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PubMed1989

Association of HLA antigen and restriction fragment length polymorphism of T cell receptor beta-chain gene with Graves' disease and Hashimoto's thyroiditis.

HLA antigen phenotypes and BglII restriction fragment length polymorphism of T cell receptor beta-chain (TCR beta) gene were analyzed in 61 patients with Graves' disease and 50 patients with Hashimoto's thyroiditis. The antigen frequency of HLA-Bw46 in both Graves' disease (23.0%) and Hashimoto's thyroiditis (24.0%) was significantly higher than that in normal population (8.0%), with relative risks (RR) of 3.45 [corrected P (Pc) less than 0.009] and 3.66 (Pc less than 0.02), respectively. Significantly increased frequency of HLA-B51 antigen was also found in Hashimoto's thyroiditis (40.0% vs. 16.3% in controls; RR, 3.42; Pc less than 0.002). Hybridization of BglII-digested DNA with TCR beta probe revealed two alleles of 9.3 and 8.6 kilobases. The allele frequency of 8.6 kilobases in Graves' disease (79%) and Hashimoto's thyroiditis (76%) was significantly higher (P less than 0.01 and P less than 0.05, respectively) than that in controls (64%). The frequency of homozygous state 8.6/8.6 was significantly increased in both Graves' disease (62%) and Hashimoto's thyroiditis (60%) over that in controls (39%); the RR of 8.6/8.6 in Graves' disease and Hashimoto's thyroiditis were 2.55 (P less than 0.01) and 2.31 (P less than 0.05), respectively. These results indicate that in Japanese subjects at least two loci are involved in the susceptibility to Graves' disease and Hashimoto's thyroiditis, one related to HLA and another to TCR beta.

Alleles↗
PubMed2001

IMGT/HLA Database--a sequence database for the human major histocompatibility complex.

The IMGT/HLA Database (www.ebi.ac.uk/imgt/hla/) specialises in sequences of polymorphic genes of the HLA system, the human major histocompatibility complex (MHC). The HLA complex is located within the 6p21.3 region on the short arm of human chromosome 6 and contains more than 220 genes of diverse function. Many of the genes encode proteins of the immune system and these include the 21 highly polymorphic HLA genes, which influence the outcome of clinical transplantation and confer susceptibility to a wide range of non-infectious diseases. The database contains sequences for all HLA alleles officially recognised by the WHO Nomenclature Committee for Factors of the HLA System and provides users with online tools and facilities for their retrieval and analysis. These include allele reports, alignment tools and detailed descriptions of the source cells. The online IMGT/HLA submission tool allows both new and confirmatory sequences to be submitted directly to the WHO Nomenclature Committee. The latest version (release 1.7.0 July 2000) contains 1220 HLA alleles derived from over 2700 component sequences from the EMBL/GenBank/DDBJ databases. The HLA database provides a model which will be extended to provide specialist databases for polymorphic MHC genes of other species.

Alleles↗
PubMed2001

HLA class I and class II allele and haplotype diversity in Martinicans.

The Martinican population is mainly the product of admixture between African people and French Caucasians. The aim of the present study is to investigate at the DNA level the polymorphism of HLA class I (HLA-A, HLA-B) and class II (HLA-DRB1, DQB1 and DPB1) genes in a population of 100 Martinicans. Allelic distributions and interlocus linkage disequilibria were compared to those observed in a French Caucasian population and in African or North American African populations. Our data revealed a higher degree of polymorphism in Martinicans than in Caucasians and showed a prominant contribution of African origin in the admixed genetic feature of this population. African characteristic alleles were significantly represented in Martinicans: A*30, *33 *34, *66, *74, *8001, B*1510, *35, *42, *53, DRB1*0302, *0804, *1202, *1304, *1503, DPB1*0101, *1701, *1801, *3901. Moreover a higher diversity of A*-B* and DRB1*-DQB1* associations was observed in Martinicans compared to Caucasians which also reflects the African genetic background of this population. In the whole, using PCR-based genotyping methods for HLA class I and class II loci, this study allows a preliminary description of HLA allele distribution in this Caribbean island and gives new elements which may be helpful in the anthropologic field as well as in HLA and disease association studies.

Africa↗
PubMed1984

Recognition of HLA-A2 and -B7 antigens by cloned cytotoxic T lymphocytes after gene transfer into human and monkey, but not mouse, cells.

