有无家族史白癜风与HLA—I类抗原的关联性研究

目的 探讨HLSA－I类抗原与中国北方汉族人群中有及无家族遗传史白癜风的相关性。方法 家庭史阳性及阴性白癜风患者各20例，采用HLA血清学分型技术检测HLA－A、B位点的抗原特异性。结果 与100例正常对照比较，有明确家族史的白癜风患者HLA－A10、B13、B15抗原频率显著增设，而无家族史的患者HLA－A30＋31、B15显著增高（Pc均＜0．01），非节段HLA－A10、A30＋31、B1、B13、B15显著增高（Pc均＜0．01），成年及未成年发病型HLA－B13、B15显著增高，儿童发病型则仅HLA－B13显著增高（Pc均＜0．01）。结论 该结果为进一步揭示白癜风的易感基因及免疫遗传发病机制提供了线索。     

Difference in clinical features and HLA antigens between familial and non-familial vitiligo of non-segmental type

Of 131 patients with non-segmental vitiligo studied, 29 (22%) had a family history of this disorder. The clinical features and HLA antigens were assessed, and a comparison made between patients with familial and those with non-familial, non-segmental vitiligo. Familial patients developed skin lesions significantly earlier than non-familial patients. There was a significant association between HLA-B46 and familial non-segmental vitiligo, whereas HLA-A31 and CW4 were found in non-familial patients. The differences in clinical features and HLA phenotypes suggest heterogeneity in the pathogenic process between familial and non-familial vitiligo patients.     

Familial alopecia areata--genetic susceptibility or coincidence?

Three generations of a not consanguineous Italian family and 40 subjects suffering from alopecia areata (AA) and residing in Northern Italy were studied. There were 321 healthy control subjects of both sexes. Six family members from three generations were affected with alopecia universalis. The subjects were HLA-phenotyped using different HLA-A, B and C antigen specificities. No significant association was found between HLA-A, B and C antigens and AA patients at the population level. Segregation analysis showed that affected members shared a common haplotype, HLA-Aw32, B18,-.     

The major histocompatibility complex in psoriasis vulgaris. III. HLA-C antigens.

HLA-C typing was performed on 40 unrelated Japanese patients with psoriasis vulgaris. The patient group consisted of 22 patients who had psoriatic HLA antigens i.e., B13 in seven cases, B17 in one case and B37 in 14 cases; and 18 patients who had none of these specific HLA antigens. HLA-C typing was also performed on 40 unrelated healthy Japanese controls. Cw6 was found in 55.0% of the patients as compared with 5.0% of the healthy controls. All patients (21 cases) who had either B13 or B37 were positive for Cw6. Both controls who were positive for Cw6 also had B37. These results suggest the possibility of a linkage disequilibrium between Cw6 from locus C and B13 and B37 from locus B, and/or an association between Cw6 and susceptibility to psoriasis.     

A susceptibility locus for epidermodysplasia verruciformis, an abnormal predisposition to infection with the oncogenic human papillomavirus type 5, maps to chromosome 17qter in a region containing a psoriasis locus

Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by an abnormal susceptibility to infection with a specific group of related human papillomavirus (HPV) genotypes, including the oncogenic HPV5 associated with the skin carcinomas developing in about half of EV patients. EV is usually considered as an autosomal recessive condition. Taking EV as a model to identify a locus underlying the susceptibility to HPV infections, we performed a genome-wide search for linkage with 255 microsatellite genetic markers in three consanguineous EV families comprising six patients, using the homozygosity mapping approach. Homozygosity restricted to affected individuals was observed for a marker of chromosome 17q (D17S784) in two families and a marker about 17 centiMorgan (cM) distal (D17S1807) in the third family. Ten additional microsatellite markers spanning 29 cM in this region were analyzed. Two-point lod score values greater than 3 were obtained for four markers and multipoint linkage analysis yielded a maximum lod score of 10.17 between markers D17S939 and D17S802. Recombination events observed in two families allowed a candidate region for the EV susceptibility locus to be mapped to the 1 cM region defined by these two markers. The EV locus (named EV1) is included in the 17qter region recently found to contain a dominant locus for the susceptibility to familial psoriasis. It has been shown that patients suffering from psoriasis are likely to constitute the reservoir of HPV5. It is thus tempting to speculate that distinct defects affecting the same gene may be involved in the two skin conditions.     

