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Results for “HLA polymorphism”

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PubMed1995

Effect of genetic risk load defined by HLA-DQB1 polymorphism on clinical characteristics of IDDM in children.

Clinical and autoimmune characteristics of 150 diabetic children of mean age 7.8 years (SD 4.1 years) were recorded at clinical manifestation and during the first 2 years of IDDM in order to investigate whether subjects with high risk HLA-DQB1 genotypes differ from those without these risk markers. When comparing subjects with the DQB1*0302/0201, DQB1*0302/x, DQB1*0201/x, or other DQB1 genotypes (x = no protective allele), no differences were found in the age of the subjects at diagnosis, the duration of hyperglycaemic symptoms, or the length of clinical remission. The frequency of islet cell antibodies (ICA) and quantitative serum levels of these antibodies were of the same magnitude in all four groups. During the initial 2 years of IDDM serum C-peptide concentrations were observed to be inversely related to the degree of genetic risk (P < 0.001 in two-way analysis of variance for repeated measures), the lowest C-peptide levels being observed in the group of DQB1*0302/0201 heterozygotes (P < 0.001 vs. DQB1*0201/x; P < 0.01 vs. DQB1*0302/x; P = 0.05 vs. others). On the other hand, the subjects with the DQB1*0201 genotype had the highest serum C-peptide concentrations, the levels being even higher than those of the patients carrying neutral or protective DQB1 genotypes (P < 0.01). These subjects also had lower daily insulin doses and blood glycated haemoglobin A1 (HbA1) levels over the initial 2 years of the disease when compared with the DQB1*0302/0201 heterozygotes (P < 0.05 and P < 0.01, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1997

T cell recognition of human pre-proinsulin peptides depends on the polymorphism at HLA DQ locus: a study using HLA DQ8 and DQ6 transgenic mice.

HLA DQ8 (DQ A1*0301/DQB1*0302) molecule is implicated in the susceptibility to insulin dependent diabetes mellitus whereas, HLA DQ6 (DQ A1*0103/DQB1*0601) molecule may have a protective effect. In this study we used mice transgenic to HLA DQ8 and HLA-DQ6 to elucidate the T cell determinants on a putative islet cell target antigen, insulin. These mice do not express endogenous mouse class II heterodimers on cell surface. Using overlapping synthetic peptides spanning the complete sequence of huma pre-proinsulin, we identified the sequences recognized by T cells in DQ8 transgenic mice and compared these to those in DQ6 transgenic mice. We observed a differential pattern of recognition of epitopes on human pre-proinsulin (HPI) polypeptide presented by the HLA DQ8 allele as compared to HLA DQ6. The sequences 1-24 and 44-63 were immunodominant in DQ8 transgenic mice while DQ6 transgenic mice primarily recognized sequences 14-33 and 74-93 of HPI. We found that the immune response generated in HLA DQ8 transgenic mice against HPI 1-24 cross-reacted to the mouse pre-proinsulin sequence 1-24. The T cell response were specifically inhibited using anti-CD4 and anti-DQ8 monoclonal antibodies. This cross-recognition of self sequences raises the possibility of modulation of experimental diabetes using this peptide.

Amino Acid Sequence↗
PubMed2003

Analysis of the French National Registry of unrelated bone marrow donors, using surnames as a tool for improving geographical localisation of HLA haplotypes.

The first statistical analysis of the French National Registry of volunteer bone marrow donors estimated the probabilities of haplotype frequencies separately for each of the 20 administrative regions of France. Here we propose to use donors' surnames to increase the accuracy of location of the donor's geographical origin. This approach allows us to estimate haplotype frequencies for administrative entities (90 departments) smaller than regions and to correct for bias resulting from recent mobility. We analysed 30,777 donors typed for HLA-A,B and 17,745 donors typed for HLA-A,B,DR,DQ. By using the donors' surnames, we identified common and rare haplotypes (those found in only one department) and estimated the degree of HLA polymorphism at the department level. We also identified departments with a distinctive genetic structure (for example, Paris, Corsica, Pyrenees and Meurthe-et-Moselle). By providing a more accurate geographical distribution of HLA polymorphisms in France, this study will enable us to optimise policies for recruiting bone marrow donors and to improve the fit between the donor file and patients' needs.

Algorithms↗
PubMed1996

HLA-DPB polymorphisms: Glu 69 association with sarcoidosis.

