients with MF. No greater frequencies of any of the HLA class I A or B antigens were found. CONCLUSIONS: Our findings further demonstrate the 'universality' of MF HLA class II susceptibility alleles, i.e. HLA-DRB1*11 and HLA-DQB1*03, suggesting that HLA polymorphism is likely to be important in the pathogenesis of MF in Jewish patients, as it is in North American caucasian patients. Not previously reported is our finding that HLA-DRB1*1104 is the specific allele more prevalent among patients with MF. Our study also underscores some differences in HLA profiles between non-Jewish and Jewish patients with MF and between Ashkenazi and non-Ashkenazi Jewish patients, indicating the possibility of diverse HLA disease associations in populations with different genetic backgrounds. Our study provides further evidence for the lack of association between HLA class I and MF.     

Human leukocyte antigen genotypes and antibody profiles associated with familial pemphigus in Japanese

Previous population-based, genetic studies have shown that human leukocyte antigen (HLA) class II loci such as HLA-DR4 (DRB1*04) and HLA-DR14 (DRB1*14) alleles are consistently associated with the occurrence of pemphigus vulgaris (PV) in Japanese as well as other ethnic populations. Among PV-related HLA-DRB1 alleles (*0406, *1401, *1405, *1406) in Japan, HLA DRB1*1405 and DRB1*0406 were found to be associated with both PV and pemphigus foliaceus (PF) phenotypes. We report four familial cases of pemphigus in two unrelated families, together with analysis of their HLA-DR and -DQ alleles, and their antibody profiles. One family comprised a woman with PF and her mother with PV: both patients shared a HLA haplotype of A31(19), B54(22), CW1 and DRB1*1405. Another family included two sisters with PF and PV, respectively: both of these patients shared a DRB1*1405-DQA1*0104-DQB1*0503 haplotype. Clinicopathological and serological monitoring revealed that the elder sister with PF presented with a PV phenotype later, and gained anti-desmoglein (Dsg)3 antibodies in addition to having a low titer of anti-Dsg1 antibodies. Conversely, the younger sister with PV developed PF with only anti-Dsg1 antibody detected. These results indicate that an HLA-DRB1*1405 (DQB1*0503) haplotype may confer susceptibility to both PV and PF, and that genetic susceptibility alone is not always responsible for the clinical phenotype and autoantibody profile.     

The association between HLA DR, DQ antigens, and vulval lichen sclerosus in the UK: HLA DRB112 and its associated DRB112/DQB10301/04/09/010 haplotype confers susceptibility to vulval lichen sclerosus, and HLA DRB10301/04 and its associated DRB10301/04/DQB10201/02/03 haplotype protects from vulval lichen sclerosus

Lichen sclerosus (LS) is considered to have an immunogenetic background. Several small studies, using serological typing, have reported that HLA-DR11, DR12, and DQ7 were increased in LS, with DR17 less frequent. This study aimed to validate and detect new HLA-DR and DQ associations with LS in females and its characteristic clinical parameters. The cases, 187 female LS patients, and 354 healthy controls were all UK North Europeans. PCR-sequence specific primers method was applied to genotype the HLA-DR, DQ polymorphisms that correspond to 17 serologically defined DR and seven DQ antigens. Statistical analysis was performed with two-tailed Fisher's exact test with Bonferroni adjustment (p value after Bonferrroni adjustment, Pc). We found increased frequency of DRB1*12 (DR12) (11.2%vs 2.5%, pc < 0.01) and the haplotype DRB1*12/DQB1*0301/04/09/010 (11.2%vs 2.5%, p < 0.001, pc < 0.05), and a lower frequency of DRB1*0301/04 (DR17) (11.8%vs 25.8%, pc < 0.01) and the haplotype DRB1*03/DQB1*02DRB1*0301/DQB1*0201/02/03 (11.2%vs 24.6%, pc < 0.0001) in patients compared with controls. HLA DR and DQ antigens were not associated with time of onset of disease, site of involvement, structural changes of genitals, and response to treatment with potent topical steroids. In conclusion, HLA-DR and DQ antigens or their haplotypes appear to be involved in both susceptibility to and protection from LS.     