Study of HLA class I,class II and complement genes (C2, C4A,C4B and BF) in Japanese psoriatics and analysis of a newly-found high-risk haplotype by pulsed field gel electrophoresis

Summary Genetic polymorphisms of HLA antigens and HLA-linked serum complement components (C2, C4A, C4B and BF) were investigated in 79 Japanese patients suffering from psoriasis. HLA typing revealed increased frequencies of HLA-A1, A2, B39, Bw46, Cw6, Cw7 and Cw11. Among complement components, positive associations were obtained with C4A4 and C4B2 and a negative association with BFF. The major histocompatibility complex haplotype (supratype), HLA-A2-Cw11-Bw46-C2C-BFS-C4A4-C4B2-DRw8 is purported to be a new high-risk haplotype in Japanese patients with psoriasis. Analysis of patients with this supratype via pulsed field gel electrophoresis showed the existence of specific, extensive DNA deletions near HLA-DR genes, but no disease-specific patterns could be observed by means of this technique. The newly-found high-risk haplotype indicates racial and ethnic differences among psoriatic patients.     

HLA Antigens and Linkage Disequilibrium Patterns in Turkish Behçet's Patients

Behçet's disease (BD) is a multisystem disorder featuring mucocutaneous, ocular, articular, vascular, intestinal, pulmonary, and neurologic involvement. Although the pathogenesis of the disease is still unknown, most studies have proposed that immunologic factors may play a major role in its development in genetically predisposed individuals. Seventy-one Turkish patients with BD, diagnosed according to the International Study Group for Behçet's Disease criteria, were studied and compared with 600 healthy controls to determine not only frequencies of HLA-A, B, and DR antigens but also whether BD shows any distinct linkage disequilibrium (LD) patterns. In addition, three-point linkage disequilibrium and relative risk (RR) values were determined. Of the HLA-A, B, and DR antigens examined, only B5 (51) was significantly increased in the patient group (X²=55.4; p<0.05; RR=6.44). DR7 was significantly decreased in the patient group (X²=6.9; p>0.05; RR=0.31). HLA haplotype B5-DR5 was found to be in negative LD in the control group, but Behçet's patients showed a strong positive LD between these two antigens. HLA haplotypes A2-B12, B5-DR2, and B12-DR4 showed negative LD in the patients; A1-B5 and B5-DR5 had positive LD in the patients. HLA haplotype A2-B5-DR5 was found to be more frequent than expected in both patients and control gorups. A2-B12-DR4 showed a negative LD in the patients. The strong LD patterns between HLA-B and DR antigens in BD suggest that the susceptibility gene to BD could reside between the these two antigens.     

Polyclonal antibody to human papillomavirus-related antigens specific to epidermodysplasia verruciformis

We have developed a polyclonal antibody for human papillomavirus (HPV)-related antigens specific to epidermodysplasia verruciformis (EV). Using this antibody, immunohistochemical studies on 12 EV patients were performed. The polyclonal antibody was obtained from rabbits immunized with roughly purified virions of HPV from an EV patient. Sections from 12 EV patients were treated with the polyclonal antibody and then the peroxidase-antiperoxidase method was used to observe the reaction. The observations revealed not only papillomavirus genus-specific common structural antigen (pgs-antigen) but also HPV-related antigens specific to EV. Pgs-antigen was observed in the nuclei of the upper keratinized cells of the benign lesions and HPV-related antigens specific to EV were observed in the nuclei and cytoplasm of both keratinizing cells of the benign lesions and malignant skin tumor cells. HPV-related antigens specific to EV were observed in sections of all 12 EV patients infected by HPV-5, 5-related, 14, 20, 21 and 38, but not in sections of other HPV infections. Using the immunoblot technique, we detected the main papillomavirus structural polypeptide (MW, 58 Kd) and two other unknown proteins (MW, 42 Kd and 33 Kd) in the benign lesion of an EV patient. Two proteins (MW, 42 Kd and 33 Kd) were also detected in the malignant tumor of the EV patients we consider these proteins to be HPV-related antigens specific to EV.     

