HLA-DRB1*04 and DRB1*14 alleles are associated with susceptibility to pemphigus among Japanese

It has previously been demonstrated that susceptibility to pemphigus vulgaris is associated with human leukocyte antigen (HLA)-DR4 serologic specificity among Ashkenase Jews, and with DR4 as well as DR6 (DR14) in other ethnic groups. We genotyped HLA-DRB1, DQA1, DQB1, and DPB1 alleles in 16 patients with pemphigus by polymerase chain reaction-restriction fragment length polymorphism, to find evidence of potential HLA class II allele associations with pemphigus in Japanese patients who have a relatively homogeneous ethnic background. All nine patients with pemphigus vulgaris and five of seven patients with pemphigus foliaceus carried one or two alleles of HLA-DRB1*04 (*0403, *0406) and HLA-DRB1*14 (*1401, *1405, *1406) subtypes. Sequence analysis of these DRB1*04 and DRB1*14 alleles revealed the amino acid homology of phenylalanine at position 26 and valine at position 86 with the DRB1*0402 allele that reportedly confers a strong susceptibility to pemphigus vulgaris in Ashkenazi Jews. Thus our findings, together with previous HLA studies on pemphigus vulgaris patients of different ethnic groups, suggest that HLA-DRB1*04 and DRB1*14 alleles are commonly associated with pemphigus vulgaris across racial barriers. These HLA-DRB1 alleles are likely to be also associated with pemphigus foliaceus. Further studies on more diverse ethnic populations will be helpful in determining the significance of the association between certain amino acid residues of the class II molecules and disease susceptibility to pemphigus vulgaris as well as pemphigus foliaceus.     

DRB1*15 and DRB1*03 extended haplotype interaction in primary Sj?gren's syndrome genetic susceptibility

OBJECTIVE: Sj?gren's syndrome (SS) is a chronic autoimmune disease with a genetic component. Among the genetic factors, the role of HLA class II genes has been suggested and a positive association with DRB1*03 allele has been described. However, there is no consensus on a unique HLA locus for this disease nor on the role of the HLA gene product in the disease. The aim of this study was to analyse prospectively MHC region involvement in the genetic susceptibility to SS by studying DRB1, DQB1, DPB1, TAP1, TAP2 genes and TNF microsatellites in a population of 45 primary SS patients. METHODS: All the polymorphisms studied were analysed at the genomic level using PCR-based methodologies. RESULTS: Concerning HLA class II alleles, the highest relative risk to develop the disease was associated with the DRB1*15-DRB1*0301 heterozygous genotype (17.8% vs 3.5% in controls - pc < 0.005, OR = 5.96). Analysing other genes located on the same region allowed us to further determine the DRB1 haplotypes at risk. For instance, the DRB1*0301 haplotype involved in the genetic susceptibility to SS was more often associated with the DPB1* 0201 and TNF-a2 alleles in SS patients than in controls. Moreover, all the DRB1*15-DRB1*0301 SS patients were TAP1-0101, TAP2-0101 homozygous, allowing us to deduce the extended genotype at risk as DRB1*15, TAP1-0101, TAP2-0101/DRB1*0301, TAP1-0101, TAP2-0101 which was carried by only 3 controls out of the 130 tested (p < 0.01, OR = 6.68). CONCLUSION: This study confirmed the role of the MHC region in the susceptibility to Sj?gren's disease, and for the first time suggests a synergistic interaction between two HLA-DRB1 extended haplotypes in the genetic mechanisms controlling the disease.     

