HLA-A, B, C, DR and DQ polymorphism in Zaireans.
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Black People↗
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Results for “HLA polymorphism”
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MHC2TA single nucleotide polymorphism and genetic risk for autoimmune adrenal insufficiency.
CONTEXT: The polymorphism of class II HLA genes modulates the genetic risk for several endocrine autoimmune diseases. The constitutive class II expression on antigen-presenting cells is under the control of the MHC class II transactivator, encoded by the MHC2TA gene, which is mapped to chromosome 16p13. The MHC2TA -168 A-->G single nucleotide polymorphism (rs3087456) has been suggested to confer susceptibility to some autoimmune diseases. DESIGN: With the aim of testing whether this MHC2TA single nucleotide polymorphism is independently associated with autoimmune Addison's disease (AAD) and/or modulates the genetic risk conferred by DRB1-DQA1-DQB1 haplotypes, we analyzed DNA samples from 128 AAD patients and 406 healthy control subjects from continental Italy. RESULTS: Frequency of allele G of MHC2TA was significantly increased among AAD patients (39% alleles), compared with 29% in healthy controls (P = 0.003). Similarly, the frequency of AG+GG genotypes was significantly higher among AAD patients than among healthy control subjects, in both a codominant (P = 0.012) and a G-dominant model (P = 0.018). Multivariate logistic regression analysis showed that MHC2TA AG+GG continued to be positively associated with genetic risk for AAD (P = 0.028, odds ratio = 1.72, 95% confidence interval = 1.06-2.78), after correction for DRB1*03-DQA1*0501-DQB1*0201, DRB1*04 (not 0403)-DQA1*0301-DQB1*0302 and DRB1*0403. Similar results were obtained when the number of G alleles was included in the model (P = 0.004; odds ratio = 1.65, 95% confidence interval = 1.17-2.32). CONCLUSIONS: Our study provides the first demonstration of the association of the polymorphism of the MHC2TA gene with genetic risk for AAD that appears to be independent from the well-known association with the polymorphism of HLA class II genes.
Adolescent↗
A method for using serum or plasma as a source of DNA for HLA typing.
A simple method for obtaining DNA from serum and plasma is described. Using appropriate primer pairs the polymorphic segments of HLA class II genes were amplified by the polymerase chain reaction (PCR) from this DNA, and typed using allele-specific oligonucleotide hybridization. When compared with DNA obtained from peripheral blood lymphocytes, the efficiency of the PCR was only minimally compromised and could be augmented by increasing the number of amplification cycles and/or by the addition of glycerol to the reaction mixture. This method serves as a reasonable alternative when no other source of DNA is available.
Base Sequence↗
Expression and susceptibility to modulation by interferons of HLA class I and II antigens on melanoma cells. Immunohistochemical analysis and clinical relevance.
Immunohistochemical analysis for non-polymorphic determinants of HLA class I or class II antigens has been greatly facilitated by the use of monoclonal antibodies. Studies on the distribution of these antigens in tumour lesions emphasize their role in the tumour-host interaction and in tumour histopathology, especially as additional markers in the assessment of prognosis of melanoma patients. Changes in the expression of HLA antigens on tumour cells in vitro as induced by gamma-interferon may also occur in vivo as a result of local production by the T lymphocytic infiltrate in tumours.
Cells, Cultured↗
[DNA analysis of HLA class II and III genes in sudden infant death (SIDS)].
In 39 cases of SID we studied the polymorphism of HLA-class II genes DRB and DQB and HLA-class III genes C4 (C4A and C4B, genes encoding the fourth complement component) and 21-hydroxylase (21OH-A and 21OH-B, genes encoding the enzyme 21-hydroxylase of the cortisol pathway) by DNA analysis. This study was performed in cooperation with the Institute of Legal Medicine, University of Munich. Compared to healthy controls the percentage of C4B gene deletions, C4B gene duplications (C4B "short") and 21OH-A gene deletions is increased in SIDS. The deviations are statistically not significant. The analysis of the HLA-DR alleles revealed a significant decrease of HLA-DR2 in SIDS compared to controls (p = 0.0016, pc = 0.016). The results of this study indicate a possible role of C4B/21OH-A gene defects as a risk factor in a subgroup of SID cases. This hypothesis has to be confirmed by studying further cases.