Fixed drug eruption induced by trimethoprim-sulfamethoxazole: evidence for a link to HLA-A30 B13 Cw6 haplotype

BACKGROUND: Recent reports indicated a significant association between fixed drug eruption (FDE) and HLA class I antigens. A strong correlation was found between B22 antigen and feprazone-induced FDE. OBJECTIVE: Our aim was to investigate the association between HLA class I antigens and FDE in Turkey, a country where feprazone is not on the market and trimethoprim-sulfamethoxazole is most often the offending drug. METHODS: HLA class I typing was performed by lymphocytotoxicity assay in 67 unrelated patients with FDE, all established by oral provocation. The frequencies are compared with those of 2378 control subjects. RESULTS: Significantly higher (P <.001) frequencies of the A30 antigen and A30 B13 Cw6 haplotype were found in 42 patients with FDE induced by trimethoprim-sulfamethoxazole. HLA-B55 (split of B22) was present exclusively in trimethoprim-sulfamethoxazole-induced FDE, and in higher frequency than in control subjects. CONCLUSION: To our knowledge, ours is the first report indicating a link between A30 B13 Cw6 haplotype and trimethoprim-sulfamethoxazole-induced FDE. In addition, HLA-B22 was increased in patients with FDE caused by a drug other than feprazone.     

Systematic linkage disequilibrium analysis of SLC12A8 at PSORS5 confirms a role in susceptibility to psoriasis vulgaris

The gene for solute carrier family 12 member A8 has recently been proposed as a candidate gene for psoriasis susceptibility (PSORS5) on chromosome 3q based on association of five single nucleotide polymorphisms (SNP) in Swedish patients. To investigate whether this locus is relevant for German psoriasis vulgaris (PsV) patients, we analyzed a group of 210 trios and a case-control group including 375 patients. Based on our investigation of the linkage disequilibrium (LD) structure of SLC12A8, we assayed 35 haplotype tag SNP and grouped them into nine LD-blocks. In the case-control study, we detected an association for six SNP and three LD-based haplotypes. Association was strongest for ss35527511 (chi2 = 11.224, p = 0.0008) and haplotype E-2 (chi2 = 11.788, p = 0.00059) and independent of the presence of an HLA-associated PSORS1 risk allele. Through extended haplotype analysis, we could show that two independent association signals exist in SLC12A8, suggesting allelic heterogeneity. None of the SNP showed association in trios, apart from a weak association of rs2228674 (transmission disequilibrium test statistics p = 0.048), probably due to insufficient power. We conclude that SLC12A8 is a susceptibility locus for PsV. In order to establish the exact nature of this association, efforts to identify the disease-causing variants are ongoing.     

Evidence for a nonallelic heterogeneity of epidermodysplasia verruciformis with two susceptibility loci mapped to chromosome regions 2p21-p24 and 17q25

Epidermodysplasia verruciformis is a rare genodermatosis associated with a high risk of skin cancer. This condition is characterized by an abnormal susceptibility to specific related human papillomavirus genotypes, including the oncogenic HPV5. Epidermodysplasia verruciformis is usually considered as an autosomal recessive disease. We recently mapped a susceptibility locus for epidermodysplasia verruciformis (EV1) to chromosome 17qter within the 1 cM interval between markers D17S939 and D17S802. We report here the genotyping for 10 microsatellite markers spanning 29 cM around EV1 in two consanguineous epidermodysplasia verruciformis families from Colombia (C2) and France (F1) comprising five patients and two patients, respectively. Using homozygosity mapping, linkage with 17qter markers was observed for family C2 only. Multipoint linkage analysis yielded maximum multipoint LOD-score values above 10 between markers D17S1839 and D17S802 encompassing the EV1 locus. A genome-wide search performed in family F1 yielded evidence for linkage between epidermodysplasia verruciformis and the chromosomal 2p marker D2S365. Nine additional microsatellite markers spanning 15 cM in this region were analyzed. Assuming an autosomal recessive inheritance with a complete penetrance, the expected maximum two-point LOD-score value of 1.8 was obtained for three markers and multipoint linkage analysis yielded a maximum LOD-score value of 3. 51 between markers D2S2144 and D2S392. Haplotype analysis allowed to map a candidate region for a second epidermodysplasia verruciformis susceptibility locus (EV2) within the 8 cM interval between markers D2S171 and D2S2347 of the 2p21-p24 region. In contrast, linkage with 2p markers was excluded for family C2 and for the three families in which we mapped EV1 previously. The disclosure of two susceptibility loci for epidermodysplasia verruciformis provides evidence for a nonallelic heterogeneity in this disease.     

