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Results for “HLA polymorphism”

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PubMed2000

Influence of HLA supertypes on susceptibility and resistance to human immunodeficiency virus type 1 infection.

Certain human leukocyte antigens, by presenting conserved immunogenic epitopes for T cell recognition, may, in part, account for the observed differences in human immunodeficiency virus type 1 (HIV-1) susceptibility. To determine whether HLA polymorphism influences HIV-1 susceptibility, a longitudinal cohort of highly HIV-1-exposed female sex workers based in Nairobi, Kenya, was prospectively analyzed. Decreased HIV-1 infection risk was strongly associated with possession of a cluster of closely related HLA alleles (A2/6802 supertype; incidence rate ratio [IRR], 0.45; 95% confidence interval [CI], 0.27-0.72; P=.0003). The alleles in this supertype are known in some cases to present the same peptide epitopes for T cell recognition. In addition, resistance to HIV-1 infection was independently associated with HLA DRB1*01 (IRR, 0.22; 95% CI, 0.06-0.60; P=.0003), which suggests that anti-HIV-1 class II restricted CD4 effector mechanisms may play an important role in protecting against viral challenge. These data provide further evidence that resistance to HIV-1 infection in this cohort of sex workers is immunologically mediated.

Acquired Immunodeficiency Syndrome↗

PubMed1997

HLA class I phenotype and gene frequencies in parts of southern Nigeria.

HLA-A, B and C antigens were determined in 101 healthy subjects from two major and several minor ethnic groups in some parts of Southern Nigeria. Compared to earlier data based on a panel of expatriate Nigerians, significant differences were observed in antigen phenotype and gene frequencies particularly at the HLA-A locus. At least three antigenic specificities not previously observed in the expatriate Nigerians were detected in the present study. These included HLA-B8. B14 and CW1. These antigens however occurred at low frequencies. The antigens A23 and B7 were in positive linkage disequilibrium along with others which involved CW4 with B53 or B35. It is concluded from our findings that HLA polymorphisms in Nigerians may not be completely reflected in major population group studies alone. It is possible that more specificities may be detected by continued testing of the minor ethnic groups. The importance of this could be immense in disease association studies involving HLA genes as well as in anthropology.

Female↗

PubMed1999

[Polymorphism of HLA-DRB1, DQB1 in the Hans of north China]

OBJECTIVE: To understand polymorphism of HLA-DRB1, DQB1 in the Hans of north China and obtain more comprehensive and accurate data on genetics at DNA level. METHODS: Polymerase chain reaction-sequence specific primers (PCR-SSP) were used to determine HLA-DRB1, DQB1 alleles in 107 unrelated healthy Han individuals of north China. RESULTS: The authors determined 14 DRB1, 9 DQB1 alleles, which included not only the allele frequencies that corresponded to the gene frequencies of DR, DQ loci determined by other 9 cooperating labs but also the allele frequencies of DRB1*15, DRB1*16, DQB1*0301, DQB1*0302, DQB1*0303, DQB1*05, DQB1*0601, DQB1*0602, and DQB1*0604 that other serology labs did not report. CONCLUSION: This study has obtained a more comprehensive and accurate data set of the normal allele frequencies and linkage disequilibrium parameters of HLA-DRB1,DQB1 in the Hans of north China, which may be of significance in the studies on population genetics and disease association.

Journal Article↗

PubMed2006

Induction of interleukin-10 and suppressor of cytokine signalling-3 gene expression following peptide immunotherapy.

