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V Lepage

Publications and source records attributed to V Lepage.

At least 19 recordsLinked to original sources
PubMed1992

Dose effect of cis- and trans-encoded HLA-DQ alpha beta heterodimers in IDDM susceptibility.

Insulin-dependent diabetes mellitus (IDDM) in whites is strongly associated with particular HLA-DQ alpha beta heterodimers composed of a DQ alpha chain with an arginine at residue 52 (Arg52+) combined to a DQ beta chain lacking an aspartic acid at residue 57 (Asp57-). With the aim of confirming this association, clarifying which heterodimers account for the highest risk of IDDM and explaining the excess risk of DR3-DQw2/DR4-DQw8, 115 unrelated white IDDM patients and 108 unrelated healthy nondiabetic control subjects were studied. With polymerase chain reaction and sequence-specific oligonucleotide probes, both patients and control subjects were typed for their HLA-DQA1 and DQB1 alleles and their DQA1-DQB1 haplotype and genotype frequencies were compared. Four major findings emerged from our analysis. 1) Arg52+ DQ alpha/Asp57- DQ beta heterodimers, formed in cis and/or in trans, are strongly associated with susceptibility to IDDM; 97% of patients and 46% of control subjects had at least one such susceptibility heterodimer (relative risk [RR] 32, confidence interval [Cl] 14.25-71.86, P less than 10(-7). 2) The degree of disease susceptibility depends on the number of such DQ heterodimers that a subject can express according to his or her DQA1-DQB1 genotype. The highest RR was observed in patients with four susceptibility DQ heterodimers (RR 41, Cl 17.05-95.9). 3) Only part of the susceptibility DQ heterodimers were significantly increased in patients, conferring IDDM susceptibility of different strength. The strongest association was with the DQA1*0501-DQB1*0302 combination formed in trans position (RR 35.2, CI 12.88-96.78, P less than 10(-7).(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗
PubMed1991

T-cell antigenic sites involved in myasthenia gravis: correlations with antibody titre and disease severity.

We have evaluated the ability of eight synthetic peptides corresponding to selected regions of the alpha-subunit from human (H) or Torpedo (T) acetylcholine receptor (AChR) to stimulate proliferative responses of peripheral blood lymphocytes (PBL) and thymic cells from patients with Myasthenia Gravis (MG) in comparison to healthy controls. Using PBL, two of the peptides were most reactive: in the 40 myasthenic patients tested, peptide 169-181 (H) induced significant proliferative responses in 10 patients and peptide 351-368 (H) in five, while there was no response in any of the 34 healthy controls tested. Interestingly, clear associations between proliferation to peptides and clinical data were observed. Indeed, among responding patients, all presented thymic hyperplasia and most showed a high anti-AChR Ab titre and/or a severe form of the disease. In addition, responses to AChR cytoplasmic sequences were observed only in severely affected patients. Correlation with HLA-DR haplotype, sought in a subgroup of patients, indicated that response to 169-181 (H) is associated with HLA-DR5 in the patients presenting a high anti-AChR antibody titre. Using thymic lymphocytes, few responses were obtained with the human peptides, suggesting that the frequency of autoreactive cells is lower than in the blood. Similar to PBL, responses to peptides were observed only with lymphocytes isolated from hyperplastic thymuses. The correlations observed between responses to peptides and clinical parameters underline the pathophysiological relevance of our data and indicate that pathogenic and nonpathogenic T-cell antigenic sites involved in the anti-AChR response could be identified by this approach.

Adult↗
PubMed1991

HLA DQB1*0301 allele is involved in the susceptibility to erythema multiforme.

Erythema multiforme (EM) is an acute, episodic inflammatory disorder of the skin and mucous membranes of various etiology that could be related to immunologic hypersensitivity response. EM has been previously reported to be associated with serologically defined HLA-DRw53 and DQw3 antigens. In this report, we reevaluate the role of HLA class II alleles in EM manifestations. With use of the polymerase chain reaction, followed by sequence-specific oligonucleotide hybridization, 35 unrelated Caucasian EM patients and 80 randomly selected healthy subjects were studied, and the DRB3, DRB4, DQA1, and DQB1 alleles were analyzed. The comparison of frequencies of these alleles indicates that (i) susceptibility to EM disease is more associated with the HLA-DQ than the HLA-DR subregions and (ii) that the DQB1*0301 is the most frequent allele among EM patients. Sixty-six percent of the patients had the DQB1*0301 allele compared to 31% of the controls (RR = 4.1; p less than 0.001). An even stronger DQB1*0301 association was found in the patient group with herpes-associated EM (76%; RR = 6.5; p less than 0.001). Our data demonstrate a clear association between an HLA-DQB1 allele and susceptibility to EM.