Sarcoidosis is a chronic granulomatous disorder, which is characterized by the accumulation of activated CD4+ T lymphocytes (T cells) at disease sites. There is up-regulation of cell surface expression of MHC molecules in sarcoidosis, and it has been suggested that specific MHC class II alleles are associated with the disease. A study of chronic beryllium disease (CBD), a granulomatous disorder which is pathologically similar to sarcoidosis, has identified an association between this disease and the presence of a glutamine residue at position 69 (Glu 69+) of the B1 chain of the HLA-DPB molecule. A further study also suggested the importance of Glu at position 55 of the same chain. The aims of the present study were to attempt to define MHC class II alleles associated with sarcoidosis by comparison of their frequency in two groups of subjects and to compare the frequency of HLA-DPB1 Glu 69+/- and Glu 55+/-alleles in the same subjects. Forty-one subjects with sarcoidosis and 76 normal subjects were studied. The polymorphic regions of the class II MHC were identified by PCR in association with sequence-specific oligonucleotide probes. There were no significant differences in the phenotype frequencies of MHC class II or Glu 55+ alleles between the two groups of subjects. However, there was a significant increase (P = 0.02) in the frequency of HLA-DPB1* Glu 69+ alleles compared with the control population. We therefore suggest that the presence of a Glu residue at position 69 on the DPB1 chain may play an important role in antigen presentation and recognition in chronic granulomatous diseases.

Alleles↗
PubMed1987

Changes in HLA A, B, C expression during "spontaneous" transformation of human urothelial cells in vivo.

The immortalized but non-tumourigenic and non-invasive human urothelial cell line, Hu 609, known to express the appropriate HLA A,B antigens (A2,-; B5,-) has previously been demonstrated to undergo "spontaneous" in vitro transformation into an invasive and tumourigenic subline, Hu 609T/MV. This subline does not express the polymorphic HLA epitopes. In the present investigation we have followed two additional "spontaneous" transformations of the Hu 609 cell line into malignant sublines. Evidence is presented that the development of morphological changes and tumourigenicity were accompanied by a gradual loss of the expression of polymorphic HLA A,B epitopes and a reduction in the expression of monomorphic HLA A,B,C antigens. Antigens could be detected again after neuraminidase treatment. We conclude that the urothelial Hu 609 cell line after "spontaneous" transformation still possesses the HLA A,B epitopes. The observed quantitative differences in HLA expression between Hu 609 and its malignant sublines may be due to masking of the HLA antigens by sialic acid containing tumour-associated highly branched glycoproteins.

Antigen-Antibody Reactions↗
PubMed2006

Analysis of HLA alleles polymorphism in Chinese patients with primary biliary cirrhosis.

BACKGROUND: A familial clustering of patients with primary biliary cirrhosis (PBC) and the presence of immunological abnormalities in family members suggest a genetic component involved in the pathogenesis of PBC. The aims of this study are to investigate the frequencies of human leukocyte antigen HLA-A, -B, and -DRB1 alleles in Chinese patients with PBC by polymerase chain reaction (PCR)-based techniques, and to assess the correlation of the above-mentioned HLA with some clinical and laboratory features. METHODS: Genotyping of HLA alleles were performed in 65 well-characterized PBC patients and 431 healthy controls with sequence-specific primers PCR amplification. RESULTS: HLA-DRB1*07 allele detected in 19 of the 65 (29.2%) PBC patients was subtyped as DRB1*0701, as well as in 13.9% of controls (PC<0.05, OR=2.55, 95%CI: 1.4-4.6). An increased frequency of DRB1*03 (18.4% vs. 7.2% in healthy controls) and a decreased frequency of DRB1*12 (16.9% vs. 28.8%) in PBC patients were statistically significant. There was no association with HLA-DRB1*08 reported. The frequencies for HLA-A, B and the other DRB1 alleles were similar between patients and healthy controls. CONCLUSIONS: The susceptibility to PBC in Chinese individuals is associated with DRB1*0701 allele. This association differs from that in North Americans, South Americans, North Europeans and even Japanese, but it is not restricted to any particular subgroup of patients.

Adult↗
PubMed1986

Molecular localization and polymorphism of HLA class II restriction determinants defined by Mycobacterium leprae-reactive helper T cell clones from leprosy patients.

MHC class II molecules carry the restriction determinants (RDs) for antigen presentation to antigen-specific Th lymphocytes. This restriction of T cell activation endows those molecules with a key role in the induction and regulation of antigen-specific immune responses. Moreover, class II molecules are the products of class II immune response (Ir) genes. The polymorphism of these Ir genes leads to genetically controlled differences in immuneresponsiveness between different individuals. An important human example is leprosy, in which HLA class II-linked Ir genes determine the immune response against Mycobacterium leprae, the causative organism of the disease. Since the immune response against M. leprae is entirely dependent on Th cells, the HLA class II-linked Ir gene products may well regulate the immune response by controlling the presentation of M. leprae antigens to Th cells. We therefore have investigated the HLA class II RD repertoire of M. leprae-reactive Th cell clones (TLC) by means of extensive panel and inhibition studies with fully class II-typed allogeneic APCs and well-defined HLA class II-specific mAbs. The TLC studied (n, 36) proliferated specifically towards M. leprae, produced IFN-gamma upon activation, and had the CD3+CD4+CD8- phenotype. The results show in the first place that the majority of the RDs for M. leprae reside on DR and not on DP or DQ molecules. This indicates a major role for DR molecules in the immune response to M. leprae and suggests that these molecules are the main products of M. leprae-specific Ir genes. Furthermore, since the expression of DR molecules is much stronger than that of DP and DQ molecules, these findings suggest that the localization of RDs for M. leprae on class II molecules correlates with the quantitative expression of these molecules. The observation that the RDs on DR molecules coded by a DR4 haplotype were situated only on those DR molecules that are known to be highest in expression can be explained in the same way. Second, four distinct RDs related with but not identical to the Dw13 allodeterminant were carried by the DR+DRw53- (alpha beta 1) molecules of a DR4Dw13 haplotype. Since the known amino acid residue differences between the allelic DR4 related Dw beta 1 chains cannot explain the observed RD-polymorphism, this observation suggests that multiple distinct RDs unique for the DR4Dw13 haplotype are expressed by these molecules. Only 2 of 36 TLC were not restricted by DR.(ABSTRACT TRUNCATED AT 400 WORDS)

