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PubMed1992

[Polymorphism of HLA class I loci HLA-A, -B, -C, in the Mandenka population from eastern Senegal].

A sample of 162 Mandenkalu from Eastern Senegal has been typed for three HLA class I loci: HLA-A, -B and -C. The Mandenka population presents a very high genetic variability with 15 alleles for locus A, 24 alleles for locus B, and at least 8 alleles for locus C. The calculated heterozygosities for the three loci A, B, and C are respectively 0.884, 0.944 and 0.829. The Mandenkalu allelic frequencies are close to that found in other sub-Saharan populations. They show, however, some peculiarities like the occurrence of the Bw 56 allele and the high frequencies of both B5 and B35.

Alleles↗
PubMed1997

Coding versus intron variability: extremely polymorphic HLA-DRB1 exons are flanked by specific composite microsatellites, even in distant populations.

Although microsatellite typing is the dominant method in genome research and indirect gene diagnosis, precise relationships of exonic and adjacent simple repeat polymorphisms are not known. We investigated exon 2 sequences of HLA-DRB1 genes and their neighbouring (GT)n(GA)m repeats including the intervening single copy spacer. DRB1 is the most polymorphic protein-coding locus in man and all vertebrates investigated. The entire DRB1 variability exists in exon 2. DRB1 genes in different haplotype groups (DR1, DR51, DR52, DR8 and DR53) are accompanied by characteristic modifications of the (GT)n(GA)m block (3' to group-specific single copy spacers). Among more than 520 alleles analysed, > 100 different types of microsatellites were observed. The perfect (GT)n and (GA)m blocks vary in length and may be partly 'degenerated', mostly in a subgroup-specific manner. Interestingly, the extent of microsatellite diversity varies in given DRB1 alleles. While the microsatellites of the DR7, DR9 alleles and in the DR1 group are virtually invariant, in DR4 and DR13, in particular, simple repeats appear hypervariable with at least 15 or 17 different length alleles, respectively. Comparing Caucasians, Bushmen and South American Indians, the microsatellite variation in identical DRB1 alleles (e.g. DRB1*0102, 03011, 1302) is smaller than within any of the DR groups in Caucasians. Taken together, extremely polymorphic DRB1 exons evolve in concert with certain variants of an exceptionally well-preserved microsatellite.

Cloning, Molecular↗
PubMed2005

HLA-B27 polymorphism in Turkish patients with ankylosing spondylitis.

The aim of this study was to determine the distribution of human leukocyte antigen (HLA)-B27 subtypes in serologically HLA-B27-positive ankylosing spondylitis (AS) patients and healthy controls from the Turkish population and to compare this with other reports from other populations. We subtyped HLA-B27 in 38 HLA-B27-positive Turkish patients with AS and 47 HLA-B27-positive healthy controls without AS by polymerase chain reaction with specific sequence primers (PCR-SSP). The results demonstrated that: B*2705 was the predominant subtype among both of the patients (71.1%) and controls (68.0%). B*2702 was observed in 26.3% and 32.0% of the patients and controls, respectively. B*2708 subtype was found in 2.6% of the patients but not among the control group. When the distribution of B27 subtypes in Turkish populations was compared with that in other populations, similar frequencies with the Caucasian-Europe groups were noted. However, this should be interpreted carefully because of the small number of individuals in our study.

Adolescent↗
PubMed1999

Analysis of HLA-DM polymorphism in juvenile dermatomyositis (JDM) patients.

Annually approximately 1:200,000 young children and adolescents are affected by juvenile dermatomyositis (JDM). Genetic factors are thought to contribute to the etiology. Since the discovery of the human leukocyte antigen class II associated DM molecule much has been learned about its role in the normal processing of HLA-class II molecules with a limited number of polymorphisms being found. Blood samples were collected from 30 patients who were seen in the clinic and 40 healthy volunteers. Exon 3 of the HLA-DM A and B genes were amplified and specific polymorphisms were identified given allele designations. The DMA*0103 allele was found in 43% of patient alleles versus 8% in the control group, this difference reached significance at a p value of 0.0004. The DMB*0102 allele was found in 20% of patients compared with 3% of the controls with a calculated p value of 0.037. Relative risk (RR) ratios with CI were as follows: DMA*0103 vs control RR = 5.7 and DMB*0102 vs control RR = 8. In conclusion, we feel that the polymorphisms represented in the DMA*0103 and the DMB*0102 alleles are increased in frequency in our JDM patients.

