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.     

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.     

Correlation between HLA and pityriasis rosea susceptibility in Brazilian blacks

Objectives The human leucocyte antigen (HLA) has been related to susceptibility factors in several diseases. This study aimed to determine the potential genetic susceptibility of patients with pityriasis rosea (PR) through HLA molecular typing analysis. Methods The method of choice was polymerase chain reaction with sequence‐specific primers (PCR‐SSP) using low‐resolution typing kits, with determination of the alleles class I (HLA‐A, HLA‐B and HLA‐C) and class II (HLA‐DRB1, DRB3, DRB4, DRB5 and DQB1) performed in 30 Afro‐Brazilian PR‐diagnosed patients and 45 healthy individuals as the control group (PR‐C). Results Analysis of the HLA typing results showed that the relative risk (RR) of 4.00 [95% confidence interval (95% CI) 1.20–13.28, two‐tailed P = 0.018] for allele HLA‐DQB1*04 class II, detected in 33.3% of PR patients, was significant. By contrast, in the control group only 11.1% of subjects had that allele. Three out of six B*51 alleles and three out of six B*53 alleles detected in PR patients were found, together with the allele DQB1*04. Conclusion We suggest that alleles DQB1*04 may be involved in the genetic susceptibility of PR based on the significant predominance of those alleles observed in the black PR patients. We also recommend that more studies are conducted on populations of other ethnic origins, preferentially with higher resolution techniques of DNA typing.     

Association of HLA subtype DRB10407 in Colombian patients with actinic prurigo

BACKGROUND: Human leukocyte antigen (HLA) DRB1*0407 had been associated with actinic prurigo in different populations. This class II HLA-DR subtype had not been studied in Colombia. OBJECTIVE: The objective of this study was to establish whether there was an association of actinic prurigo with HLA DR in a Colombian population. MATERIALS AND METHODS: Forty patients with a clinical diagnosis of actinic prurigo and 40 healthy subjects, paired by age, sex and birthplace, were studied. HLA typing for HLA DRB1 and DRB1*04, if necessary, was performed by the PCR-SSP method using blood samples. RESULTS: A high frequency of HLA DRB1*0407 was found in the patients (97.5% vs. 30%; P<0.00001). The allelic frequency of HLA DRB1*0407 was 63.8% in the case group, and 14.5% in the controls (P<0.00001). In the control group, there was a higher frequency of the alleles DRB1*01 (14.5% vs. 1.25%; P=0.0027) and DRB1*13 (23.7% vs. 2.5%; P=0.00013). LIMITATIONS: The small number of controls does not allow us to drive conclusions about other HLA alleles. CONCLUSIONS: HLA subtype DRB1*0407, found in actinic prurigo patients in studies conducted in England, Scotland, Ireland and Mexico, was also associated in Colombian patients. This finding, concordant in patients from different ethnic groups, could be helpful in the diagnosis of this disease and probably important in its pathogenesis. DRB1*01 and DRB1*13 alleles were more frequent in controls than in patients; we do not know whether they play any role in the resistance to the disease.     

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.     

Comparisons of clinical features of HLA‐DRB1*07 positive and negative vitiligo patients in Chinese Han population

Background Human leucocyte antigen (HLA)‐II alleles have been found to be associated with vitiligo in different populations, and several studies also suggested that HLA class II alleles/haplotypes were associated with a different type vitiligo. Of HLA class II alleles, DRB1*07 has consistently shown a positive association with vitiligo in Chinese Han population. Objective To further explore the relationship between DRB1*07 and vitiligo and to evaluate the DRB1*07 effect on the clinical features of vitiligo in Chinese Han population. Methods This study investigated DRB1*07 allele distribution in 1178 unrelated Chinese vitiligo patients and 1743 healthy controls using polymerase chain reaction/sequence specific primer method and observed clinical differences between DRB1*07 positive and DRB1*07 negative patients. Results The analysis of the 1178 cases and 1743 controls revealed a highly association between DRB1*07 allele and vitiligo [odds ratio (OR) = 1.97, P = 2.13 × 10^?17]. DRB1*07 positive patients had early disease onset (OR = 1.49, P = 0.001), higher frequency of family history (OR = 1.44, P = 0.006) compared with DRB1*07 negative patients. Conclusions The DRB1*07 showed significant association with vitiligo in the study population. This study confirmed that DRB1*07 positive patients had some obvious clinical differences from DRB1*07 negative patients in the Chinese Han population.     

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.     

Multiple basal cell carcinomas: no association with HLA-DRB, HLA-DQAI or HLA-DQBI in Swedish patients

Summary Many diseases with autoimmune features are associated with alleles of the human leucocyte antigen (HLA). However, few if any malignant disorders have reproducibly been shown to be HLA-associated. In three independent studies, using serological tissue typing techniques, an increase of the HLA class II specificity DR1 has been found in patients with multiple basal cell carcinomas. These observations prompted us to determine the frequencies of DRB1, DQA1, and DQB1 alleles by high-resolution genomic tissue-typing methods, including subdivision of the serological DR 1 specificity in the four sequence-defined alleles, DRB1*0101 to DRB1*0104, in 50 unrelated Swedish patients with a history of four or more basal cell carcinomas and 250 healthy controls. The frequency of DR1 was the same in patients and controls (18%). All DR1-positive patients and controls carried the DQA1* 0101 and DQBI*0501 alleles. Six of the nine DR1-positive patients were DRB1*0101-positive. one DRB1*0102 and two carried the DRB1*0103 allele. This distribution of DRB1*01 alleles did not differ from the one found in the controls. We conclude that genetic factors associated with the HLA class II region do not contribute significantly to the aetiology of multiple basal cell carcinomas.     