Chromosome Aberrations↗
[Association of genetic polymorphisms in human leukocyte antigen-DQA1 with intrahepatic cholestasis of pregnancy in Chengdu district].
OBJECTIVE: To explore the relationship between human leukocyte antigen-DQA1 (HLA-DQA1) allele gene polymorphism and intrahepatic cholestasis of pregnancy (ICP). METHODS: Forty-five patients with ICP, eighteen ICP families, forty-five normal pregnant women and eighteen normal control families were tested for HLA-DQA1 allele gene polymorphism by polymerase chain reaction with sequence-specific primer (PCR-SSP) method. RESULTS: The frequency of HLA-DQA1*0301 in normal pregnant women was markedly higher than that in the ICP group (P>0.05). No significant differences were observed between the frequencies of other detected HLA-DQA1 alleles in both groups. The analysis of feto-maternal or couples sharing of the HLA-DQA1 alleles showed that no significant differences were observed between the two groups. CONCLUSION: The above findings suggest that there is no significant association between the genetic polymorphisms in HLA-DQA1 and ICP in Chengdu district; HLA-DQA1*0301 may be a protective gene against ICP. It may prevent the development of ICP.
Adult↗
The molecular classification of the clinical manifestations of Crohn's disease.
BACKGROUND & AIMS: Crohn's disease is a common inflammatory disorder of the gut characterized by variation in both location and behavior. Chromosome 16 and the HLA region on chromosome 6 have been implicated in susceptibility to disease. Mutations in the NOD2/CARD15 gene, recently identified on chromosome 16, have been associated with disease overall but are found in only 25% of patients. No data regarding their contribution to specific disease subtypes exist. Here we report a detailed genotype-phenotype analysis of 244 accurately characterized patients. METHODS: A total of 244 white patients with Crohn's disease recruited from a single center in the United Kingdom were studied. All patients were rigorously phenotyped and followed-up for a median time of 16 years. By using linkage disequilibrium mapping we studied 340 polymorphisms in 24 HLA genes and 3 NOD2/CARD15 polymorphisms. RESULTS: We show that NOD2/CARD15 mutations determine ileal disease only. We confirm that alleles on specific long-range HLA haplotypes determine overall susceptibility and describe novel genetic associations with susceptibility, location, and behavior of Crohn's disease. CONCLUSIONS: The clinical pattern of Crohn's disease may be defined by specific genotypes. This study may provide the basis for a future molecular classification of disease.
Adolescent↗
Electrophoretic analysis of HLA-DR2 molecules isolated from HLA-Dw2 and HLA-Dw12 cell lines.
To answer the question of whether or not polymorphism exists among HLA-DR2 molecules derived from cells homozygous for HLA-DR2, but expressing different HLA-D specificities, HLA-DR2 molecules were isolated from HLA-Dw2 and HLA-Dw12 homozygous cells using a monoclonal antibody operationally monospecific for HLA-DR2, and were compared to each other by two-dimensional gel electrophoresis. No electrophoretically discernible polymorphism was found in either the heavy or the light chain subunits of the HLA-DR2 molecules. These findings are in marked contrast with previous observations that each of the HLA-DR4-associated HLA-D clusters expresses an electrophoretically distinct HLA-DR4 light chain.
Antibodies, Monoclonal↗
[HLA genotyping: indications and limits].
The polymorphism of the class I (HLA-A, B, C) and class II (HLA-DR, DQ, DP) antigens was for a long time investigated using serological methods. Today molecular biology methods are available to define the numerous HLA alleles by genotyping [(82 HLA-A alleles, 174 HLA-B, 38 HLA-C, 166 HLA-DRB1, 27 HLA-DQB1, 71 HLA-DPB1) (nomenclature 1996)]. Many different molecular biology methods can be used to define these alleles (PCR- RFLP, PCR-SSOP, PCR-SSP, PCR-SBT), the choice of method depends on the number of genotypes achieved per day and the time required to obtain a result. The resolution degree of results can reach two levels: low resolution: provides results almost identical to those obtained by serological methods. Low resolution is sufficient to find HLA-identical siblings for bone marrow transplantation, to type organ donor-recipient pairs and for diagnosis in most HLA disease associations; high resolution: defines HLA allele subtypes. High resolution is essential to type bone marrow donor-recipient pairs when the donor is unrelated. Molecular biology methods will gradually replace serological methods in the future. The only restriction is that some alleles, defined at the genomic level, are not expressed at the cell surface and are thus not functional.