HLA class II associations in juvenile Graves' disease: indication of a strong protective role of the DRB1*0701,DQA1*0201 haplotype

Previous studies have shown that HLA-DRB1*0301 and DQA1*0501 are associated with susceptibility to Graves' disease. Ninety Danish patients with early onset of Graves' disease and 102-192 controls were analyzed for HLA-DR and -DQ to investigate if the same associations exist in the juvenile form of Graves' disease. Both DRB1*0301 and DQA1*0501 were highly significantly increased in the patients with relative risks of 8.0 and 4.6, which are higher than those seen in adults. Stratification showed that DRB1*0301 is more strongly associated than DQA1*0501. Surprisingly, the DRB1*0701,DQA1*0201 haplotype was completely absent from this group of patients, indicating a strong protective role of this haplotype in juvenile Graves' disease.     

Frequency of loci of HLA-DRB1* and -DQB1* alleles in the Slovak population]

Results on HLA-DRB1* and HLA-DQB1* allele frequencies in the Slovak population by PCR-SSP method are presented. HLA-DRB1* alleles were determined in 130 and HLA-DQB1* alleles in 143 healthy unrelated individuals. The highest frequency was observed for the alleles HLA-DRB1*1101-13 (0.203), HLA-DRB1*0701 (0.142), HLA-DQB1*0301 (0.244), and HLA-DQB1*0201 (0.209). The least frequent alleles were HLA-DRB1*1402-6-9, HLA-DRB1*0901 (both 0.0038), HLA-DQB1*0401 (0.007), and HLA-DQB1*0601 (0.0035). The results obtained by DNA-typing were compared with those calculated from the serological study. No statistically significant differencies were found. The allele frequencies obtained in our study were also compared with those of the Czech and Austrian populations. No statistically significant differencies were observed. (Fig. 2, Tab. 3, Ref. 13.)     

Analysis of HLA-DRB1-related alleles in Japanese patients with lung cancer--relationship to genetic susceptibility and resistance to lung cancer

PURPOSE: To investigate differences in HLA status among lung cancer patients, patients with hematological malignancies, and healthy controls in order to determine the genetic susceptibility and resistance features of HLA-DRB1-related alleles in Japanese patients with lung cancer. METHODS: HLA class I (HLA-A, -B, and -C) antigens and HLA class II (HLA-DRB1) alleles were determined in 36 patients with lung cancer, 35 patients with hematological malignancies, and 90 healthy controls. HLA class I status was investigated by serological techniques, and HLA class II by polymerase chain reaction/restriction-fragment-length polymorphism analysis. RESULTS: Lung cancer patients showed an increased frequency of HLA-DRB1*0901, and a decreased frequency of HLA-DRB1*1302 and DRB1*14-related alleles when compared to the other subjects. CONCLUSION: These results suggest that genetic factors influence the susceptibility and resistance to lung cancer. However, this study should be considered preliminary because of the relatively small number of patients examined and the possibility of racial differences in HLA status of lung cancer patients between Japan and other countries.     

Familial juvenile onset psoriasis is associated with the human leukocyte antigen (HLA) class I side of the extended haplotype Cw6-B57-DRB1*0701-DQA1*0201-DQB1*0303: a population- and family-based study

To further evaluate the nature of the HLA association with psoriasis, HLA haplotypes of 60 patients with type 1 (early onset, positive family history) and 30 patients with type II (late onset, no family history) psoriasis were investigated by polymerase chain reaction sequence-specific oligonucleotide hybridization (HLA class II) and serology (HLA class I). Ethnically matched blood donors (146) served as controls. In type I, but not type II psoriasis, the Caucasian HLA extended haplotype (EH) Cw6-B57-DRB1*0701-DQA1*0201-DQB1*0303 named according to the B allele EH-57.1 was highly significantly overrepresented (p cor= 0.00021). This particular EH was present in 35% of type I psoriatics but only 2% of controls. EH-57.1+ individuals therefore carry a 26 times higher risk of developing type I psoriasis than individuals who are EH-57.1-negative Further analysis of individual HLA alleles revealed that within EH-57.1, HLA class I antigens (Cw6-B57) were associated to a much higher extent with type I psoriasis than the HLA class II alleles (DRB1*0701-DQA1*0201-DQB1* 0303). Pedigree analysis of three multiply affected families over three generations revealed a cosegregation of disease with EH-57.1. These results strongly suggest that a gene for familial psoriasis is associated with the class I side of the extended haplotype Cw6-B57-DRB1*0701-DQA1*0201-DQB1*0303.     