Psoriasis susceptibility locus on 18p revealed by genome scan in Finnish families not associated with PSORS1

The major susceptibility locus for psoriasis, PSORS1, resides on chromosome 6p and includes the candidate genes HLA-C, HCR, and CDSN. Based on a nationwide collection of psoriasis patients and genotyping for the PSORS1 susceptibility haplotype, we selected for a genome scan nine families who do not show association with PSORS1 to more easily detect minor loci for psoriasis susceptibility. In the genome scan, five loci gave initial evidence of linkage and were studied with a denser marker map. After fine mapping, only one locus on 18p11.23 showed suggestive evidence of linkage (nonparametric multipoint linkage analysis score, 3.58; p = 0.0038). The bootstrapping analysis showed that one large family contributed the majority of the linkage (p = 0.0039), but was supported by other families. Haplotype sharing between the linked families and haplotype association analysis gave additional support for the locus. Further, the 18p locus has shown nominal evidence of linkage with psoriasis in the British population. Taken together, these findings confirm the presence of a minor susceptibility locus for psoriasis on 18p11.     

T cell defect in patients with epidermodysplasia verruciformis due to human papillomavirus type 3 and 5

Most of the patients with epidermodysplasia verruciformis (EV) were anergic to sensitization to dinitrochlorobenzene (DNCB) and were shown to have a decreased number of T lymphocytes and reduced lymphocyte PHA responsiveness. Preserved cell-mediated immunity (CMI) was found only in the abortive cases of EV infected with human papillomavirus type 3 (HPV-3). CMI was impaired to the same extent in patients with EV induced by HPV-3 and HPV-5, and in EV cases with combined infection with both viruses. In contrast to this, malignant transformation, i.e. of Bowen's carcinoma type, was observed only in the 7 patients infected with HPV-5. This could indicate that malignancy in EV is related rather to the oncogenic potential of HPV-5 type than to the extent of T cell defect that was similar in both EV varieties due to HPV-3 and HPV-5.     

An HLA class II region restriction fragment length polymorphism (RFLP) in patients with dermatitis herpetiformis: association with HLA-DP phenotype

Dermatitis herpetiformis (DH) is characterized in part by an associated gluten-sensitive enteropathy (GSE), and a strong association with the HLA antigens HLA-A1, -B8, -DR3, and -DQw2, essentially identical to that seen in patients with isolated GSE (celiac disease). A 4.0-kb RsaI RFLP has been identified using a DQ beta-chain cDNA and localized to the HLA-DP beta-chain region. This RFLP has been found more frequently in patients with isolated GSE than in normal HLA matched controls. We have analyzed genomic DNA from 24 patients with DH and 15 HLA-matched controls to determine if this 4.0-kb RsaI RFLP was present in patients with DH. Twenty-one of 24 (87%) of patients with DH were found to have this RFLP as compared to 7 of 10 (70%) HLA-DR3, -DQw2 matched control subjects (p = 0.23). Thus, the 4.0-kb RsaI RFLP detected in patients with isolated GSE is also present in patients with DH; however, its frequency in DH patients does not differ significantly from that of HLA matched controls. Family studies of patients with DH revealed that although the 4.0-kb RsaI RFLP segregated with the HLA-A1, -B8, -DR3, -DQw2 haplotype in one family, it did not segregate with this disease-associated haplotype in two other families. In both patient and control populations, this RFLP was associated with HLA-DPw1 or -DPw3 phenotypes; 25 of 26 (96%) HLA-DPw1 or -DPw3 subjects were found to have this RFLP compared to only 1 of 6 (17%) who did not express HLA-DPw1 or -DPw3 (pc = 0.0009). These population and family data suggest that this 4.0-kb RsaI RFLP is primarily associated with the HLA-DPw1, -DPw3 phenotype, rather than the clinical manifestations of DH. These data further document that the strongest association of DH with HLA antigens remains with HLA-DQw2 and HLA-DR3 antigens.     