Alleles↗
[Association of insulin gene variants with type 1 diabetes mellitus in Czech population].
BACKGROUND: The objective of the study was to quantify the association of insulin gene variants with type 1 diabetes mellitus (TIDM) in the Czech population. METHODS AND RESULTS: In an association study, we compared genotypes of 332 T1DM patients (age at T1DM onset was 8.1 +/- 4.4 yrs) with 292 healthy nondiabetic controls of similar age. All subjects were previously genotyped for HLA-DQB1, -DQA1 polymorphisms and DRB1*04 subtypes. The insulin gene was typed using the -23 HphI single nucleotide polymorphism after we had demonstrated a nearly complete linkage disequilibrium between this polymorphism, and the etiological VNTR in the Czech population. The protective variant of the insulin gene was present in 24% T1DM patients, and in 48% controls (OR=0.34, CI 95% 0.24-0.48), a risk comparable to weaker-associated HLA-DQ alleles. The association was independent of the HLA-conferred T1DM risk. The insulin gene polymorphism had no influence on the age at T1DM onset. CONCLUSIONS: We conclude that the insulin gene genotyping confers important information on T1DM risk in our population, and should be used in determining the disease risk along with the HLA-DQ typing.
Child↗
Public epitope specificity of HLA class I antibodies induced by a failed kidney transplant: alloantibody characterization by flow cytometric techniques.
BACKGROUND: Patients whose kidney grafts fail develop alloantibodies that react with many HLA molecules. We analyzed the epitope specificity of HLA class I alloantibodies in the sera of 55 patients who had been sensitized by kidney grafts, and investigated the immunogenicity of various polymorphic epitopes. METHODS: HLA class I alloantibodies were detected and characterized by flow cytometry (FlowPRA beads). Potential "immunizing epitopes" were identified by comparing the amino acid sequences of HLA class I antigens/alleles of the donor, recipient and the antibody-reactivity pattern. RESULTS: In the 55 anti-HLA class I-positive patients, 82 different antibody reactivity patterns were identified; all but 5 (94%) were determined by a "public epitope" of donor HLA-A and/or -B molecules. Forty-five of 50 patients who showed HLA-A Res-MMs with their donors produced HLA-A antibodies, but only 31 of 51 subjects with HLA-B Res-MMs produced HLA-B antibodies (P=0.001; O.R.=5.81). The antibody patterns were specific for a "single" epitope of the mismatched donor molecules in 91% of patients. Forty-three of the 120 (36%) mismatched HLA-A and/or -B epitopes were positively correlated with antibody production. The polymorphic determinants of higher immunogenic capacity were b80N (Bw6-associated) and ab82-83LR (Bw4-associated) public epitopes. CONCLUSIONS: The humoral immune response against a kidney graft mainly produces HLA class I antibodies specific for "public epitopes" of mismatched donor molecules. A "single" donor-epitope may determine the production of a spread antibody pattern. In renal transplantation, epitope matching is better than HLA antigen matching for avoiding or minimizing development of HLA antibodies.
Antibody Specificity↗
HLA-DR and DQ matching by DNA restriction fragment length polymorphism methods and the outcome of mixed lymphocyte reaction tests in unrelated bone marrow donor searches. The IMUST Study.