Antibodies, Monoclonal↗
PubMed2000

HLA-DQ polymorphism and degree of heteroplasmy of the A3243G mitochondrial DNA mutation in maternally inherited diabetes and deafness.

AIM: Maternally inherited diabetes and deafness (MIDD) associates with a mutation at position 3243 in mitochondrial DNA. Phenotypic expression of MIDD includes Type 1-like and Type 2-like diabetes. This study examined whether HLA-DQ phenotype and the degree of heteroplasmy in leucocyte and oral mucosa DNA influence clinical expression of the 3242 mutation. METHODS: In a group of 20 unrelated probands with MIDD, eight with Type 1- like diabetes, 12 with Type 2-like diabetes, HLA-DQ type and degree of heteroplasmy for the 3243 mutation were determined. HLA-DQA1/DQB1 phenotypes were categorized as predisposing, neutral or protective for autoimmune-mediated Type 1 diabetes. RESULTS: No differences were observed between Type 1 and Type 2-like MIDD groups with respect to the cumulative frequency of protective and predisposing HLA-DQ types. Predisposing HLA-DQ types are more prevalent in MIDD patients than in the control population (P < 0.05). Degrees of heteroplasmy for the 3243 mutation showed large variations in patients, ranging from 1 to 52% in leucocyte DNA. A strong correlation was seen between heteroplasmy in leucocyte DNA and DNA from oral mucosa cells (r = 0.89, P < 0.001). No correlation was observed between the degree of heteroplasmy and diabetic phenotype, even when group size was extended with diabetic relatives of patients with MIDD. The age of diagnosis of diabetes was not correlated with heteroplasmy, but the degree of heteroplasmy tended to decrease with age. CONCLUSIONS: The phenotype of diabetes in MIDD appears to be independent of HLA-DQ phenotype and degree of heteroplasmy in leucocyte and oral mucosa DNA indicating that other, as yet unknown, factors modulate clinical expression of the 3243 mutation.

Adolescent↗
PubMed1989

A novel T-cell-defined HLA-DR polymorphism not predicted from the linear amino acid sequence.

Recent investigations have shown that alloreactive T cells are capable of responding to structures defined by specific linear amino acid sequences on class II molecules. In the present study we show that also a polymorphism can be recognized that is not defined by such linear amino acid sequences. Two human T-cell clones, sensitized to DRw13 haplotypes, are described. The description of clone c50 serves to exemplify the first model. This DRB1-specific clone responds to stimulator cells that carry DR molecules, different in their DRB1 first and second hypervariable regions (HV1 and HV2) but identical in their HV3 regions (i.e., DRw13,Dw18; DRw13,Dw19; DR4,Dw10; and DRw11,LDVII). The second clone, c1443, behaves nonconventionally. It responds to DRw13,Dw18; DRw13,Dw19; and DR4,Dw4 stimulator cells, although no specific amino acid sequence is shared between these specificities. The latter pattern of reactivity suggests the existence of a novel polymorphism recognized by alloreactive T cells. This particular polymorphism may also be biologically significant.

Amino Acid Sequence↗
PubMed1980

Restriction and persistence of polymorphisms of HLA and other blood genetic traits in the Parakanã Indians of Brazil.

Results concerning HLA types and 22 other blood genetic systems are reported for the Parakanã Indians of northern Brazil, a tribe that is notable for the light color and pilosity of some of its members. No clear evidence of Caucasoid admixture was found, but the Parakanã show unusual frequencies in the EsD1, PGM1(1) Gc2, CpB, Fya, Dia, and LM genetic markers. In addition, the very rare Rh allele ry is present, as well as what seems to be a new PGM2 variant. There is very limited heterogeneity in the HLA system. All these distinctive features may have arisen through a combination of founder effects and genetic drift. However, low FIS values, as well as higher mean ages in heterozygous as compared to homozygous persons, suggest that an heterotic effect is counteracting these dispersive forces.

Adolescent↗