The genes that code for the human major histocompatibility class I antigens, HLA-A2 and HLA-B7, were introduced into human, monkey, and mouse cell lines by cotransfection with suitable biochemical markers and the fluorescence-activated cell sorter was used to identify and/or select stable cell populations expressing high surface levels of these antigens. Levels of expression obtained were similar to those observed for endogenous HLA antigens on various human cell lines and were 25-80% of those observed on the human B-lymphoblastoid cell line JY. Serologically defined HLA-A2 and HLA-B7 polymorphic determinants remained intact on all transfected recipient cells analyzed. Cloned human allospecific cytotoxic T lymphocytes (CTL) specific for HLA-A2 or HLA-B7 were capable of lysing appropriate HLA-transfected human cells with comparable efficiency to JY cell lysis. Two of 10 CTL clones lysed appropriate monkey cell transfectants with approximately equal to 20% the efficiency of human cell transfectants. No specific lysis of any HLA-transfected mouse cell lines, including a B cell lymphoma, was observed despite comparable levels of surface antigen expression or after induction of higher levels by mouse gamma-interferon. Furthermore, L cells expressing human beta 2-microglobulin in addition to HLA-A2 or -B7 were not lysed by these CTL. Thus, an additional species-specific component may be involved in lysis by allogeneic CTL--possibly related to the function(s) of other surface proteins on target cells.

Animals↗
PubMedDate not supplied

The level and the persistence of islet cell antibodies in healthy schoolchildren are associated with polymorphic residues of the HLA-DQ beta chain.

Cytoplasmic islet cell antibodies (ICA) were determined in a group of non-diabetic Caucasian schoolchildren (n = 4208). The prevalence rate for ICA positivity was 1.05 per cent (95 per cent confidence interval: 0.8-1.4 per cent). Analysis of HLA risk factors revealed that HLA-DRB1*03 (p less than 0.01), HLA-DRB1*04 (p less than 0.01) and HLA haplotypes with non-charged amino acids (non-Asp) at codon 57 of the HLA-DQ beta (p less than 0.01) chain were significantly increased when compared to controls. High levels of islet cell antibodies, i.e. Juvenile Diabetes Federation units (JDF units) equal to or greater than 30 JDF units were found to be associated with amino acids other than aspartic acid at codon 57 of the DQ beta chain molecule. Also the persistence of circulating ICA was found to be associated with non-Asp homozygosity of the proband (p less than 0.03).

Adolescent↗
PubMed1995

Mechanisms underlying the formation of the T cell receptor repertoire in rheumatoid arthritis.

The contributions of germline-encoded T cell receptor segments and of HLA-DR polymorphisms in shaping the repertoire of human CD4+ CD45RO- T cells were investigated in healthy unrelated individuals and in patients with rheumatoid arthritis, an HLA-DRB1 04-associated disease. By comparing frequencies of V beta-J beta combinations, healthy individuals segregated into independent clusters, which strongly correlated with the HLA-DRB1 allele expression. The repertoire fingerprint imposed by the HLA-DRB1 alleles involved only a selected group of J beta elements, whereas the distribution of the other J beta segments was HLA independent. The HLA-restricted J beta elements are characterized by a Gly-Pro-Gly sequence within the conserved Phe-Gly-X-Gly motif, which induces rigidity in an otherwise more flexible protein backbone. The T cell receptor repertoire distinguished patients with RA from healthy HLA-DR-matched individuals, suggesting that patients share a selection mechanism that significantly distorts the composition of the T cell receptor repertoire.

Amino Acid Sequence↗
PubMed1982

Serologic identification of the human secondary B cell antigens. Correlations between function, genetics, and structure.

The secondary B cell (SB) antigens are polymorphic HLA-linked antigens on human B cells and macrophages that are identified by primed T cell responses but are genetically distinct from the HLA-DR, MB, and MT antigens. Serologic identification of the SB molecule, using the monoclonal antibody ILR1, now makes it possible to correlate the function of these determinants in human T cell recognition with an Ia-like molecular structure and a genetic locus that marks a new HLA subregion. Three lines of evidence indicate that the ILR1 molecule identifies an epitope on some alleles of the SB gene: (a) the polymorphism of ILR1 -reactivity in the population correlates with SB2 SB3; (b) T cell proliferative response to SB2 and SB3 are specifically inhibited by ILR1; and (c) ILR1 reactivity is exactly concordant with the expression of SB2 in a panel of HLA-deletion mutant lymphoblastoid cell line. Together with previous studies, these results indicate that the SB antigens are on Ia-like molecules. Furthermore, the serologic studies of HLA-deletion mutant cell lines demonstrate that there are two HLA regions centromeric to HLA-B controlling expression of Ia-like molecules: a region toward HLA-B that controls expression of HLA-DR, and a region toward GLO that controls expression of SB.