Combined effect of HLA-DRB1*1501 and interleukin-1 receptor antagonist gene allele 2 in susceptibility to relapsing/remitting multiple sclerosis

Susceptibility to multiple sclerosis (MS) is associated with HLA-DRB1*1501. Many reports have suggested associations with other loci but these results remain unconfirmed. We studied the IL-1 receptor antagonist (IL-1ra) gene polymorphism and the HLA-DR and DQ allele frequencies by DNA-based methods in both the primary chronic progressive form (PP MS) and the relapsing/remitting form (R/R MS). The frequency of DRB1*1501 and IL-1ra allele 2 were significantly higher in R/R MS. Association was more marked in the female sex and in patients with benign forms of R/R MS. On the other hand DR4 subtypes carrying a Val at position 86 in the DR beta chain were increased in PP MS. The present study indicates that MS is genetically heterogeneous and shows a combined effect of HLA-DR and IL-1ra genes in susceptibility to the R/R form of the disease.     

HLA class I and II alleles and susceptibility to generalized pustular psoriasis: significant associations with HLA-Cw1 and HLA-DQB1*0303

HLA alleles in generalized pustular psoriasis (GPP) were investigated to clarify the etiology and/or pathogenesis of this disease. Not only serological typing of HLA class I and II antigens but also genotyping of HLA class II alleles were carried out in twenty-six unrelated Japanese patients with GPP. These patients were classified according to their history of psoriasis vulgaris (PV). Serological typing revealed a significantly high incidence of HLA-Cw1 (Pc = 0.04) in the patients as compared with Japanese healthy controls. The frequency of HLA-B46 was particularly high in the patients with GPP and a previous history of PV. Genotyping of HLA class II alleles showed a highly significant increase in HLA-DQB1*0303 (Pc = 0.01) in the patients vs. the healthy controls. In particular, HLA-DQB1*0303 was significantly more frequent in the patients with no prior history of PV than in those with a history of PV. Analysis on linkage disequilibrium showed remarkably different patterns for HLA class II haplotypes between the patients and the healthy controls. Based on the comparative analysis among the amino acid sequences of the beta 1-domain of the HLA-DQB1*03 alleles, proline at residue 55 was suggested to be important as a common amino acid for determination of the susceptibility to GPP. These results revealed not only an association between the etiology and/or pathogenesis of GPP and HLA, but also different mechanisms of the immune response between the patients with GPP and PV.     

Identification of the DRB1*1313 allele in a sibling pair

Amines such as dopamine, norepinephrine and epinephrine were analysed in the brain regions of O.mossambicus exposed to quinalphos, phenthoate and their combination for 96 hr. The three types of treatments significantly (P < 0.05) altered the amines level at various intervals in the brain regions.     

Polymorphisms of the CYP1A1 and glutathione S-transferase genes associated with susceptibility to lung cancer in relation to cigarette dose in a Japanese population