Child↗
PubMed1994

NKB1: a natural killer cell receptor involved in the recognition of polymorphic HLA-B molecules.

Natural killer (NK) cells kill normal and transformed hematopoietic cells that lack expression of major histocompatibility complex (MHC) class I antigens. Lysis of HLA-negative Epstein Barr virus-transformed B lymphoblastoid cell lines (B-LCL) by human NK cell clones can be inhibited by transfection of the target cells with certain HLA-A, -B, or -C alleles. NK cell clones established from an individual demonstrate clonal heterogeneity in HLA recognition and a single NK clone can recognize multiple alleles. We describe a potential human NK cell receptor (NKB1) for certain HLA-B alleles (e.g., HLA-B*5101 and-B*5801) identified by the mAb DX9. NKB1 is a 70-kD glycoprotein that is expressed on a subset of NK cells and NK cell clones. DX9 monoclonal antibody (mAb) specifically inhibits the interaction between NK cell clones and B-LCL targets transfected with certain HLA-B alleles, but does not affect recognition of HLA-A or HLA-C antigens. An individual NK cell clone can independently recognize B-LCL targets transfected with HLA-B or HLA-C antigens; however, DX9 mAb only affects interaction with transfectants expressing certain HLA-B alleles. These findings demonstrate the existence of NK cell receptors involved in the recognition of HLA-B and imply the presence of multiple receptors for MHC on an individual NK clone.

Alleles↗
PubMed2006

HLA-DQ polymorphism in Turkish patients with myasthenia gravis.

Genetic susceptibility to myasthenia gravis (MG) is reported frequently and varies depending on the clinical presentation of the patients. HLA-DQ genotyping was performed in 132 patients using polymerase chain reaction and sequence-specific oligonucleotide hybridizations in the Turkish population for the first time in this study. Antibody positivities against acetylcholine receptor and titin were 81 and 27%, respectively. Sixty-five percent of the patients had disease onset before 40 years of age (EOMG). Overall distribution of DQA1*0103 (odds ratio (OR): 0.5) and DQB1*0502 (OR: 1.9) alleles was different in patients and an ethnically matched healthy control group. Among the subgroups, DQB1*02 was significantly more frequent in EOMG (OR: 1.8), in women with MG (OR: 2.4), and in women with EOMG (OR: 2.8), whereas DQA1*0102 and DQB1*502 (OR: 2.3 for both) were increased and DQA1*0103 (OR: 0.04) was decreased in men with MG. Seropositivity was associated with both DQA1*03 (OR: 12.1) and DQB1*0302 (OR: 14.2) in the patient group. DQA1*02 (OR: 4.9) was associated with the presence of anti-titin antibodies, whereas DQA1*0101 (OR: 3.7) and *0102 (OR: 2.9) were more frequent in patients without this antibody. The presence of thymoma in MG was positively associated with DQB1*0301 (OR: 2.8), and DQB1*02 (OR: 0.3) was significantly less frequent in this group. The HLA-DQ associations in subgroups of MG suggest that the heterogeneity of the disease may be influenced by different genes or even by different alleles. DQ alleles have proved to be relatively informative polymorphisms in studying MG.

Adolescent↗
PubMed2002

Molecular analysis of HLA-DRB1 polymorphism in north-east Spain.

The DRB1* polymorphism in 941 randomly selected individuals from the Umbilical Cord Blood Bank of Barcelona (92.75% of Spanish origin) was determined by sequence-based typing. The HLA profile was similar to that of other Mediterranean populations, with DRB1*0701 and *0301 being the most frequent alleles. This may be a consequence of the mixture of alleles as a result of migration from contiguous geographical areas.

Alleles↗
PubMed2006

HLA-DRB1 polymorphism is associated with Kell immunisation.