The use of DNA restriction fragment length polymorphism (DNA-RFLP) typing for HLA-DR and DQ genes was assessed in 96 patients who were HLA-A,B and DR matched by serology with one or more potential unrelated marrow donors (UD). Two hundred recipient-donor pairs from 10 transplant centres in the UK were studied. DNA-RFLP revealed serological errors in HLA-DR typing and identified additional recipient-donor mismatches. Of the 200 allegedly serologically matched pairs, 55 (28%) were mismatched for HLA-DR and/or DQ by DNA-RFLP typing. Of the 200 pairs, 68 (34%) mixed lymphocyte reactions (MLR) were negative and 132 (66%) positive. There was a significant correlation between DNA-RFLP defined mismatch and MLR positivity. However quantitative studies revealed no trend towards increasing MLR relative response index (RRI) with cumulative RFLP defined mismatch (i.e. for DR plus DQ compared with DR or DQ alone). RFLP matching for HLA-DR and DQ failed to predict a negative MLR. The RRI in the graft-versus-host direction was greater in RFLP matched pairs who carried HLA-DR4 than in matched pairs lacking DR4, suggesting that failure of RFLP to characterize DR4 subtypes was one reason why routine prediction of a negative MLR was not possible. Despite these limitations we have shown that DNA-RFLP is a reliable method for HLA-DR, DQ typing in routine UD searches in diverse clinical centres. By reducing the number of UD tested in MLR, RFLP typing can substantially reduce the work involved in donor selection.
Bone Marrow Transplantation↗
The role of the conserved residue in pocket A and the polymorphic residue in pocket E of HLA-B*3501 in presentation of human minor histocompatibility peptides to T cells.
We investigated T cell recognition for human minor histocompatibility (hmH) peptides using HLA-B*3501 restricted, hmH specific cytotoxic T lymphocytes (CTL) clones. These CTL clones killed C1R cells expressing HLA-B*3501 but not C1R cells expressing chimeric antigens between HLA-B*3501 and HLA-B*5101. They also failed to kill C1R cells expressing HLA-B*3501 mutants at residue 152 (B*3501-V152E) or at residue 171 (B*3501-Y171H). The CTL clone failed to kill C1R cells expressing these mutant molecules loaded with the hmH peptides isolated from C1R-B*3501 cells although it killed a self-B cell line expressing HLA-B3501 loaded with the specific hmH peptides. The CTL clone also failed to kill T2 cells expressing the mutant molecules loaded with the specific peptides whereas it killed T2 cells expressing HLA-B*3501 loaded with the specific peptide. On the other hand, naturally occurring specific hmH peptides were isolated from purified B*3501-V152E and B*3501-Y171H molecules, indicating that both HLA-B*3501-V152E and HLA-B*3501-Y171H molecules can bind the hmH peptides. These findings indicate that both the conserved residue 171 in pocket A and the polymorphic residue 152 in pocket E are critical in recognition of the T cells but not binding of the hmH peptides. Furthermore, these results provide the possibility that the TCR recognizes a conformational structure of hmH peptides bound to HLA-B*3501 molecules.
Antigen Presentation↗
HLA class I antigen (heavy and light chain) expression by Langerhans cells and keratinocytes of the normal human epidermis: ultrastructural quantitation using immunogold labelling procedure.
Using an immunogold labelling procedure, we quantified the density of major histocompatibility (MHC) class I antigens on the surface of Langerhans cells (LCs) and keratinocytes of the normal human epidermis. According to ultrastructural features, keratinocytes were divided into three subpopulations: stratum basalis (SBK), stratum spinosum (SSK), and stratum granulosum keratinocytes (SGK), and analyzed separately. For this purpose, three monoclonal antibodies (MCAs) were employed: an anti-HLA A,B,C, and anti-B2-microglobulin (B2-m), and a polymorphic anti-HLA A2 Aw69 MCA. Under electron microscopy, quantitative analysis demonstrated: (a) the presence of a high amount of HLA monomorphic determinants on SBK and SSK and moderate but significant labelling of SGK; (b) the very weak density of MHC class I antigens on the surface of epidermal LCs; (c) the expression, at an identical level, of the HLA heavy chain common determinant (HLA A,B,C), B2-m, and the alloantigen HLA A2 by all epidermal cells (ECs) apart from SGKs and LCs that presented far fewer HLA A2 sites than monomorphic determinants (B2-m and HLA A,B,C); (d) the absence of HLA class I on corneocytes and a moderate labelling of melanocytes. A knowledge of the precise quantitative distribution of HLA class I antigens among various cell subpopulations of the normal human epidermis would be very useful for the study and follow-up of cutaneous malignancies that are known to lose these molecules as well as for the understanding of immune responses, especially allospecific, that involve the skin.
Epidermal Cells↗
Polymorphism of the DPB1 locus in Hani ethnic group of south-western China.