Antibodies, Monoclonal↗
PubMed2004

Tumor necrosis factor and interleukin-10 gene promoter polymorphisms in Brazilian population and in Terena Indians.

The Terena Amerindians are located in the midwestern region of Brazil. We have previously reported a restricted polymorphism for HLA class I and class II in 99 unrelated Terena using PCR-SSO and more recently for MICA. There are single nucleotide polymorphisms (SNPs) that determine high or low production of certain cytokines. We have now studied the frequencies of mutant allele (A) at position -308 in the promoter of the gene tumor necrosis factor (TNF)-alpha (pro-inflammatory cytokine) and the alleles A and T, at position -1082 and -819, respectively, in the promoter of the interleukin (IL)-10 gene, in 51 of these subjects from the Terena tribe using PCR SSP and in 195 normal unrelated healthy Brazilians using PCR-RLFP. All 51 Terena Indians tested (100%) had the G/G genotype at position TNF-alpha -308, with no mutation found thus far. In contrast, among the Brazilian general population, the allelic frequency of A was 18.9%. When anti-inflammatory cytokine IL-10 was studied at two different positions, -1082 and -819, a high mutation rate was found when Terena were compared with the general Brazilian population (P <.05). The genetic cytokine profile may be required to balance the restricted HLA repertoire for peptide presentation in this native population.

Brazil↗
PubMed1989

Remarkable sequence conservation of the HLA-DQB2 locus (DX beta) within the highly polymorphic DQ subregion of the human MHC.

The HLA-D region of the major histocompatibility complex (MHC) is characterized by a remarkable diversity. Most of the HLA class II genes are highly polymorphic, and in addition, the number and organization of individual loci in that region varies in different haplotypes. This extensive allelic polymorphism of immune response genes has well-known functional implications. Within the HLA-D region, two loci, DQA2 and DQB2 (formerly called DX alpha and DX beta), represent a very special case: the detailed structure of these two genes is entirely compatible with expression, yet their expression has never been demonstrated in any tissue. Consequently, there exists no known corresponding protein product. Pseudogenes are known to accumulate mutations, as observed for instance in the case of HLA-DPA2,-DPB2, or -DRB2 genes. We have therefore investigated the extent of DQ2 genes' polymorphism by DNA sequence comparison and by oligonucleotide hybridization across a large number of different haplotypes, and compared it with other genes in the HLA-D region. We show here that, contrary to the adjacent DQ1 genes, DQ2 genes exhibit little and possibly no polymorphism. This conservation of DQ2 genes in many haplotypes indicates that the DQ1-DQ2 duplication event must have preceeded the extensive diversification of DQ1 genes and raises the puzzling question of why DQ2 genes have remained nonpolymorphic. This suggests that either these genes correspond to an unusually invariant region of the MHC or they are under a strong selective pressure for the conservation of the amino acid sequence of a putative DQ2 gene product. The latter would imply that the HLA-DQ2 genes are expressed into a protein product endowed with essential functional properties.

Alleles↗
PubMedDate not supplied

Type 1 diabetes genetic susceptibility encoded by HLA DQB1 genes in Romania.

Most cases of type 1 diabetes (T1DM) are due to an immune-mediated destruction of the pancreatic beta cells, a process that is conditioned by multiple genes and environmental factors. The main susceptibility genes are represented by the class II HLA-DRB1 and DQB1 alleles. The aim of our study was to reconfirm the contribution of HLA-DQB1 polymorphisms to T1DM genetic susceptibility for the Romanian population. For this, 219 Romanian T1DM families were genotyped at high resolution for HLA DQB1 using the PCR-SSOP method (Polymerase Chain Reaction - Sequence Specific Oligonucleotide Probes). Allele transmission to diabetics and unaffected siblings was studied using the Transmission Disequilibrium Test (TDT). We found an increased transmission of DQB1*02 (77.94% transmission, p(TDT) = 7.18 x 10(-11)) and DQB1*0302 (80.95% transmission, p(TDT) = 2.25 x 10(-10)) alleles to diabetics, indicating the diabetogenic effect of these alleles. Conversely, DQB1*0301, DQB1*0603, DQB1*0602, DQB1*0601 and DQB1*05 alleles are protective, being significantly less transmitted to diabetics. In conclusion, our results confirmed the strong effect of HLA-DQB1 alleles on diabetes risk in Romania, with some characteristics which can contribute to the low incidence of T1DM in this country.