K immunisation is observed in some polytransfused patients and pregnant women but does not occur in all cases of K incompatibility. This study analysed the role of genetic background in this selective response to K antigen by investigating HLA-DRB1 alleles associated with K immunisation in a southern European population. HLA-DRB1 genotyping was performed by polymerase chain reaction sequence-specific oligonucleotide/sequence-specific primer procedures in 54 K immunised patients and 200 healthy controls. The frequency of HLA-DRB1*11 was significantly higher in K immunised patients than healthy controls: 31 of 54 (57%) vs. 56 of 200 (28%) (P(c) < 0.001). In the remaining K immunised HLA-DRB1*11-negative patients, the frequency of HLA-DRB1*13 was increased: 14 of 23 (61%) vs. 49 of 144 in healthy controls (34%) (P < 0.02). The combined frequency of the two HLA-DRB1 alleles (HLA-DRB1*11 and HLA-DRB1*13) was 83% in K immunised patients when compared with 52% in healthy controls (P(c) < 0.001). K and k differ by a single amino acid T193 (M). The DRB1*11 and DRB1*13 alleles share a HLA-DRB1 gene sequence containing S in position 13, D in 70 and A in 74, and coding for the P4 pocket within the HLA-DR binding groove. This feature of the HLA-DRB1 gene could be involved in the K peptide presentation through a polymorphism ligand specific for the T193 (M) of K. In conclusion, this study demonstrated a high frequency of HLA-DRB1*11 or HLA-DRB1*13 alleles in K immunised patients, which could be due to specific K peptide presentation by HLA-DR molecules.

Alleles↗
PubMed2000

Tumor necrosis factor alpha 5'-flanking region, tumor necrosis factor receptor II, and HLA-DRB1 polymorphisms in Japanese patients with rheumatoid arthritis.

OBJECTIVE: New polymorphisms affecting transcriptional activity were recently reported within the 5'-flanking region of the tumor necrosis factor alpha gene (TNFalpha). In addition, genome-wide linkage screening indicated 1p36 as one of the candidate chromosomal regions where the TNF receptor II gene (TNFR2) is located. In the present study, HLA-DRB1, TNFalpha promoter, and TNFR2 genotypes were determined to examine whether these polymorphisms are associated with rheumatoid arthritis (RA), either independently or in combination. METHODS: Genotypes of HLA-DRB1, TNFalpha upstream promoter, and TNFR2 codon 196 were determined in 545 Japanese patients with RA and 265 healthy controls. Association of these genes with susceptibility to RA was analyzed both independently and after stratification by one of the genotypes. RESULTS: As expected, the HLA-DRB1 shared epitope was strongly associated with RA. In addition, a significant negative association of DRB1*1405 and 1302 was observed. Furthermore, DRB1*1405 was suggested to possess a protective role for the development of RA in DRB1*0405-positive individuals. A significant increase in TNFalpha-U02 in RA was detected, which was not independent of DRB1*0405. A significant association was not observed between TNFR2-196M/R polymorphism and RA. CONCLUSION: Among the 3 genes examined in this study, HLA-DRB1 was considered to be most strongly associated with RA.

Antigens, CD↗
PubMed1987

Identification of HLA-DP polymorphism with DP alpha and DP beta probes and monoclonal antibodies: correlation with primed lymphocyte typing.

Thirty-four lymphoblastoid cell lines that had been previously typed for HLA-DP antigens by primed lymphocyte typing (PLT) were tested by Southern blotting and by ELISA. Using two DP beta probes and a DP alpha probe with a series of enzymes, it is possible to identify restriction fragment length polymorphism (RFLP) patterns characteristic of DPw1, -2, -3, -4, and possibly -5. ELISA typing results, based on two polymorphic DP antibodies DP11.1 and ILR1, were compared with PLT-defined and RFLP-defined types. Thus, using a range of probes and enzymes it is possible to identify DP polymorphism. The value of monoclonal antibodies for such studies is demonstrated, and the molecular data can, in some cases, pinpoint the amino acids responsible for the specificity of the monoclonal antibodies.

Alleles↗
PubMed1986

HLA-DQ polymorphism analyzed by sequential restriction endonuclease DNA digestion.

A direct, physical correspondence between certain Pst I-generated genomic DNA fragments and Taq I-generated fragments, revealed with HLA-DQ alpha or -DQ beta gene probes, has been demonstrated. As an immediate consequence, the nature of the DQ and DX hybridized genes contained in the fragments was established. Taq I-generated DQ allelic forms which associate with serologically defined DR1, DR2, and DRw6 specificities were also proven to be sensu stricto "splits" of the Pst I-generated allelic form associated with all three DR specificities.

Alleles↗
PubMed2001

Polymorphisms in HLA class I genes associated with both favorable prognosis of human immunodeficiency virus (HIV) type 1 infection and positive cytotoxic T-lymphocyte responses to ALVAC-HIV recombinant canarypox vaccines.