An association of lung cancer susceptibility with an MspI restriction site polymorphism of the CYP1A1 gene was reported in our previous study. This polymorphism has been subsequently found to be closely linked to another isoleucine-valine (Ile-Val) polymorphism, which resulted in an Ile-Val amino acid replacement in the heme-binding region of P4501A1. We report here that genetic risk for squamous cell carcinoma of the lung was associated with these two polymorphisms of the CYP1A1 gene in terms of genotype frequencies and cigarette-smoking dose and that a more increased risk was observed for the individuals with "susceptible" genotypes of CYP1A1 combined with a deficient genotype of a mu-class glutathione S-transferase (GST1), which detoxifies the electrophilic metabolites of aromatic hydrocarbon procarcinogens activated by P4501A1. We first compared the total amounts of cigarettes consumed during a lifetime among 85 patients with squamous cell carcinoma of the lung, whose CYP1A1 and GST1 genes were identified. The patients with a susceptible homozygote of each of the MspI and Ile-Val polymorphisms contracted the carcinoma after smoking fewer cigarettes than those with other genotypes. When the GST1 polymorphism was taken into account, the cumulative cigarette amounts in combined genotyping of the two genes showed distinct differences, resulting in the lowest cigarette dose observed for the patients with a susceptible MspI or Ile-Val genotype of CYP1A1 combined with a deficient GST1 homozygote. Next, a case-control study revealed that the individuals with the susceptible MspI or Ile-Val genotype combined with deficient GST1 were at remarkably high risk with an odds ratio of 16.00 or 41.00, respectively (95% confidence interval, 3.76-68.02 or 8.68-193.61, respectively), at a low dose level of cigarette smoking.     

Both psoriasis and benign migratory glossitis are associated with HLA-Cw6

This study was undertaken to investigate human leucocyte antigen (HLA) associations with benign migratory glossitis and psoriasis in Brazilian patients and particularly to determine whether benign migratory glossitis is also associated with HLA-Cw6, the classical association observed in psoriasis. The results showed a highly significant association of Cw6 with both psoriasis and benign migratory glossitis, with this antigen being present in 59.1% of the patients with psoriasis, in 43.8% of the patients with benign migratory glossitis, and in only 12.6% of the controls. Other significant positive associations, although at a lower significance level, were with B13, both in psoriasis and in benign migratory glossitis, and with B17, only in psoriasis. To our knowledge, this is the first report on the association of Cw6 with benign migratory glossitis. We believe that this finding reinforces the concept of a pathogenetic relationship between benign migratory glossitis and psoriasis.     

Association to HLA-DRB1*08, HLA-DPB1*0301 and homozygosity for an HLA-linked proteasome gene in juvenile ankylosing spondylitis

To assess the role of HLA genes other than those encoding B27 in predisposing to JAS and AAS, we analyzed the distribution of B*4001, as well as the DRB1, DPB1, and LMP2 alleles, using PCR-based techniques in 63 JAS and 44 AAS patients (all B27 positive). The NBMDR (N = 4724) provided a source of controls matched with the patients for B27 (or other markers when necessary). We found an increase of the B*4001, DRB1*08, and DPB1*0301 alleles, as well as the LMP2 b/b genotype (the latter was most pronounced among patients with acute iridocyclitis), in JAS compared to B27-positive controls. The increase of DRB1*08 and DPB1*0301 was due to an increase of DRB1*08 and DPB1*0301 in combination, whereas the association with B*4001 could be due to linkage disequilibrium with LMP2b. None of these associations were detected in AAS. We conclude that in JAS, in addition to the association to B27, there are also weaker but distinct associations to the DRB1*08, DPB1*0301 alleles and homozygosity for LMP2b.     

HLA-DRB1*08 influences the development of disease in Mexican Mestizo with spondyloarthropathy

OBJECTIVE: HLA class II encoded factors may influence the phenotype of ankylosing spondylitis (AS). These include HLA DRB1*07 for peripheral arthritis, and polymorphism of the HLA-linked LMP2 locus and HLA DRB1*08 for acute anterior uveitis (AAU). We studied the relationship between DRB1*08 and disease phenotype in additional populations of individuals with AS. METHODS: The patient population included 385 unrelated HLA-B27 positive individuals with AS. These included 204 Caucasians and 2 populations of Mexican Mestizo with AS: 106 with predominately adult onset disease from Guadalajara and 75 with predominately juvenile onset disease from Mexico City. The control population of 428 individuals included 210 random and 36 HLA-B27 positive unrelated Canadian Caucasians and 173 random and 9 HLA-B27 positive Mexican Mestizo from Mexico City. DRB1*08 typing was by sequence specific polymerase chain reaction. RESULTS: A significantly higher prevalence of DRB1*08 was observed in Mexican patients with juvenile onset disease (44.9%) and especially those with undifferentiated spondyloarthropathy (55.6%) compared to normal unrelated Mexican Mestizo (25.4%) (p < 0.01 for both) and in patients with undifferentiated spondyloarthropathy versus B27 controls (11.1%) (p = 0.03), although no significant differences were observed in within patient group comparisons based on phenotypic features of disease such as AAU and age at onset. No significant relationship between DRB1*08 and disease phenotype was evident in Caucasian individuals. CONCLUSION: Our data suggest DRB1*08 may influence the phenotype of spondyloarthritis in Mexican Mestizo, but do not support the view that DRB1*08 influences the development of AAU, as reported in a Japanese population.     