Polymorphisms in interleukin-15 gene on chromosome 4q31.2 are associated with psoriasis vulgaris in Chinese population

Through a series of linkage analyses in a large Chinese family cohort of psoriasis, we previously identified and confirmed a non-HLA psoriasis linkage locus PSORS9 within a small region at 4q31.2-32.1. Within the critical region of the PSORS9 locus, IL-15 has been long recognized as a strong candidate gene for psoriasis. In this study, we investigated the association between IL-15 genetic polymorphisms and psoriasis in a large Chinese sample. Highly significant evidence for association was identified at a single-nucleotide polymorphism (SNP) (g.96516A --> T) within the 3'-untranslated region (UTR) of the IL-15 gene (P=0.00006, after correction for multiple testing). Haplotype analysis using the SNPs within the 3'UTR region also provided strong supporting evidence for association (P=0.00005), where we identified a haplotype of the 3'UTR region of IL-15 associated with increased risk to psoriasis (odds ratio=1.65). This association was also supported by the results of our expression activity analyses, where we demonstrated that the identified risk haplotype is associated with an increased activity of IL-15. Therefore, we provided early evidence for the important role of IL-15 genetic variants in the pathogenesis of psoriasis, probably by increasing interleukin production and inflammation in the lesions of psoriasis.     

Analysis of HLA antigens in Croatian patients with psoriasis

In common with most autoimmune diseases, psoriasis is associated with some HLA antigens. We studied the distribution of HLA antigens in Croatian patients with psoriasis: 108 patients were divided into groups according to family history and age of disease onset. HLA antigens were analyzed serologically and HLA-C alleles were analyzed using polymerase chain reaction. We found significant increases in HLA-A2, -B17, -B37 and -B13 antigens and highly significant increases in HLA-Cw*0602 and DR7 antigens in psoriatic patients compared with controls. Patients with type I psoriasis (early onset, positive family history) showed highly significant associations with Cw*0602 [p < 0.00001; relative risk (RR) = 14.45] and DR7 (p < 0.00001; RR = 15.09) antigens. Patients with type II psoriasis (late onset, no family history) had a significant association with Cw*03 antigen (p = 0.008; RR = 0.17). In conclusion, HLA-B13, -B17, Cw*0602 and -DR7 antigens are associated with a significant risk of psoriasis in the Croatian population and the Cw*0602 allele has the strongest association, especially for type I psoriasis.     

Polymorphisms of the IL12B and IL23R genes are associated with psoriasis

Psoriasis is a common inflammatory and hyperproliferative skin disease with a multifactorial genetic basis. A recent study reported that psoriasis was associated with the IL12B haplotype rs3212227 (3'-untranslated region)-rs6887695 (60 kb, 5') and the IL23R haplotype rs7530511 (L310P)-rs11209026 (Q381R). We examined these four single-nucleotide polymorphisms (SNPs) for association with psoriasis in two groups of North American and German Caucasians: (1) 1,810 cases and 2,522 controls; and (2) 509 pedigrees. Both IL12B markers showed highly significant association with psoriasis in the case-control (rs3212227, odds ratio (OR)=1.62, P=1.7 x 10(-15); rs6887695, OR=1.49, P=2.7 x 10(-15)) and in the family-based analysis (rs3212227, P=2.2 x 10(-3); rs6887695, P=1.7 x 10(-3)). The IL23R SNPs also showed significant association in the cases and controls (rs7530511, OR=1.22, P=3.9 x 10(-3); rs11209026, OR=1.40, P=3.8 x 10(-4)). For both genes, common risk haplotypes were identified whose statistical significance approached (IL23R) or exceeded (IL12B) genome-wide criteria. We found no statistical evidence for interactions of these haplotypes with HLA-Cw6. Our results confirm associations between IL12B and IL23R and psoriasis in Caucasians, and provide a genetic basis for the clinical association between psoriasis and Crohn's disease.     