Carriers of certain human leukocyte antigen class I alleles show favorable prognosis of human immunodeficiency virus type 1 (HIV-1) infection, presumably due to effective CD8(+) cytotoxic T-lymphocyte responses, but close relationships between class I variants mediating such responses to natural and to vaccine HIV-1 antigen have not been established. During 6 to 30 months of administration and follow-up in trials of ALVAC-HIV recombinant canarypox vaccines, cells from 42% of 291 HIV-1-negative vaccinated subjects typed at class I loci responded to an HIV-1 protein in a lytic bulk CD8(+) cytotoxic T-lymphocyte assay. By 2 weeks after the second dose, higher proportions of vaccinees carrying one of two alleles consistently associated with slower progression of natural HIV-1 infection reacted at least once: B*27 carriers reacted to Gag (64%; odds ratio [OR] = 10.3, P = 0.001) and Env (36%; OR = 4.6, P = 0.04), and B*57 carriers reacted to Env (44%; OR = 6.6, P < 0.05). By 2 weeks after the third or fourth dose, B*27 carriers had responded (two or more reactions) to Gag (33%; OR = 4.4, P < 0.05) and B*57 carriers had responded to both Gag (39%; OR = 5.3, P = 0.013) and Env (39%; OR = 9.5, P = 0.002). Homozygosity at class I loci, although conferring an unfavorable prognosis following natural infection, showed no such disadvantage for vaccine response. Individual class I alleles have not previously demonstrated such clear and consistent relationship with both the clinical course of an infection and cellular immunity to a vaccine against the infectious agent. This proof of principle that class I an alleles modulate both processes has implications for development of HIV-1 and presumably other vaccines.

AIDS Vaccines↗
PubMed1986

New HLA DNA polymorphisms associated with rheumatoid arthritis.

Studies of restriction enzyme fragment length polymorphisms (RFLP) have further clarified two DNA polymorphisms detected in DR4 positive individuals with a DQ beta probe. These patterns have been designated DQ beta omega, characterized in the Dw4 homozygous typing cell (HTC) BM14 and DQ beta phi, characterized in the Dw4 HTC MCF, and so do not correspond with different Dw types. These patterns clearly segregate in families with HLA haplotypes. We suggest that omega and phi may be polymorphisms of the DX beta gene. The previously reported DX alpha polymorphisms U and L were found with all DR types and in association with DQ beta omega (U) and DQ beta phi(L). In addition DQ beta phi was found to be strongly associated with TA10 positively (a subdivision of DQw3) although this association was not absolute. Associations between RFLP and other HLA Class II and I antigens seen in DR4 patients and DR4 controls suggest the existence of at least two preferential allelic associations (PAA), one containing omega/U and the other phi/L. PAA1: DX alpha U-DQ beta omega-TA10 negative-DQw3-Dw4-DR4----Bw62-Bw6-Cw3-A2 PAA2: DX alpha L-DQ beta phi-TA10 positive-DQw3-Dw4-DR4----B44-Bw4-Cw3-A2 The frequency of the omega pattern was higher, although not significantly in the RA patients compared with controls. However, a significantly higher frequency of omega was found in RA patients with extra-articular manifestations (EA) compared (a) with controls (p less than 0.04) and (h) with those patients without EA (p less than 0.05). In addition the frequency of phi was significantly higher in RA patients with nodules and/or erosions (N/ER) compared with patients without these features (p less than 0.008). When cumulative scores were assigned to patients after assessing the number of components fulfilled for each PAA, PAA1 appeared to be pronounced in patients with EA and PAA2 in patients with N/ER. The frequency of a previously reported DQ beta T6 band found with the enzyme Taq 1 and DQ-beta probe was found at a higher frequency in RA patients compared with controls. In addition a significantly higher frequency of this band was found in female RA patients compared to males.

Arthritis, Rheumatoid↗
PubMed1998

The role of HLA-B27 polymorphism and molecular mimicry in spondylarthropathy.

Ankylosing spondylitis (AS), reactive arthritis (ReA) and other related spondyloarthropathies (SpAs) are characterized by a strong association with the major histocompatibility complex allele HLA-B27. Experimental evidence from humans and transgenic rodents suggests that HLA-B27 is itself involved in the pathogenesis of SpA. Population and peptide-specificity analysis of HLA-B27 suggest it has a pathogenic function related to antigen presentation. Putative roles for infectious agents have been proposed in ReA and suggested in AS. However, the mechanism by which HLA-B27 and bacteria interact to induce arthritis is not clear. Molecular mimicry between bacterial epitopes that cross-react with self-B27 peptides is the most persuasive explanation for the pathogenesis of SpA. The experimental studies reviewed here have greatly increased our knowledge of the structure, function and disease association of HLA-B27.

Animals↗