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D Charron

Publications and source records attributed to D Charron.

At least 37 records · Page 2Linked to original sources
PubMed2002

Epistasis between DSG1 and HLA class II genes in pemphigus foliaceus.

Pemphigus foliaceus (PF) is a rare and severe cutaneous autoimmune disease caused by autoantibodies directed against desmoglein 1 (DSG1), a desmosomal adhesion glycoprotein. We previously showed that the DSG1 gene is polymorphic and that a coding synonymous T/C single nucleotide polymorphism at position 809 is associated with PF. To determine whether the disease occurred as a consequence of complex genetic interactions, we simultaneously examined the contribution of major histocompatibility complex (MHC) class II and DSG1 polymorphisms to PF susceptibility. Our analysis performed in 31 PF patients and 84 healthy controls first confirmed the previously reported common DRB1*04 and DRB1*14 genetic background in PF and individualized DRB1*0102, DRB1*0402 and DRB1*0406, and DRB1*1404 as susceptibility MHC class II alleles in French Caucasian PF patients. It also showed that the C/C(809) genotype was associated with PF. Combined analysis of HLA class II and DSG1 polymorphisms with several distinct statistical methods including logistic regression, showed that the DRB1*04 allele and the C/C(809) genotype interact to confer a higher susceptibility to PF. These data demonstrate the role of epistasis between individual genes in PF susceptibility and illustrate the genetic complexity of organ-specific autoimmune diseases.

Autoantigens↗
PubMed2002

The role of HLA genes in familial spondyloarthropathy: a comprehensive study of 70 multiplex families.

OBJECTIVES: To investigate whether HLA alleles, other than HLA-B27, influence predisposition to spondyloarthropathy (SpA) in multiplex families. METHODS: Seventy French families with at least two affected SpA members were recruited. Patients, and their first degree relatives were typed for HLA-A, B, C, and DR, and extended HLA haplotypes were determined. The distribution of HLA-A, C, and DR alleles carried on HLA-B27+ haplotypes in SpA families was compared with the distribution of these alleles among HLA-B27+ haplotypes in the French general population. Contribution to SpA susceptibility of HLA-A, B, C, and DR alleles, other than HLA-B27, was tested by transmission disequilibrium test. The contribution of HLA alleles to specific presentation features of SpA was examined. RESULTS: Frequencies of HLA-A, C, and DR alleles carried on HLA-B27+ haplotypes from SpA families were comparable with those seen in the French population, except for DR13 which was overrepresented among patients (pcorr<0.001). Most interestingly, the HLA-DR4 allele was transmitted in excess to patients with SpA, independently of linkage to HLA-B27 (pcorr=0.05), and in a direction opposite to that for HLA-B27+ unaffected siblings (pcorr=0.01). Finally, the distribution of HLA alleles was not related to the presentation feature of SpA. CONCLUSION: HLA predisposition to familial SpA appears not to be limited to HLA-B27, but some HLA-DR alleles also have a significant influence. In particular, HLA-DR4 contributes significantly to a genetic predisposition to SpA, which may have implications in our understanding of SpA pathogenesis.

Adult↗
PubMed2001

Both genetic and clinical factors predict the development of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Graft-versus-host disease is the main complication of hematopoietic stem cell transplantation. Recently, pro- and anti-inflammatory cytokines and mismatches of minor histocompatibility antigens between HLA-identical sibling donor/recipient pairs have been implicated in the development of acute graft-versus-host disease. It is not known, however, whether these factors are independent of other clinically recognized risk factors such as age and disease stage. METHODS: In this study, we searched for risk factors of acute graft-versus-host disease using multivariate Cox regression analysis in 100 consecutive patients who underwent allogeneic stem cell transplantation from an HLA-identical sibling donor. Eight polymorphisms from five different cytokine genes were studied (tumor necrosis factor alpha, tumor necrosis factor beta, interleukin (IL) 6, IL-10, and interferon gamma). Mismatches for the minor histocompatibility antigen HA-1 were searched in HLA-A*0201 individuals. In addition to these new risk factors, patient, donor, disease, and transplant risk factors were analyzed by multivariate analysis using the Cox proportional hazards model. RESULTS: Acute graft-versus-host disease was independently associated with IL-10 gene polymorphisms both from the recipient (relative risk=7.9, P<0.0001) and the donor (relative risk=3.5, P=0.02), a donor's positive serology for cytomegalovirus, and HA-1 mismatches in HLA-A*0201 individuals (relative risk=2.8, P=0.05). Chronic graft-versus-host disease was independently associated with IL-6 gene polymorphism from the recipient (relative risk=4.2, P=0.02), older age (relative risk=2.5, P=0.0009), and previous acute graft-versus-host disease (relative risk=9.7, P=0.003). CONCLUSION: In addition to previously described clinical risk factors, genetic risk factors are independently associated with the risk of developing graft-versus-host disease and may, thus, be considered for the selection of the donor.