BACKGROUND: Allergen-derived (T cell epitope) peptides may be safer for immunotherapy than native allergen, as they do not cross-link immunoglobulin (Ig)E. However, HLA polymorphism results in multiple potential epitopes. Synthetic peptides of phospholipase (PL) A(2) were selected for a peptide vaccine, on the basis of binding affinity for commonly expressed HLA-DR molecules. OBJECTIVE: To evaluate treatment with an HLA-DR-based PLA(2) peptide vaccine in subjects with mild honeybee allergy in an open, controlled study. METHODS: Twelve volunteers with allergy to bee venom received nine intradermal injections of PLA(2) peptides, with six untreated subjects serving as controls. Outcome was assessed by the size of the late-phase cutaneous reaction to allergen, peripheral blood mononuclear cell (PBMC) proliferation, cytokine release, and expression of genes associated with immune regulation. RESULTS: Subjects receiving peptides showed a decrease in the magnitude of the late-phase cutaneous reaction to bee venom compared with controls (P=0.03). The proliferation of venom-stimulated PBMCs decreased in treated subjects compared with controls (P=0.01). Peptide treatment reduced the production of IL-13 by PLA(2)-stimulated PBMCs (P<0.01) and IFN-gamma (P<0.01), and increased the production of IL-10 (P=0.02). Transcription of the suppressor of cytokine signalling (Socs)3 gene was significantly increased following therapy. A transient, but modest, increase in allergen-specific IgG was also observed. CONCLUSION: HLA-DR-based T cell epitopes modify surrogate markers associated with successful immunotherapy and induction of immune regulation, supporting the concept that this form of treatment may be efficacious in human allergic disease.

Adult↗

PubMed1997

Use of Cord Blood Cells for Banking and Transplant.

Allogeneic hematopoietic stem cell (HSC) transplantation has been used to treat thousands of patients, both adults and children, who have life-threatening hematological diseases. The principal limitations of allogeneic bone marrow transplantation (BMT) are, for the majority of patients, the lack of suitable HLA-matched donors and the complications of graft-versus-host disease (GVHD) associated with HLA mismatches. The lack of an HLA-identical sibling donor in 70% of the cases has been overcome through the establishment of registries of potential marrow donors. These registries, however, often are restricted in terms of HLA polymorphism and ethnic diversity. Despite a bone marrow donor registry which contains >3.7 million donors worldwide, some patients cannot be transplanted because of the lack of a suitable HLA-identical donor. New approaches have been investigated, including the use of HLA partially mismatched, T cell-depleted, mobilized peripheral blood HSC or umbilical cord HSC.

Journal Article↗

PubMed1999

Applicability of the case-parent design in the etiological research of Type 1 diabetes in Chile and other genetically mixed populations.

In case-control studies, spurious associations between Human Leukocyte Antigen (HLA) alleles and Type 1 diabetes could arise as a result of population stratification, if there are ethnic differences between cases and non-related controls. The Chilean population has several unique features which make it ideal for the study of the effect of stratification by ethnicity on genetic epidemiological research. The incidence rates of Type 1 diabetes in Chilean Aboriginal populations are very low compared to Caucasian populations, while the frequency of the alleles in HLA loci also vary across ethnic groups. In order to avoid the confounding effect of ethnicity, one possible remedy would be the use of cases and their parents in place of non-related controls. The case-parent design offers an adequate framework for the study of the association between HLA polymorphisms and Type 1 diabetes in the Chilean population and can also be applicable to other genetically mixed populations especially in the Americas.

Adolescent↗

PubMed1992

Distinctive polymorphism at the HLA-C locus: implications for the expression of HLA-C.

The HLA-C locus remains an enigma. The serological polymorphism is poorly defined, HLA-C molecules are expressed at the cell surface at about 10% the levels of HLA-A and -B, and their importance for antigen presentation to either CD8-bearing T cells or natural killer cells is unclear. Our understanding of HLA-C polymorphism has also lagged behind that of HLA-A and -B. We have applied the polymerase chain reaction to the characterization of cDNA encoding HLA-C antigens. Combining the recent results with previously characterized HLA-C alleles gives a data base of 26 sequences, which was used to analyze the nature of HLA-C polymorphism and compare it to the variation seen in HLA-A and -B. The sequences form 10 families of alleles that correlate well with the patterns of serological crossreactivity, including the C blanks, and all major HLA-C allelic families appear to have been sampled. The families further divide into two groups of HLA-C alleles defined on the basis of linked substitutions in the 3' exons. In comparison with HLA-A and -B, HLA-C alleles are more closely related to each other, there being less variation in residues of the antigen recognition site and more variation at other positions. In particular, the helix of the alpha 1 domain of HLA-C molecules is unusually conserved. Despite the reduced diversity in the antigen recognition site, it is evident that HLA-C genes have been the target of past selection for polymorphism. Within the antigen recognition site, it is the alpha 1 domain that is most diagnostic of HLA-C, whereas the alpha 2 domain is similar to that of HLA-B, the locus to which HLA-C is most closely related. In particular, conserved motifs in the alpha 1 helix and the conserved glycine at the base of the B pocket (position 45) provide a combination of features that is uniquely found in HLA-C molecules. We hypothesize that these features restrict the peptides bound by HLA-C molecules and in this manner reduce the efficiency of HLA-C assembly and expression at the cell surface. The overall picture HLA-C polymorphism obtained from this sampling of HLA-C alleles is unlikely to change as further alleles are characterized.