Adolescent↗
PubMed1990

Linkage of a nasopharyngeal carcinoma susceptibility locus to the HLA region.

The frequency of nasopharyngeal carcinoma is nearly 100-fold higher in southern Chinese than in most European populations. Earlier studies have suggested that an increased risk of nasopharyngeal carcinoma is associated with specific haplotypes in the HLA region: relative risks slightly over twofold were found for haplotypes A2, Bw46 and the antigen B17. We now report a linkage study based on affected sib pairs which suggests that a gene closely linked to the HLA locus confers a greatly increased risk of nasopharyngeal carcinoma. The maximum likelihood estimate is of a relative risk of approximately 21. The relationship between this suspected disease susceptibility gene (or genes) and known viral and environmental aetiological factors remains to be elucidated.

China↗
PubMed1990

A combination of HLA-DQ beta Asp57-negative and HLA DQ alpha Arg52 confers susceptibility to insulin-dependent diabetes mellitus.

Family and population studies indicate that predisposition to insulin-dependent (type I) diabetes mellitus (IDDM) is polygenic. It has been shown that the absence of the aspartic acid in position 57 (Asp57) of the DQ beta chain is positively correlated to IDDM. However, Asp57-negative haplotypes do not always confer susceptibility and conversely, some Asp57-positive haplotypes seem to be disease associated. It has been suggested that other HLA class II sequences, probably belonging to the HLA DQA1 gene, confer susceptibility to IDDM. This report, based on extensive oligonucleotide dot blot hybridization of PCR-amplified DQA1 and DQB1 genes, reinforces the importance of the Asp57-negative DQ beta chain, but also introduces the possibility that a DQ alpha chain bearing an arginine in position 52 (Arg52) confers susceptibility to IDDM. A molecular model of susceptibility to IDDM is proposed. This model strongly suggests that the disease susceptibility correlates quantitatively with the expression at the cell surface of a heterodimer, composed of a DQ alpha-chain bearing an Arg52 and a DQ beta chain lacking an Asp57. In view of the respective positions of the two residues and their charge, we might anticipate that both residues DQ beta Asp57 and DQ alpha Arg52 are critical for modulation of susceptibility, presumably via viral-antigenic peptide and/or autoantigen presentation.

Base Sequence↗
PubMed1990

HLA DQ alpha/beta molecule associated with the susceptibility to insulin-dependent diabetes mellitus. A model for HLA/autoimmune disease association.

We have proposed a molecular model of susceptibility to Insulin-Dependent Diabetes Mellitus (IDDM) based on the proportional expression at the cell surface of the following susceptible (S-S) HLA-DQ heterodimere composed of a chain DQ alpha Arg 52 positive (S) and a chain HLA-DQ beta Asp 57 negative (S). All other DQ alpha/beta chains associations are considered as protective molecules. This model allows a predictive scale of risk for the disease.

Alleles↗
PubMed1990

Typing for HLA DQ using oligonucleotidic probes.

We have typed 25 homozygous B lymphoblastoid cell lines, defined as reference panel during the Xth International Histocompatibility Workshop, using PCR (Polymerase Chain Reaction) and oligonucleotidic probes recognizing sequences of DQA and DQB genes. The polymorphism of 8 HLA-DQA1, and 12 DQB1 alleles is reported and the advantages of this technique are compared to that of other typing methods, currently used.

Cell Line↗
PubMed1989

[HLA class II typing of peripheral blood B lymphocytes separated using monoclonal antibodies].

The different methods proposed for preparation of B lymphocyte suspensions are not always simple, rapid and reliable. Presence of monocytes in the B cell suspension makes difficult HLA-DQ typing. For these reasons we propose a method using monoclonal antibodies (McAb) and complement to lyse the non B cells. Mononuclear cells, isolated from peripheral blood by Ficoll-Hypaque, are suspended in a mixture of anti-CD2, CD3, CD11b (OKM1 recognizing monocytes and granulocytes) McAb. This method of preparation of B cell suspension is rapid and provide better typing reactions than did the suspensions prepared by depletion of sheep red blood cell rosetting cells.