Adolescent↗
PubMed2001

Mutation in the class II trans-activator leading to a mild immunodeficiency.

The expression of MHC class II molecules is essential for all Ag-dependent immune functions and is regulated at the transcriptional level. Four trans-acting proteins control the coordinate expression of MHC class II molecules: class II trans-activator (CIITA), regulatory factor binding to the X box (RFX)-associated protein; RFX protein containing ankyrin repeats, and RFX5. In humans, defects in these genes result in MHC class II expression deficiency and cause combined immunodeficiency. Most patients with this deficiency suffer from severe recurrent infections that frequently lead to death during early childhood. We investigated three sisters, now ages 21, 22, and 24 years, in whom MHC-II deficiency was detected. Even though the eldest sibling was asymptomatic and the other two had only mild immunodeficiency, none of the three class II isotypes was expressed on T cell blasts, fibroblasts, EBV B cell lines, or epidermal dendritic cells. Residual HLA-II expression was detected in fresh PBMC. Somatic complementation identified the disease as CIITA deficiency. A homozygous T1524C (L469P) substitution was found in the coding region of the CIITA cDNA and was shown to be responsible for the defect in MHC-II expression. This missense mutation prevents the normal functioning of MHC-II but does not lead to the nuclear exclusion of the L469P CIITA. Transfection experiments demonstrated that the CIITA L469P mutant had residual MHC class II trans activation activity, which might explain the unusual clinical course of the patients studied. This study shows that an attenuated clinical phenotype or an asymptomatic clinical course can be observed in patients despite a profound defect in the expression of MHC class II genes. The frequency of the inherited MHC class II deficiency might thus be underestimated.

Adolescent↗
PubMed2001

Constitutive expression of MHC class II genes in melanoma cell lines results from the transcription of class II transactivator abnormally initiated from its B cell-specific promoter.

In melanoma cell lines, two different patterns of MHC class II expression have been described, either an IFN gamma-inducible expression of HLA-DR and HLA-DP, with a faint or null expression of HLA-DQ, resembling that described for melanocytes, or a constitutive expression, i.e., IFN-gamma independent, of all three HLA-D isotypes. As this latter phenotype has been associated with a more rapid progression of melanoma tumors, we have analyzed in different melanoma cell lines the molecular mechanisms leading to this abnormal pattern of MHC class II expression. In agreement with the evidence of a coordinate transcription of the HLA-D genes in these cell lines, we have shown the constitutive expression of CIITA (class II transactivator) transcripts, CIITA being known as the master switch of MHC class II expression. Unexpectedly, these transcripts initiate from promoter III of the CIITA gene, a promoter that is mainly used constitutively in B lymphocytes. This expression was further shown to occur through factor(s) acting on the enhancer located upstream of CIITA promoter III, which was previously described in epithelioid cells as an IFN-gamma-response sequence. The hypothesis of a general abnormality of the IFN-gamma transduction pathway was dismissed. Constitutive transcription of CIITA from promoter III having been observed in unrelated melanoma cell lines, we propose the hypothesis that this phenomenon might not be a random event, but could be linked to the neoplasic state of the melanoma cells.