Alleles↗

PubMed1992

HLA class II sequence polymorphisms and susceptibility to rheumatoid arthritis in Greeks. The HLA-DR beta shared-epitope hypothesis accounts for the disease in only a minority of Greek patients.

OBJECTIVE: In Northern Europeans, rheumatoid arthritis (RA) is strongly associated with a relatively conserved pentapeptide sequence of HLA-DR beta found notably in the HLA-DR4 subtypes Dw4 and Dw14 and in DR1. A previous serologic study of HLA class II polymorphism in a Greek population with RA failed to show significant associations with any antigen. METHODS: We characterized HLA-DRB polymorphisms in Greek patients with RA and in control subjects by restriction fragment length polymorphism analysis. Allelic DRB subtypes were examined by polymerase chain reaction amplification and oligonucleotide hybridization. RESULTS: DNA analysis in the RA patients showed that although individual HLA-DR allelic associations were weak, a relatively conserved HLA-DR beta motif was significantly associated with RA in this population of Greek patients. The third hypervariable region amino acid sequences QRRAA, QKRAA, or RRRAA were found in the HLA-DR beta 1 of 43.5% of the RA patients versus 15.5% of the controls (uncorrected P = 0.00004). CONCLUSION: Sequences shown to influence susceptibility to RA in patients in the UK also play a role in patients in Greece. However, 57% of Greek patients lack the putative HLA-DR beta motif, which suggests that considerable immunogenetic heterogeneity underlies disease susceptibility in this population.

Amino Acid Sequence↗

PubMed2001

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.

Case-Control Studies↗

PubMed2006

[HLA-DQB1 allele polymorphism and clinical characteristics of 15 familial myasthenia gravis cases in north China].

OBJECTIVE: To investigate the relationship between the HLA-DQB1 allele polymorphisms and the clinical features of 15 familial myasthenia gravis (MG) cases in north China. METHODS: By polymerase chain reaction-sequence specific primers (PCR-SSP), the HLA-DQB1 gene polymorphisms were determined in 64 MG patients (15 familial and 49 sporadic) and 52 healthy individuals as control group. The clinical characteristics of 15 familial MG patients and 49 sporadic were analyzed. The measurement data was analyzed by t test and enumeration data by chi-square test. RESULTS: The frequency of DQB1*0501 was significantly increased in familial MG, especially in the ocular type, compared with sporadic MG (P<0.05, OR=3.08) and healthy controls (P<0.01, OR=4.439). Comparing with healthy controls, the frequency of DQB1*0301/4 was increased (P<0.05, OR=2.56), while the frequency of DQB1*0601 was significantly decreased (P<0.05, OR=0.33) in sporadic MG. The familial patients had an early age of disease onset, but less severity and good prognosis. CONCLUSION: The familial MG has distinctive clinical features. DQB1*0501 allele is positively related to the genetic susceptibility to familial MG patients in north China, especially to the ocular type. DQB1*0301/4 allele is positively related to the pathogenesis of sporadic MG. DQB1*0601 may be a protecting allele for sporadic MG. The phenotype of MG may be the result of interaction of hereditary defects and environmental factors. The familial MG may be different from sporadic patients in genetic immune mechanism.

Adolescent↗

PubMed1988

IgA serum levels and HLA complement markers in gastric cancer patients.