Antibodies, Monoclonal↗
PubMed1989

Definition of a new supertypic HLA class II determinant (LAR) associated with HLA-DR2 and -DR7.

A serum from a patient (LAR), immunized by pregnancies and blood transfusions, reacted with cells carrying HLA-DR2 and/or -DR7 specificities (titer 1:200-1:1000). Absorption-elution experiments showed that the allo-serum recognized a determinant shared by DR2 and DR7 cells. The high correlation coefficients (0.90-1) with these specificities suggested that the supertypic specificity LAR was carried by the first DR molecule encoded by DRB1 gene. LAR is another example of new supertypic specificities, reflecting structural homologies between alleles at HLA class II loci.

Epitopes↗
PubMed1989

HLA typing with monoclonal antibodies: evaluation of 356 HLA monoclonal antibodies including 181 studied during the 10th International Histocompatibility Workshop.

During the 10th International Histocompatibility Workshop (10th WS), 181 HLA MoAbs were studied using lymphocytotoxicity micro-technique (LCT) and/or enzyme immuno-assay (EIA), and their capacity to serve as typing reagents was evaluated. 129 MoAbs were tested by both techniques. Results obtained with 92 class I and 86 class II polymorphic MoAbs (10th WS) were compared to published data concerning 180 class I and 176 class II polymorphic MoAbs, listed in an HLA-MoAbs Register maintained in our laboratory. The following conclusions can be proposed: 1/HLA-A, B typing by LCT with MoAbs is possible for about 14 specificities. Some specificities are clearly recognized (HLA-A3, B8, B13, Bw4, Bw6), others are recognized as cross-reacting groups (B7+27+w22+40), others are not currently recognized by any MoAb with restricted specificity (B5, B15). Several MoAbs confirmed the existence of shared epitopes between products from a single locus (A2-A28, A25-A32), or from A and B loci (A2-B17, Bw4-A9-A32). A single HLA-Cw MoAb has been described. 2/HLA class II typing by LCT with MoAbs is more difficult than class I typing. DR2, DR3, DR4, DR5 and DR7 as well as DRw52 and DRw53 are well defined; other DR specificities are poorly or not at all defined. Particular associations (DR1+DR4, DR3+DRw6, all DR except DR7) are recognized by several MoAbs. All DQw specificities are well recognized, including new specificities defined only by MoAbs: WA (DQw4), TA10 (DQw7), 2B3 (DQw6+w8+w9). Only two HLA-DP MoAbs have been described. 3/Satisfactory results, similar to those of LCT, were obtained with EIA using lymphoid cell lines as targets. 4/Human MoAbs (12 in the Register) are satisfactory typing reagents. They could represent in the future a significant contribution to HLA typing with MoAbs.

Antibodies, Monoclonal↗
PubMed1988

Erythema multiforme is associated to HLA-Aw33 and DRw53.

Erythema multiforme is an acute eruption of the skin and mucous membranes of various aetiologies. Forty-one unrelated patients were HLA typed for 53 specificities of the HLA-A, B, C, DR and DQ series. Frequencies of Aw33 and DRw53 were significantly increased: Aw33, 17.0% in patients vs 2.8% in controls (corrected p = 0.01, relative risk = 7.2); DRw53, 70.7% in patients vs 30.5% in controls (corrected p = 0.0005, relative risk = 5.5).

Adult↗
PubMed1986

Biochemistry of HLA-DRw6: evidence for seven distinct haplotypes.

The DRw6 specificity, which has a frequency of 11% in the Caucasian population, cannot be positively defined, since no monospecific allo-antiserum is available. This particular status among DR specificities led us to study the DRw6 haplotypes at the molecular level. We performed 2D-PAGE analysis of HLA-DR molecules in 44 different DRw6 haplotypes. The data were obtained from six homozygous typing cells, eight families informative for the segregation of the DRw6 haplotype, and 15 unrelated donors. Five unique beta-chain electrophoretic patterns were detected, indicating the existence of five structurally distinct DRw6 beta-chains. Each haplotype expresses one or two beta-chains. The different combinations of the DR beta-chains present in a single haplotype allow to characterize seven unique DRw6 haplotypes. In contrast to what has been previously found for DR2 and DR4, there is no DR beta-chain common to all the DRw6 cells. Correlation of the biochemical data with the recent serologic (DRw13 vs DRw14) and cellular (Dw9, Dw18, Dw19) splits of the DRw6 specificity will be discussed.

Antibodies, Monoclonal↗