Epidermodysplasia verruciformis-like eruption complicating human immunodeficiency virus infection

Three human immunodeficiency virus (HIV)-infected patients presented with disseminated pityriasis versicolor-like skin lesions. Histological examination showed features characteristic of epidermodysplasia verruciformis (EV). Hybridization studies demonstrated the presence of human papillomavirus (HPV) type 5 (HPV5) DNA in two patients and HPV20 in one. A relative increase in CD8 +, CD57 + cells, which are known to inhibit cell-mediated cytolysis, was observed in all patients. HLA-DQB 0301 haplotype, which has been associated with EV, was detected in two patients. The findings suggest that infection with EV-associated HPV types can complicate HIV infection. Both cellular immune defects and a hitherto unknown genetic background might explain the occurrence of EV in HIV-infected patients.     

Psoriasis and arthritic lesions in relation to the inheritance of HLA genotypes: a family study.

This family consists of forty-eight subjects, all of whom have been examined with regard to the presence of psoriasis and nearly all for the presence of arthritic lesions (sacroiliitis and peripheral arthritis). All the members have been tissue-typed not only for HLA-A, B and C locus products but also for D locus products. This has enabled us to study the entire HLA chromosomal region. In the family concerned we have found that those subjects haploidentical with the proband have, to a very large degree, either one or all clinical manifestations, which demonstrates a close genetic relationship between joint (especially sacroiliitis) and cutaneous manifestations. These findings prompt us to repeat our previously made proposal about different phenotypic expressions of the same genotype. In this family study the disease-associated haplotypes did not contain the genes for B13, 17 or 37 antigens which are known to occur frequently in psoriatic patients. However, not all psoriasis patients have these antigens. Despite that, we believe that the gene(s) which increase the likelihood of developing psoriasis are identical in all patients and therefore family studies where the proband does not carry the particular psoriasis associated B-alleles are equally illuminating as to the inheritance pattern of disease.     

Single-point haplotype scores telomeric to human leukocyte antigen-C give a high susceptibility major histocompatibility complex haplotype for psoriasis in a Caucasian population

Psoriasis is a chronic inflammatory skin disease that affects 0.1%-5% depending on the population. PSORS1 is the major susceptibility locus, accounting for approximately 33%-50% of the genetic component of psoriasis among Caucasians. PSORS1 is located within the major histocompatability complex (MHC) locus on 6p21.3. Its position has been refined to hundreds of kilobase and the region located at approximately 100-200 kb telomeric to human leukocyte antigen (HLA)-C is a very strong candidate. To determine the MHC psoriasis risk haplotype, we screened the whole 46 kb interval for single-nucleotide polymorphisms (SNP) and identified 138 SNP. We genotyped 29 SNP throughout this region in psoriatic nuclear families. We calculated the frequency of haplotypes generated by the 29 SNP using all genotyped founder individuals and found four common haplotype with frequency >0.10. We then used SNPtagger to derive the best six SNP and fed these into Transmit using 148 nuclear families. We found that CTGGAC haplotype is a single-point score haplotypes telomeric to HLA-C and gives a 1 df, chi2 of 50.27 (p<0.0001). Most importantly the six selected SNP accurately tagged the most common haplotype found in this region. Moreover, using the same program (Transmit) we show that the association with CTGGAC is higher than the one with HLA-Cw6 (chi2=10.53; p=0.0051). Our results give scores as high as the highest single-point scores suggesting that it is unlikely to be able to discriminate the origin of the association on this analysis on strength of association.