Adolescent↗
PubMed2005

Primary omental gestational choriocarcinoma ascertained by deoxyribonucleic acid polymorphism analysis.

BACKGROUND: Abdominal choriocarcinoma is extremely rare. It is important to examine whether the disease is primary or metastatic and gestational or non-gestational. CASE: A 26-year-old nulli-gravid woman underwent laparoscopy for presumed ectopic pregnancy. The uterus, ovaries and fallopian tubes surrounded by hemoperitoneum were unremarkable. A hemorrhagic 7-cm-sized tumor was identified on the greater omentum and excised. Histology was consistent with choriocarcinoma. Analysis of human leucocyte antigen (HLA) gene polymorphism on deoxyribonucleic acid (DNA) demonstrated that tumor DNA contained both HLA locus antigens of patient and of her husband. Clinical remission was achieved with six courses of chemotherapy. CONCLUSION: To our knowledge, this is the first reported case of choriocarcinoma that occurred primarily on the omentum ascertained to be of gestational origin by DNA polymorphism analysis.

Adult↗
PubMed1989

HLA-DQ beta 3.1 allele is a determinant of susceptibility to DR4-associated rheumatoid arthritis.

Rheumatoid arthritis is associated with HLA-DR4 in several ethnic groups. Since DR4 haplotypes encode a diverse array of class II molecules, it is of interest to characterize the nature of the primary association. We have examined molecular polymorphisms of HLA class II gene products expressed by normals and rheumatoid arthritis patients using monoclonal antibodies and two-dimensional electrophoresis. Most homozygous DR4 rheumatoid arthritis patients express DR beta 1 molecules associated with Dw4 or Dw14 mixed lymphocyte culture determinants. In Caucasoids, two DR4-linked DQw3-associated beta-chain alleles are defined by two-dimensional electrophoresis. These variants, designated DQ beta 3.1 and 3.2, are associated with the serologic determinants DQw7 and DQw8, respectively. A panel of 40 DR4-positive normals was also examined for nucleotide sequence polymorphisms associated with DQB3.1 and 3.2 genes using the polymerase chain reaction and specific oligonucleotide probes. At the DQ beta level the rheumatoid arthritis panel was distinguished by enrichment for the DQ beta 3.1 allele with 100% of patients positive for DQw7. Results presented here suggest that specific DQ beta alleles may modify the effect of HLA-DR4 beta 1 alleles in conferring susceptibility to rheumatoid arthritis in a phenotype-specific fashion.

Antibodies, Monoclonal↗
PubMed2001

Association analysis of HLA-class II and class III gene polymorphisms in the susceptibility to mediterranean visceral leishmaniasis.

HLA-DRB1, -DQB1, TNFalpha, TNFbeta, HSP70-2 and HSP70-hom genetic polymorphisms were analyzed in 156 unrelated patients who developed mediterranean visceral leishmaniasis (MVL) due to Leishmania infantum, and 154 unrelated healthy controls, who have got asymptomatic infection with this parasite and were selected on the basis of a positive leishmanin skin test (LST). A significantly reduced frequency of HLA-DR2 was observed among MVL patients (16.1%), compared with controls (26.3%) (relative risk = 0.54; p = 0.04). HLA-DR2/DR13 as well as HLA-DQB1*0201/- genotype frequencies were significantly lower in patients vs controls (relapse rate = 0.17 and 0.46, respectively; p < 0.05). However, using Bonferroni correction, none of these associations remained significant. No association was found, between either the -308 base pair TNFalpha gene polymorphism or the NcoI polymorphism in the first intron of the TNFbeta gene and susceptibility to MVL. Analysis of PstI and NcoI polymorphisms in the coding region of HSP70-2 and HSP70-hom genes, respectively, revealed a significantly higher frequency of homozygotes for the HSP70-2/PstI negative allele, among patients (21.8%) vs controls (12.6%) (relapse rate = 1.94; p = 0.04). Again, this result was not significant after using Bonferroni correction. These results do not support association between susceptibility to MVL and the MHC class II and class III loci analyzed in this study.

Animals↗
PubMed1990

Both HLA class II and class III DNA polymorphisms are linked to juvenile rheumatoid arthritis susceptibility.