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.     

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.     

Human leukocyte antigens class I and class II in patients with pemphigus in southern Turkey

Background Genetic factors that predispose individuals to pemphigus are considered to play important roles in the development of the disease. Furthermore, population studies of patients with pemphigus have clearly shown that the most prevalent alleles differ across ethnic groups. Objectives This controlled study was designed to detect the distribution of human leukocyte antigen (HLA) class I and II alleles in Turkish patients with pemphigus. Methods Sixty patients diagnosed with pemphigus according to clinical findings, histology, immunofluorescence, and enzyme‐linked immunosorbent assay (ELISA) were enrolled in the study. The control group consisted of 60 healthy adult transplant donors. HLA typing was carried out using a polymerase chain reaction (PCR) with sequence‐specific primers (SSP) method. Results The frequencies of HLAs A*11, CW*01, DRB1*04, DRB1*14, DQB1*05, and DPB1*0401 were found to be statistically significantly higher in the disease group than in controls. By contrast, the frequencies of HLAs B*18, B*50, DRB1*11, DQB1*02, DQB1*06, DPB1*0301, and DPB1*1102 were statistically significantly lower in the pemphigus group than in controls. Linkage dysequilibrium analysis showed that DRB1*14/DQB1*05, A*11/DQB1*05, and A*11/DRB1*14 alleles were detected frequently in pemphigus patients, and DRB1*11/DQB1*05, DRB1*14/DQB1*02, B*50/DQB1*02, and B*50/DPB1*0301 alleles appeared frequently in healthy controls. Conclusions The results suggest that DRB1*04, DRB1*14, DQB1*05, and DPB1*0401 class II HLAs and A*11 and CW*01 class I HLAs are associated with pemphigus in southern Turkey. Observed differences in LD patterns between patients and controls suggest that the coexistence of the respective alleles is strongly determinant of predisposition towards (DRB1*14/DQB1*05 and A*11/DQB1*05) or protection against (B*50/DQB1*02) the disease.     

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.     

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 markers in familial Lichen Sclerosus

Background: Lichen sclerosus (LS) has been identified with increased frequency in families,often associated with HLA markers, mainly DQ7. A genetic co‐etiology seems likely in this setting. Moreover, there is an association of LS with autoimmune disorders, such as the presence of anti‐thyroid peroxidase autoantibodies (anti‐TPO), a hallmark of autoimmune thyroid diseases. Patients and Methods: In 3 families affected by LS, we verified their HLA markers, and identified previously undiagnosed cases of LS and autoimmune disorders. 30 individuals were examined with history, skin biopsy, HLA class I and II typing by PCR‐SSP, and measurement of anti‐TPO, free thyroxine and thyroidstimulating hormones (TSH) levels. Results: There were 8 cases of LS, 50 % of them anti‐TPO+. Autoimmune disorders were found in 40 % (total) and in 87.5 % of those affected. Most common HLA markers were B*15, B*57, CW*03, CW*07, CW*18, DRB1*04, DRB1*07, DRB4*. The three latter have been previously associated with LS. Conclusion: New cases of LS and autoimmune disorders can be detected in first degree relatives of patients with LS. The presence of anti‐TPO antibodies strongly suggests autoimmune thyroiditis. There is intra‐familial association between the haplotype HLA‐B*15 ‐DRB1*04 ‐DRB4* and anti‐TPO,emphasizing their link with thyroiditis. New familial approaches might help to make clear the pathogenesis of LS and its association with autoimmune diseases.     

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.     

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.     

Linkage and association of HLA class II genes with vitiligo in a Dutch population

BACKGROUND: Serological typing of HLA has shown discrepancies in HLA associations with vitiligo in different ethnic populations. OBJECTIVES: To perform genotyping of HLA class II genes on a Dutch vitiligo population in order clearly to identify susceptible and protective HLA alleles in vitiligo. METHODS: HLA typing was carried out by amplifying genomic DNA by polymerase chain reaction (PCR) followed by dot-blot hybridization with sequence-specific oligonucleotides (SSO). Fifty Dutch vitiligo probands, and their parents (150 individuals) and 204 healthy controls were studied. RESULTS: Family-based case-control association studies and linkage disequilibrium analysis showed the linkage and association of DRB4*0101 allele with vitiligo (P(c) = 0.0016, relative risk = 2.21). The family-based association study also provided evidence for linkage and association of DQB1*0303 allele with vitiligo (chi(2) = 7.36, P = 0.006). We measured the clinical relevance of the test by calculating the prevalence corrected positive predictive values (PcPPV). The PcPPV of disease for the DRB4*0101 allele was 0.017 and for the DRB4*0101/0101 genotype was 0.0358. In other words, a DRB4*0101/0101 genotype carries a 3.58% risk of developing vitiligo. CONCLUSIONS: Both DRB4*0101 and DQB1*0303 alleles provide significant susceptibility for vitiligo.     

华东地区汉族HLA-Ⅱ类基因与白癜风临床特征的相关性

目的：探讨华东地区汉族HLA-Ⅱ类基因与白癜风临床特征的相关性。方法：采用聚合酶链反应-序列特异性寡核苷酸探针(PCR-SSOP)方法检测华东地区汉族白癜风患者HLA-DRBl、DQAl和DQBl位点的等位基因，使用SPSS 10．0统计软件分析。结果：HLA-DQAl ^*0103与伴发内分泌疾病的患者有显著正相关，DRB l^*09与C4降低的患者明显负相关。按临床类型分析，发现局限型与DRBI*09和DQAl*03正相关，非节段型与DQAl*03正相关。结论：在华东地区汉族人群中，白癜风的临床特征与HIA-Ⅱ类基因有一定的相关性。     

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.     

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.