Polymorphism of HLA-DPB1 was revealed with a sequencing-based typing (SBT) method in 47 unrelated healthy individuals from Yunnan Hani ethnic minority. The alleles DPB1*5901 and DPB1*7001 were detected for the first time in Chinese populations. A dendrogram showed that the Hani ethnic group belongs to the southern group of Chinese.
Asian People↗
Future HLA matching strategies in clinical transplantation.
BACKGROUND: HLA matching has shown to be beneficial in clinical transplantation. Due to the enormous polymorphism of the HLA system, however, it is not feasible to select a completely HLA-matched donor for every potential recipient. Only for patients with frequently occurring HLA phenotypes is it realistic to expect a well-matched donor within a reasonable waiting time. The majority of patients will be transplanted with a partially mismatched donor. In order to select the optimal donor for this category of patients, it is important to take advantage of the differential immunogenicity and thus differential importance of mismatched HLA antigens. METHODS: Based on retrospective analyses of graft survival data and in vitro tests measuring T-cell alloreactivity, the relative importance of different mismatches was evaluated. RESULTS: It has been possible to define acceptable or permissible mismatches with a low immunogenicity, which are associated with a good graft survival, versus taboo mismatches with a high immunogenicity and a poor graft survival. CONCLUSIONS: Further developing this new line of permissible versus taboo mismatches, a new strategy will emerge for future HLA matching, which will not only suit a rare number of patients with frequent haplotypes but a great percentage of all patients. This principle of different immunogenicity of different mismatches can not only be applied to T-cell alloreactivity as shown here, but also to B-cell alloreactivity, where a recently developed computer algorithm (HLA matchmaker) can be instrumental in selecting donors with HLA mismatches, which do not lead to alloantibody formation.
B-Lymphocytes↗
[Structure and function of human transplantation antigens].
Human transplantation antigens encoded in the major histocompatibility complex (MHC) region play a key role in regulating the immune responses. Here, we will describe the summary of our analyses on the structure and function of the human MHC molecules, HLA antigens as follows. 1) The genomic organization of the HLA antigen region was examined by cosmid cloning and pulsed-field gel electrophoresis technique. The HLA antigen region spans over at least 3,000 kb, and constitutes a multigene family. 2) Genetic polymorphisms in the HLA gene region were analyzed by Southern hybridization with restriction endonuclease digested genomic DNA using the class II cDNAs as probes (RFLP) and found to be tightly associated with each allo specificity. 3) The functional expression of the HLA class II gene product were observed after transfer of their cloned genes into the mouse fibroblast and human lymphocytes. 4) Narcolepsy is completely associated with HLA-DR2 Dw2, but no difference in the sequence of the DQ beta 1 domain could be found between narcoleptic and healthy individuals. This fact suggests that narcolepsy is not caused by mutation in the DQ beta gene. Based on results, it was inferred that one or both of the two Asps within the second variable region in the first domain of the DR beta chain is directly correlated with predisposition to narcolepsy.
Amino Acid Sequence↗
Polymerase chain reaction (PCR)/single-strand conformation polymorphism (SSCP) analysis of the human HLA-DQB regions.
Genetic diagnosis of 13 alleles of HLA-DQB1 (0501, 0502, 5031, 5032, 0601, 0602, 0604, 0201, 0301, 0302, 3032, 0401 and 0402) from 65 human DNA samples was achieved by applying single-strand conformation polymorphism (SSCP) analysis to DNA fragments amplified by the polymerase chain reaction (PCR) using a convenient primer set for DQB1 (recommendation of the International Histocompatibility Workshop, 1991). Differences between strand images (narrow/distinct or broad/diffuse) from the individual alleles and their electrophoretic mobilities are regarded as criteria for confirming the genetic diagnosis of DQB1 alleles. This primer set amplifies not only DNA fragments belonging to DQB1, but also to DQB2, and classification of 3 phenotypes (1.1, 1.2 and 1.1/1.2) in the presence of two alleles at the latter locus was suggested. Consequently, PCR/SSCP of DNA amplified by this primer enables classification of the phenotypes, at least under our experimental conditions, into 3 x 91 groups. Two advantages of SSCP analysis over VNTR with regard to the use of amplified DNA in forensic practice are described.
Alleles↗