HLA-DR5 and DRw8 are not significantly linked to juvenile rheumatoid arthritis (JRA) in the Spanish population. However, we have found restriction fragment length polymorphisms (RFLPs) beta DR-2.9-kb-EcoRI and C4-14.3-kb-EcoRI, that correlate significantly with JRA. Eighty-six percent of our patients present either HLA-DR5 or the beta DR-2.9-kb-EcoRI allogenotope or lack the C4-14.3-kb-EcoRI allogenotope compared to 48% in controls; however, these particular DR and C4 RFLPs may not represent the corresponding DRB1 or C4 genes but rather neighboring ones which may be relevant to confer JRA susceptibility. The C4-14.3-kb-EcoRI RFLP decrease in patients may reflect a decrease in C4 B "long" phenotypes. Also, both RFLPs are the only markers able to identify most of the JRA patients in our population. On the other hand, the findings of both class II and III genes associated to JRA may reflect the existence of epistatic interactions (cis or trans) within the HLA gene cluster which lead to a particular pathology in certain diseases.

Arthritis, Juvenile↗
PubMed1991

Techniques used to define human MHC antigens: monoclonals, class I and class II biochemistry.

A variety of straightforward biochemical techniques have been applied to the analysis of HLA molecules. These techniques centre largely on two components: monoclonal antibodies (mAbs) and gel analysis systems. Although only the basic applications are discussed here, the techniques have broad applications. Monoclonal-gel systems may be used for the characterisation of polymorphisms in HLA class I alpha chains or class II alpha and beta chains. This requires the use of mAbs which are locus-specific and monomorphic. Alternatively, B lymphoblastoid cell lines (B-LCL) whose HLA antigen mobilities are known in advance may be used for screening uncharacterised monoclonals for locus specificity.

Alleles↗
PubMedDate not supplied

HLA and H2 class II transgenic mouse models to study susceptibility and protection in autoimmune thyroid disease.

Using single H2 and HLA class II transgenic mice, in the absence of endogenous H2 class II molecules, we have studied the permissiveness of class II molecules for experimental autoimmune thyroiditis (EAT). Resistant strains expressing susceptible class II molecules, H2Ak or HLA-DR3, developed EAT, clearly demonstrating the importance of class II gene inheritance. Polymorphism for HLA-DRB1 was observed, as DR3, but not DR2 or DR4, molecules were permissive for EAT induction with either mouse (m) or human (h) thyroglobulin (Tg). HLA-DQ polymorphism was also detectable, as hTg-induced EAT developed in DQ8+, but not DQ6+, mice. Class II gene interactions leading to reduced EAT severity were observed in H2 transgenic mice, when H2E transgene was expressed in H2A+ mice or H2A molecules were introduced into our novel H2A- E+ transgenic model. Similarly, in DR3+ mice, only the DQ8 transgene reduced EAT severity, depending on both background genes (C57BL/10 or NOD) and Tg species. Based on computer-predicted, class II-binding motifs, potential pathogenic Tg peptides, either unique to hTg (H2A- E+ model) or shared between mTg and hTg (HLA-DR3+ model), were identified. We have also developed a Graves' disease model by immunizing DR3+ mice with TSH receptor DNA. Thus, transgenic models are excellent tools to study human autoimmune thyroid diseases in the context of murine EAT.

Animals↗
PubMed1987

HLA class II DNA analysis by RFLP reveals novel class II polymorphism.

Polymorphism of the HLA-D/DR region has been defined by serologic and cellular methods. Additionally, protein and DNA analyses not only confirmed and refined the definition of the established polymorphisms but also revealed further polymorphisms for which no serologic or cellular correlate are known (yet). To study these in more detail, we analyzed the banding patterns obtained from Southern blot hybridizations with DR beta and DQ alpha cDNA probes. Specific fragments reflecting already defined polymorphisms could be identified. A refined HLA-D/DR definition based upon the presence of DNA subtypes could be introduced. Fragments have also been identified that are associated with the DR/Dw specificities. Moreover, individuals with different DR types may also share fragments in hybridization assays. These shared hybridizing fragments (SHFs) are, for instance, found in individuals typed as DR4, DR5, DR7, and DRw8. In total, 20 SHFs were found using two restriction enzymes and the DR beta and DQ alpha cDNA probes. Some of these SHFs correlate with antigenic determinants defined by broad reacting alloantisera, such as DRw52, but for 14 of these SHFs, no serologic equivalent has been found so far. Thus, SHFs reflect a conservation at the DNA level of the HLA class II region, which suggests that the polymorphic class II genes may be more conserved than previously thought. The possible biologic implications of conserved sequences in the HLA class II genes will be discussed.

Cell Line↗