Immunoglobulin serum levels and class III HLA polymorphisms (Bf, C4A, and C4B) have been analyzed in 55 gastric cancer patients (13 having at least a first-degree relative affected by the same tumor) from the Republic of San Marino. This was done to search for possible immunoglobulin deficiencies (in particular IgA), which have been proposed to have a prognostic value in gastric cancer, and to identify possible associations between such a tumor and HLA class III determinants. All subjects had normal Ig levels with the exception of one patient (having the worst prognosis) characterized by a combined IgA, IgG, and IgM deficiency. Normal Ig levels were found in all the examined relatives of the proband. The Bf, C4A, and C4B allele frequencies we found did not differ significantly from those reported for healthy subjects in Italian samples.

Alleles↗

PubMed1995

TAP1 and TAP2 polymorphism in HLA-B27-positive subpopulations: no allelic differences in ankylosing spondylitis and reactive arthritis.

The polymorphic TAP1 and TAP2 genes encode subunits of the transporter that delivers peptides to the HLA class I molecules. Because the polymorphism of the TAP genes has been shown to affect peptide transport, it has been suggested that TAP genes are potential regulators of the immune response. We studied TAP1 and TAP2 polymorphism in two multifactorial HLA-B27-associated diseases, ankylosing spondylitis (N = 30) and reactive arthritis (N = 30), in order to establish whether TAP genes are involved in the different pathogenesis of these diseases. Healthy HLA-B27-positive individuals (N = 55) were chosen as the primary controls and 93 individuals represented the random Finnish population as secondary controls. We found differences between the random and HLA-B27-positive populations, thus suggesting that certain TAP alleles are prevalent in HLA-B27 haplotypes. No differences were found between the AS and ReA groups nor between either of them and the healthy HLA-B27-positive controls. Thus it seems unlikely that TAP polymorphism, ar the level studied, has a dominant role in the pathogenesis of these diseases. However, a family study is needed in order to determine whether the same TAP complexes are carried by the same haplotypes in these diseases.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1994

Genetic polymorphisms in HLA-A, -B, -C and -DR antigens in Japanese patients with palmoplantar pustulosis.

Genetic polymorphisms in HLA-A, -B, -C and -DR antigens were investigated in 78 unrelated Japanese patients with palmoplantar pustulosis (PPP) and compared with a total of 472 normal persons. Only HLA-DR9 showed a significantly increased frequency among all HLA antigens investigated (chi 2 = 11.57, p < 0.001). It is suggested that major histocompatibility complex class II antigens including HLA-DR antigen may determine the susceptibility to PPP and PPP may be a distinct disease entity from psoriasis.

Adult↗

PubMed2000

[Allelic polymorphism of HLA-DQA1 locus in Han nationality in Hunan province].

OBJECTIVE: To explore the genetic polymorphism of HLA-DQA1 locus in Han nationality in Hunan province. METHOD: Sixty samples randomly selected from healthy individuals of Han nationality in Hunan province were typed for HLA-DQA1 by PCR/SSP in combination with silver-staining PCR/SSCP. RESULTS: Ten types of HLA-DQA1 alleles were found in all 60 samples, HLA-DQA1*0302, *0501, *0102 were the common alleles with gene frequencies of 0.2254, 0.2254, and 0.2041 respectively. Twenty-six kinds of genotypes were found, and the genotype distribution fitted the Hardy-Weinberg equilibrium test (P > 0.05). Five samples which had ambiguity in their PCR/SSP typing were further clarified with PCR/SSCP analysis. CONCLUSIONS: Normal gene frequency values of HLA-DQA1 alleles in Han nationality in Hunan province are provided; PCR/SSCP can be used to eliminate the ambiguity which might exist in PCR/SSP typing for HLA-DQA1 locus.

Alleles↗

PubMed1981

Measles, histocompatibility leukocyte antigen polymorphism, and natural selection in humans.