Mucous membrane pemphigoid: HLA-DQB1*0301 is associated with all clinical sites of involvement and may be linked to antibasement membrane IgG production

BACKGROUND: Class I human leucocyte antigens (HLA) -A, -B, -Cw and class II HLA-DRB1, -DQB1 alleles were determined in 131 British Caucasian patients with mucous membrane pemphigoid (MMP) using serological and DNA-based methods. OBJECTIVES: To analyse the class I and II alleles expressed in well-defined clinical and immunopathological subgroups of MMP, in order to establish whether specific alleles or haplotypes might in part explain disease susceptibility, clinical sites of involvement or disease severity. METHODS: Subgroups of patients were analysed according to the following clinical criteria: age of onset, sex, sites of clinical involvement (oral, ocular, skin, nasal, genital, pharyngeal, oesophageal, laryngeal, perianal), disease severity and history of autoimmune disease. Subgroups were also analysed according to the following immunopathological criteria: autoantibody profile, the presence of circulating antibasement membrane IgG or IgA antibodies and the detection of target basement membrane zone (BMZ) antigens (BP230 and BP180) by IgG autoantibodies. RESULTS: Class I HLA typing showed no significant disease or subgroup associations. Class II DRB1 typing showed a significantly increased allelic frequency in MMP vs. controls for DRB1*11 (RR = 2.08, Pc < 0.0000056). For DQB1, MMP vs. controls, there was a significantly increased allelic frequency for DQB1*0301 (Pc < 0.00000028) in both males and females; all clinical sites of involvement, with the exception of laryngeal, oesophageal and perianal sites and in patients with detectable circulating anti-BMZ IgG compared with those negative for IgG (P < 0.0096, Pc < 0.019). A positive trend was noted in patients with ocular involvement compared with no ocular involvement and in patients with a clinical score > or = 10 compared with < 10. We found no difference in DQB1*0301 allele frequency between subgroups with or without BP180 or BP230 target antigens. Haplotype frequencies showed an increase in DRB1*04, DQB1*0301 (Pc < 0.000066) and DRB1*11, DQB1*0301 (Pc < 0.000002) among patients compared with controls. CONCLUSIONS: The DQB1*0301 allele confers a predisposition to all subgroups of MMP and may have a role in T-cell recognition of basement membrane antigens, resulting in the production of anti-BMZ IgG autoantibodies. The positive trend between increased allelic expression of DQB1*0301 in patients with ocular disease and in those with a higher clinical score, further suggests a role for this allele in disease severity.     

Association between psoriasis vulgaris and MHC-DRB, -DQB genes as a contribution to disease diagnosis

We analyzed 100 control individuals and 60 patients with psoriasis vulgaris from the population of Campinas, Brazil. Typification of class II HLA alleles (HLA-DRB1-5 and -DQB1) was carried out through the DNA/PCR/SSP at medium and high resolution. DNA was extracted through a salting-out procedure: 13 DRB1 alleles, 3 DRB3 alleles, 1 DRB4 allele, 2 DRB5 alleles, and 5 DQB1 alleles were identified at a medium resolution using the PCR/SSP, and 45 DRB1 alleles were identified at a high resolution in analyzed patients. Results showed associations with psoriasis vulgaris: positive associations HLA-DRB3*02 (p < 0.05, chi(2) = 5.10, RR = 2.14); HLA-DRB1*0102 alleles (p < 0.05, RR = 5.44). Negative associations were found for HLA-DRB4*01 (chi(2) = 3.23, RR = 0.55) and HLA-DRB1*1302 alleles (p < 0.05, RR = 0.23). The haplotypes revealed positive association for HLA-DRB1*0102/DQB1*05 (p < 0.05, RR = 5.44) and HLA-DRB1*0701/DQB1*03 alleles (p < 0.02, RR = 9.00). These findings suggest a possible association of the DRB1 allele with the group of patients showing an early onset of the illness, as well as an association with haplotypes HLA-DRB1*0102/DQB1*05 and HLA-DRB1*0701/DQB1*03.     