HLA-DRB and -DQB1 alleles in Polish patients with hepatitis B associated membranous nephropathy

The lower blepharoplasty procedure has had numerous surgical variations described and remains a challenge to those performing the operation. Disappointments with the technique revolve around complications such as lateral third scleral show, hollow sunken eyelids, rounding of the eye and overall long-term, tired, drawn appearance of the lower lids. Multiple adjuncts to the blepharoplasty procedure have been described. These vary in their difficulty of execution and associated complications. The concept of internal muscle suspension has been accepted as a successful adjunct by many authors but often the technique chosen has been a complicated one, adding time and complexity to the procedure.     

HLA antigens associated with susceptibility/resistance to HIV-1 infection

We studied the distribution of HLA-A, B, C, DR and DQ antigens in a cohort of HIV-1+ individuals and their heterosexual HIV seropositive (concordant) or seronegative (discordant) partners of Black non-Hispanic, Hispanic or Caucasian non-Hispanic ethnicity. The prevalence of DQ7 and Cw7 was significantly higher in the HIV-1+ compared to seronegative Black and Hispanic individuals, respectively. The frequency of DQ4 was significantly elevated in the Black seronegatives, whereas B53 was increased in the Hispanic seronegatives in comparison to the seropositives. No significant differences were observed between the Caucasian HIV infected and non-infected individuals. Analysis of the primary concordant HIV+ and discordant HIV+ individuals showed a marked increase in the prevalence of B44 in the Hispanic discordant seropositives, whereas the Caucasian primary concordants had a marked increase in the prevalence of A26. The prevalence of DQ7 and Cw7 was significantly increased in the Black and Hispanic secondary concordant seropositives, respectively in comparison to the seronegatives. The proportion of couples with matching HLA antigens was similar among the HIV-1+ concordant and discordant groups. These results provide additional evidence that HLA polymorphism may confer a genetic risk or protection for HIV-1 infection in individuals of various ethnic backgrounds.     

Use of T cell receptor/HLA-DRB1*04 molecular modeling to predict site-specific interactions for the DR shared epitope associated with rheumatoid arthritis

OBJECTIVE: To use molecular modeling tools to analyze the potential structural basis for the genetic association of rheumatoid arthritis (RA) with the major histocompatibility complex (MHC) "shared epitope," a set of conserved amino acid residues in the third hypervariable region of the DRbeta chain. METHODS: Homology model building techniques were used to construct molecular models of the arthritis-associated DRB1*0404 molecule and a T cell receptor (TCR) from T cell clone EM025, which is specific for DR4 molecules containing the shared epitope sequence. Interactive graphics techniques were used to orient the TCR on the DR molecule, guided by surface complementarity analysis. RESULTS: The predicted TCR-MHC-peptide complex involved multiple interactions and specificity for the shared epitope. TCR residues CDR1beta D30, CDR2beta N51, and CDR3beta Q97 were positioned to potentially participate in hydrogen bond interactions with the shared epitope DRbeta residues Q70 and R71. CONCLUSION: These results suggest a structural mechanism in which specific TCR recognition and possibly Vbeta selection are directly influenced by the disease-associated MHC polymorphisms.     