5' Untranslated Regions↗
PubMed2001

Immune recovery under highly active antiretroviral therapy is associated with restoration of lymphocyte proliferation and interferon-gamma production in the presence of Toxoplasma gondii antigens.

The in vitro lymphocyte proliferative response (LPR) and interferon (IFN)-gamma production in the presence of Toxoplasma antigen were evaluated in 97 human immunodeficiency virus (HIV)-1-infected patients with CD4 cell counts of <100 cells/microL (group 1), currently >300 cells/microL but previously <100 cells/microL (group 2), or always >300 cells/microL (group 3) and in 28 non-HIV-infected blood donors (group 4), all seropositive to Toxoplasma. In group 2, 81% of patients had a positive LPR, versus 20% in group 1 (P<10(-3)). IFN-gamma production was greater in group 2 than in group 1 (922 vs. 0 Deltapg/mL; P=10(-4)). Multivariate analysis found a significant association between a positive LPR to Toxoplasma antigen and a CD4 count >300 cells/microL (odds ratio [OR], 16.3; 95% confidence interval [CI], 5.3-50.2) and anti-Toxoplasma IgG titer >150 IU/mL (OR, 5; 95% CI, 1.6-15.2). Immune reconstitution under highly active antiretroviral therapy was associated with a restoration of immune responses against Toxoplasma.

Adult↗
PubMed2001

Uncoordinated HLA-D gene expression in a RFXANK-defective patient with MHC class II deficiency.

We describe the analysis of a patient, JER, presenting classical immunological features of MHC class II deficiency. Unexpectedly, some HLA transcripts (HLA-DRA, HLA-DQA, and HLA-DMA) were found to be expressed in the JER cell line at nearly wild-type levels, while HLA-DPA and the HLA-D beta-chain transcripts were not detected. Gene reporter experiments confirmed the differential transcriptional activities driven by the HLA-D promoters in the JER cells. A defect in RFXANK was first suggested by genetic complementation analyses, then assessed with the demonstration of a homozygous mutation affecting a splice donor site downstream exon 4 of RFXANK. Because the severe deletion of the resulting protein cannot account for the expression of certain HLA-D genes, minor alternative transcripts of the RFXANK gene were analyzed. We thereby showed the existence of a transcript lacking exon 4, encoding a 28-aa-deleted protein that retains a transcriptional activity. Altogether, we characterize a new type of mutation in the RFXANK gene in a MHC class II-defective patient leading to an uncoordinated expression of the HLA-D genes, and propose that this phenotype is ensured by severely limited amounts of an active, although truncated RFXANK protein.

Alternative Splicing↗
PubMed2001

Interleukin 1 gene cluster polymorphisms in multiplex families with spondylarthropathies.

Interleukin 1alpha (IL-1alpha) has been implicated in the pathogenesis of infectious, auto-immune and inflammatory diseases. Polymorphisms in the genes encoding IL-1alpha, IL-1beta and the IL-1 receptor antagonist (ILRN) molecules have been associated with several inflammatory diseases. As the marker D2S160 has been characterized as a candidate locus for Ankylosing Spondylitis (AS) after a genome-wide scan, and since this locus is located approximately 0.3 cM telomeric to the IL-1 gene cluster, we hypothesized that these cytokines might be good candidates for Spondylarthropathies (SpA). Therefore we tested this hypothesis using the transmission disequilibrium test (TDT) in 37 families representing 217 subjects from three intragenic IL-1 gene cluster polymorphisms, the IL1B Taq I, the ILRN 2nd intron, and the IL1A Nco I, taking HLA B27 status into account or not. In conclusion, by means of intra-familial TDT analysis we found no linkage or intra-familial association between SpA and the three IL-1 gene-cluster polymorphisms in SpA multiplex family material.

Adult↗
PubMed2001

Complementarity and redundancy of the binding specificity of HLA-DRB1, -DRB3, -DRB4 and -DRB5 molecules.