The association of psoriasis with human leukocyte antigens in Korean population and the influence of age of onset and sex

To identify HLA markers that may contribute to the genetic susceptibility of Koreans to psoriasis, we studied 84 psoriasis patients, with serologic HLA types of A, B, and genotypes of HLA-Cw, DRB1, DQA1, DQB1, DPB1 alleles. The distribution of HLA markers and the associated haplotypes were analyzed according to age and sex. HLA-Cw*0602 showed the strongest association with psoriasis (relative risk = 36.0, p < 10-8, Pc < 8 x 10-7). The frequencies of A1 (relative risk = 17.0, p < 9 x 10-7, Pc < 7 x 10-5), A30 (relative risk = 5.5, p < 2 x 10-5, Pc < 0.001), B13 (relative risk = 5.6, p < 4 x 10-6, Pc < 3 x 10-4), B37 (relative risk = 30.3, p < 7 x 10-7, Pc < 6 x 10-5), DRB1*07 (relative risk = 5.9, p < 2 x 10-6, Pc < 8 x 10-5), DRB1*10 (relative risk = 26.4, p < 4 x 10-6, Pc < 3 x 10-4), DQA1*02 (relative risk = 6.2, p < 5 x 10-7, Pc < 4 x 10-4), DQB1*02 (relative risk = 2.5, p < 0.005, Pc = ns) and DPB1*1701 (relative risk = 24.6, p < 9 x 10-6, Pc < 7 x 10-4) were also significantly increased in Korean psoriasis patients. Type I and type II psoriasis were subdivided into groups of below and above 30 y of age, because of the significant difference found in HLA-Cw*0602 phenotype frequency between the two groups (83.9% vs. 54.5%, p < 0. 009). In addition to HLA-Cw*0602, the frequencies of B37 and DPB1*1701 were significantly higher in type I as opposed to type II psoriasis. HLA-A30-B13-Cw*0602-DRB1*07-DQA1* 02-DQB1*02 was identified as a high risk haplotype. This was particularly true at an early age in the female. HLA-A33-B44-Cw*1401-DRB1*13-DQA1* 01-DQB1*06-DPB1*0401 was defined as a protective haplotype for psoriasis. The extended haplotype HLA-A1-B37-Cw*0602-DRB1*10-DQA1*01-DQB1*05 was discovered to be a high-risk factor in Koreans. To summarize, this study demonstrates the differential association of HLA according to sex, and identifies a newly found high-risk haplotype and a protective haplotype in Korean psoriasis patients.     

Genotyping for HLA-A, B and C alleles in Japanese patients with pemphigus: prevalence of Asian alleles of the HLA-B15 family

BACKGROUND: There have been only limited reports on major histocompatibility complex class I antigens in pemphigus. OBJECTIVES: To characterize HLA-A, B and C class I alleles by genotyping in Japanese patients with pemphigus, and to analyse the possible association of class I alleles with disease susceptibility within a relatively homogeneous ethnic population. METHODS: Alleles of HLA-A, B and C, and DRB1 and DQB1 loci were fully determined in 51 Japanese patients with pemphigus. RESULTS: Asian alleles of the HLA-B15 family, including the allele B*1507, which was significantly increased in comparison with normal controls, were prevalent in patients with pemphigus vulgaris (PV). The prevalence of B*15 alleles in patients with PV was not due to linkage disequilibrium with HLA-DR4 or DR14 alleles, which have been shown to confer strong susceptibility to PV across racial barriers. In contrast to the unique distribution of the HLA-B alleles, HLA-A and C alleles were unremarkable in patients with PV when compared with normal control subjects. CONCLUSIONS: These results suggest that there may be differences in the ethnic concentrations of different HLA-B alleles in patients with PV.     