Profound lymphocytopenia (greater than 2,000 lymphocytes/mm3) occurring within two days of rash in 69 South African black children with measles predicted either death or progression to chronic lung disease in 51 (77%) of 66 children who were followed for at least six weeks. Lymphocytopenia was significantly associated with the presence of histocompatibility leukocyte antigen (HLA) AW32 (P = 0.01), with a relative risk of 5.5. There was a trend toward an association between the presence of particular antigens in the HLA complex and the various indices of humoral and cellular immunity studied. These findings are discussed in terms of variation in the clinical spectrum of the disease and in relation to the evolution of HLA polymorphism.

Antibodies, Viral↗

PubMed1993

[Genetic HLA system in the Northern Khant population compared with other Ugro-Finnish peoples].

The northern khants different from the east khants in frequencies of some genes from the HLA-A, B, Cw system and in the absence of the disequilibrium linkage. Population-genetic mechanisms underlying HLA polymorphism differences between the two groups of khants which may have resulted during the historical development of these groups or from the difference of climate conditions under which these ethnic groups had lived, are under discussion.

Adolescent↗

PubMed2002

Association of MICA polymorphism with HLA-B51 and disease severity in Korean patients with Behcet's disease.

The HLA-B51 allele is known to be associated with Behcet's disease (BD) in many ethnic group. However, it has not yet been clarified whether the HLA-B51 gene itself is the pathogenic gene related to BD or whether it is some other gene in linkage disequlibrium with HLA-B51. Recently, the Triplet repeat (GCT/AGC) polymorphism in transmembrane region of the MHC class I chain-related A (MICA) gene was identified. To investigate the association of MICA with BD, we studied the MICA polymorphism in 108 Korean BD patients and 204 healthy controls in relation to the presence of HLA-B51 and clinical manifestations. The triplet repeat polymorphism was determined by polymerase chain reaction (PCR)-denaturing polyacrylamide gel electrophoresis (PAGE). The phenotype frequency of the MICA*A6 allele (relative risk, RR=2.15, p=0.002) and HLA-B51(RR=1.87, p=0.022) were significantly increased in the Korean patients with BD. A strong linkage disequilibrium was observed between the MICA*A6 and HLA-B51 in both the patients with BD and control subjects. Stratification analysis showed that MICA*A6 homozygosity was strongly associated with BD in the HLA-B51-negative population, and HLA-B51 was also associated with MICA*A6-negative population. In conclusion, MICA*A6 rather than HLA-B51 was strongly associated with Korean patients with BD, and the MICA*A6 allele is a useful susceptibility marker of BD, especially in the HLA-B5-negative

Adult↗

PubMed2003

Ex vivo screening for immunodominant viral epitopes by quantitative real time polymerase chain reaction (qRT-PCR).

The identification and characterization of viral epitopes across the Human Leukocyte Antigen (HLA) polymorphism is critical for the development of actives-specific or adoptive immunotherapy of virally-mediated diseases. This work investigates whether cytokine mRNA transcripts could be used to identify epitope-specific HLA-restricted memory T lymphocytes reactivity directly in fresh peripheral blood mononuclear cells (PBMCs) from viral-seropositive individuals in response to ex vivo antigen recall. PBMCs from HLA-A*0201 healthy donors, seropositive for Cytomegalovirus (CMV) and Influenza (Flu), were exposed for different periods and at different cell concentrations to the HLA-A*0201-restricted viral FluM158-66 and CMVpp65495-503 peptides. Quantitative real time PCR (qRT-PCR) was employed to evaluate memory T lymphocyte immune reactivation by measuring the production of mRNA encoding four cytokines: Interferon-gamma (IFN-gamma), Interleukin-2 (IL-2), Interleukin-4 (IL-4), and Interleukin-10 (IL-10). We could characterize cytokine expression kinetics that illustrated how cytokine mRNA levels could be used as ex vivo indicators of T cell reactivity. Particularly, IFN-gamma mRNA transcripts could be consistently detected within 3 to 12 hours of short-term stimulation in levels sufficient to screen for HLA-restricted viral immune responses in seropositive subjects. This strategy will enhance the efficiency of the identification of viral epitopes independently of the individual HLA phenotype and could be used to follow the intensity of immune responses during disease progression or in response to in vivo antigen-specific immunization.

Journal Article↗