Sialyl-Lewis x and Sialyl-Lewis a are associated with MUC1 in human endometrium

Endometrial epithelial cells express MUC1 with increased abundance in the secretory phase of the menstrual cycle, when embryo implantation occurs. MUC1 is associated with the apical surface of epithelial cells and is also secreted, being detectable in uterine fluid at elevated levels in the implantation phase. However, its physiological role is uncertain; it may either inhibit intercellular adhesion by steric hindrance or carry carbohydrate recognition structures capable of mediating cell-cell interaction. Here we show that endometrial epithelium expresses both Sialyl-Lewis x (SLex) and Sialyl-Lewis a (SLea), with a distribution and pattern of menstrual cycle regulation similar to that of MUC1. Using Western blotting and double determinant ELISA of uterine flushings, we demonstrate that SLex is associated with MUC1 core protein. The endometrial carcinoma cell lines HEC1A and HEC1B are shown to express MUC1 in a mosaic pattern, while three other cell lines express much lower amounts. HEC1A expresses both SLex and SLea while HEC1B expresses SLea only. Immunoprecipitation has been used to demonstrate that SLea is associated with MUC1 in HEC1B cells, and both SLex and SLea are associated with MUC1 in HEC1A cells.     

Major histocompatibility complex class II DR alleles DRB1*1501 and those encoding HLA-DR13 are preferentially associated with a diminution in maternally transmitted human immunodeficiency virus 1 infection in different ethnic groups: determination by an automated sequence-based typing method

Transmission of human immunodeficiency virus 1 (HIV-1) from an infected women to her offspring during gestation and delivery was found to be influenced by the infant's major histocompatibility complex class II DRB1 alleles. Forty-six HIV-infected infants and 63 seroreverting infants, born with passively acquired anti-HIV antibodies but not becoming detectably infected, were typed by an automated nucleotide-sequence-based technique that uses low-resolution PCR to select either the simpler Taq or the more demanding T7 sequencing chemistry. One or more DR13 alleles, including DRB1*1301, 1302, and 1303, were found in 31.7% of seroreverting infants and 15.2% of those becoming HIV-infected [OR (odds ratio) = 2.6 (95% confidence interval 1.0-6.8); P = 0.048]. This association was influenced by ethnicity, being seen more strongly among the 80 Black and Hispanic children [OR = 4.3 (1.2-16.4); P = 0.023], with the most pronounced effect among Black infants where 7 of 24 seroreverters inherited these alleles with none among 12 HIV-infected infants (Haldane OR = 12.3; P = 0.037). The previously recognized association of DR13 alleles with some situations of long-term nonprogression of HIV suggests that similar mechanisms may regulate both the occurrence of infection and disease progression after infection. Upon examining for residual associations, only only the DR2 allele DRB1*1501 was associated with seroreversion in Caucasoid infants (OR = 24; P = 0.004). Among Caucasoids the DRB1*03011 allele was positively associated with the occurrence of HIV infection (P = 0.03).     

Crystal structure of HLA-DR2 (DRA*0101, DRB1*1501) complexed with a peptide from human myelin basic protein

Susceptibility to multiple sclerosis is associated with the human histocompatibility leukocyte antigen (HLA)-DR2 (DRB1*1501) haplotype. The structure of HLA-DR2 was determined with a bound peptide from human myelin basic protein (MBP) that is immunodominant for human MBP-specific T cells. Residues of MBP peptide that are important for T cell receptor recognition are prominent, solvent exposed residues in the crystal structure. A distinguishing feature of the HLA-DR2 peptide binding site is a large, primarily hydrophobic P4 pocket that accommodates a phenylalanine of the MBP peptide. The necessary space for this aromatic side chain is created by an alanine at the polymorphic DRbeta 71 position. These features make the P4 pocket of HLA-DR2 distinct from DR molecules associated with other autoimmune diseases.