Human leukocyte antigen class II alleles and natural history of HPV 2/27/57-induced common warts

Epidemiological studies have demonstrated an association between HLA-DQB1*03 alleles and the risk of cervical cancer induced by human papillomavirus (HPV). As persistence of HPV infection is required for developing cervical cancer, we wanted to elucidate the role of HLA-class II allele polymorphisms in the persistence of common warts induced by HPV 2, HPV 27 or HPV 57. Therefore, we determined the distribution of HLA-DQA1, -DQB1, and -DRB1 alleles in 71 patients presenting with HPV 2/27/57-induced common warts which had persisted for at least 18 months as well as in 92 individuals who had never suffered from common warts or whose warts had healed in less than 18 months. Among patients with long-lasting warts, the carriership frequencies and allele frequencies of DQA1*0301, DQB1*0301, DRB1*07 and DRB1*09 were higher, and the allele frequencies of DQA1*0501, DQB1*0603, DRB1*01 and DRB1*03 were lower. Statistically significant differences (Bonferroni adjusted Fishers exact test) were found for carriership frequency of DQA1*0301 (46.5 vs 21.7%, P=0.013) and for carriership frequency (18.3 vs 1.1%, P=0.0015) and allele frequency (12 vs 0.5%, P=0.000013) of DQB1*0301. A greater proportion of patients with long-lasting warts than of subjects without persistent warts were homozygous at the DQA1 (14.1 vs 6.5%) and DQB1 (16.9 vs 8.6%) gene loci. These results suggest that the natural history of cutaneous HPV 2/27/57-induced common warts may be modulated by allele polymorphisms at the HLA-DQA1 and HLA-DQB1 gene loci.     

汉族红斑型天疱疮与HLA-Ⅱ类基因的相关性研究

目的 探讨HLA-DR、DQB1位点基因在红斑型天疱疮（PE）易感性中的作用。方法 用聚合酶链反应-序列特异性引物（PCR-SSP）方法，对37例红斑型天疱疮患者进行了HLA-DR、DQB1等位基因的分型，并分别与57例和53例作了对照。结果 与正常对照组比较，PE患者组DR4（DRB1*0406）、DRB1*14、DQB1*0302、DQB1*0503基因频率比对照组显著增高。结论 HLA-DRB1*14、DQB1*0503可能是汉族PE患者易感的单倍型。     

HLA DQB1*0301 allele is involved in the susceptibility to erythema multiforme

Erythema multiforme (EM) is an acute, episodic inflammatory disorder of the skin and mucous membranes of various etiology that could be related to immunologic hypersensitivity response. EM has been previously reported to be associated with serologically defined HLA-DRw53 and DQw3 antigens. In this report, we reevaluate the role of HLA class II alleles in EM manifestations. With use of the polymerase chain reaction, followed by sequence-specific oligonucleotide hybridization, 35 unrelated Caucasian EM patients and 80 randomly selected healthy subjects were studied, and the DRB3, DRB4, DQA1, and DQB1 alleles were analyzed. The comparison of frequencies of these alleles indicates that (i) susceptibility to EM disease is more associated with the HLA-DQ than the HLA-DR subregions and (ii) that the DQB1*0301 is the most frequent allele among EM patients. Sixty-six percent of the patients had the DQB1*0301 allele compared to 31% of the controls (RR = 4.1; p less than 0.001). An even stronger DQB1*0301 association was found in the patient group with herpes-associated EM (76%; RR = 6.5; p less than 0.001). Our data demonstrate a clear association between an HLA-DQB1 allele and susceptibility to EM.     

Polymorphisms of HLA-DR and -DQ genes in Japanese patients with bullous pemphigoid

Bullous pemphigoid (BP), an autoimmune skin disease of the elderly, is mediated by autoantibodies that bind to hemidesmosomes of epidermal basal cells. This study investigated BP-associated HLA-DR and -DQ genes among Japanese patients. We analyzed HLA-DR and -DQ genes among 23 Japanese BP patients based on the polymerase chain reaction-restriction fragment length polymorphism. Eighteen of these 23 patients (78%) carried at least one allele of HLA-DRB1*04 or DRB1*1101, with significant increases in HLA-DRB1*04 (*0403, *0406)/DQA1*0301/DQB1*0302 and DRB1*1101/DQA1*0505/DQB1*0302 haplotypes as well as the individual alleles DRB1*1101 and DQB1*0302 (corrected p < 0.05 for each comparison), when compared to control subjects. These data differ from the accepted DQB1*0301 (DQ7) association with the same disease among Caucasians. These findings indicate that different HLA class II haplotypes genetically influence susceptibility to BP among different ethnic groups. Our findings, together with previous reports on Caucasian patients with the pemphigoid group of bullous diseases, suggest that HLA-DRB1 molecules might participate in the regulation of autoimmune responses to BP antigens.     

Class II MHC typing in pemphigoid gestationis

Pemphigoid gestationis (PG) is a rare, autoimmune skin disease associated with pregnancy or the immediate postpartum period, previously shown to be associated with the HLA class II antigens DR3 and DR 4. Advances in molecular analytical techniques now allow the identification of HLA alleles previously difficult to define by serological assays. Unsuspected polymorphism within the HLA-DR 3 and DR 4 classes can, therefore, be identified. The aim of our study was to apply these newer techniques to the question of genetic predisposition in PG by re-evaluating the association with DR 3 and by studying a possible link with DQ. We have investigated by restriction fragment length polymorphism, the DQA, and by sequence specified oligonucleotide probing the DQB and DRB 1 (HLA DR) specificities of 41 women with immunofluorescence-confirmed PG. The principal finding of this study is that there is an association between PG and DRB 1*0301 (DR3) and DRB 1*0401/040X (DR4). Although there is also an increase (P= 0.06) in the concurrent presence of both antigens, this appears to be due to the association with either antigen alone. We also found an increase in the frequency of DQA1*2 (P= 0.016 vs. control) and a decrease in frequency of DQB 1*0201 (P= 0.022 vs. controls) and DQB1*0602 (P= 0.026 vs. controls).     

HLA class II alleles in patients with alopecia areata

Our purpose was to determine which HLA class II alleles are associated with Turkish alopecia areata patients. Also we investigated whether there was a relationship between the age of onset and severity of disease and HLA alleles or not. Sixty-five patients with alopecia areata were included in this study, and 50 healthy transplant donors were used as a control group. The total group of alopecia areata patients as well as various subgroups according to scalp hair loss were compared to the control group. HLA DNA typing was performed by polymerase chain reaction/sequence specific primer method. The frequency of DQB1*03 allele was 86.1% in all patients compared to 62.0% in controls (P = 0.005). While the frequency of DQB1*03 was significantly increased, the frequency of DRB1*03 was decreased in the all patients group (4.6% versus 22.0%, P = 0.01). In the group of scalp hair loss less than 25%; the frequency of DRB1*03 was decreased (3.2%, P = 0.02). The group of patients with 25-75% scalp hair loss was compared to control group; the frequencies of DRB1*04 (66.7% versus 28.0%, P = 0.02) was increased. When the alopecia totalis, alopecia universalis or alopecia totalis/alopecia universalis group was compared to control group; DQB1*03 was associated with an increased frequency in this group versus control group (90.9%, P = 0.03). There were no significant differences for the other DQ alleles and the DR alleles tested in the patients and in the controls. When patients with early onset were compared to patients with late onset; no significant allele differences were found. Our findings suggested that DQB1*03 allele is a marker for general susceptibility to alopecia areata and may also serve as special genetic marker for susceptibility for the severe form of alopecia areata in our population. However, this association is not related to age at onset of the disease.     

HLA-DRB1等位基因与四川汉族人寻常型天疱疮的相关性研究

目的 探讨HLA-DRB1等位基因与四川汉族人寻常型天疱疮的相关性.方法 采用聚合酶连反应-序列特异性引物(PCR-SSP)对19例四川汉族寻常型天疱疮患者和25例健康对照组进行低分辨和高分辨HLA-DRB1等位基因分型,计算各等位基因频率.采用x2检验比较两组等位基因频率.结果 在寻常型天疱疮患者和健康对照者中共检出9种低分辨DRB1等位基因和19种高分辨DRB1等位基因.与健康对照组相比,寻常型天疱疮患者DRB1*14等位基因频率(39.47％,15/38)及DRB 1*1405等位基因频率(15.79％,6/38)均显著高于健康对照组[8.00％(4/50),2.00％(1/50)],差异均有统计学意义(x2=17.43、4.25,均P＜0.05).结论 DRB1*14可能是四川汉族寻常型天疱疮患者的常见易感基因,其中DRB1*1405与寻常型天疱疮最具有相关性.