The second HLA-DR molecules, which are encoded by loci different from HLA-DRB1 are weakly polymorphic. Predominant alleles such as HLA-DRB3*0101, HLA-DRB4*0101 and HLA-DRB5*0101 are therefore interesting targets to define antigenic peptides with major impact for the entire population. Strikingly, they have been poorly investigated. Thus we have characterized peptides from the major bee venom allergen that bind efficiently to these molecules and compared them to peptides specific for preponderant HLA-DRB1 molecules. Interestingly, DRB5*0101 and DRB1*0701 molecules share four binding peptides and use some identical anchor residues. Similarities are also found between DRB3*0101 and its haplotype-associated molecules DRB1*0301 and DRB1*1301. In sharp contrast, DRB4*0101 exhibits a unique binding specificity, which results from particular structural features of its peptide binding site. Ybeta81 seems to alter the amino acid preferences of the P1 pocket, while Rbeta71, Ebeta74, Nbeta26 and Cbeta13 confer to the P4 pocket a unique topology. Our results show that the two HLA-DR molecules expressed in most haplotypes studied here have mostly complementary binding patterns. Only haplotype HLA-DR52 exhibits peptide binding redundancies. Finally our results document functional similarities among HLA-DR molecules and allow us to propose peptide sequences that might be useful for bee venom immunotherapy.

Alleles↗
PubMed2001

HLA-DR mediated cell death is associated with, but not induced by TNF-alpha secretion in APC.

Tumor necrosis factor alpha (TNFalpha) is a pleiotropic cytokine involved in inflammatory responses which can trigger both cell apoptosis and cell activation. In antigen presenting cells (APC), TNFalpha increased antigen presentation, notably by up-regulation of HLA class II expression. In addition to their role in antigen presentation, HLA-DR molecules transduce intracellular signals which lead to cytokine up-regulation or cell death. We have previously observed that the susceptibility of APC to HLA-DR mediated apoptosis increase throughout their maturation. We therefore investigated the relationship between TNFalpha production and susceptibility to HLA-DR-mediated apoptosis of different APC. The hematopoietic progenitor cell line (KG1), monocytic cell line (THP-1), monocyte-derived dendritic cell (DC), and B-lymphoid cell line (Raji) have been studied. We report that apoptosis susceptibility and spontaneous TNFalpha release are correlated in these different cells. However, while autocrine TNFalpha production was critical for DC maturation, upregulation of TNFalpha release after HLA-DR crosslinking was not observed and neutralization of endogenous TNFalpha did not modify HLA-DR-mediated apoptosis. These data reveal that HLA-DR mediated apoptosis susceptibility and spontaneous TNFalpha release are regulated in a parallel manner and that while TNFalpha may induce maturation of APC to an "apoptosis sensitive" stage, there is no direct role for TNFalpha in HLA-DR-mediated apoptosis of APC.

Antigen-Presenting Cells↗
PubMed2001

Immune reconstitution after hematopoietic stem cell transplantation: gaining experience without losing naivety.

In addition to lymphocyte phenotyping and functional assays, new tools are now available to monitor specific aspects of the immune response in the follow-up of hematopoietic stem cell transplantation: reconstitution of T-cell diversity (spectratyping or immunoscope), ex vivo thymic function by measuring "T-cell receptor rearrangement excision DNA circles" and antigen-specific T-cell responses (HLA tetramers). Combining these methods should contribute to improve our current knowledge of how the immune system is reconstituted in different settings of hematopoietic stem cell transplantation and how we could improve this recovery process.

Antigens↗
PubMed2001

HLA class I and class II are both associated with the genetic predisposition to primary Sjögren syndrome.

Primary Sjögren syndrome (pSS) is an autoimmune disease characterized by progressive destruction of the exocrine glands leading to mucosal and conjunctival dryness. It is marked by lymphocytic infiltration of the glands and the accumulation of several types of autoantibodies such as rheumatoid factor (RF), antinuclear, anti-SS-A (anti-Ro) and anti-SS-B (anti-LA) autoantibodies. The susceptibility to pSS and/or the presence of SS-A/SS-B autoantibodies in pSS patients is associated with DRB1*03-DQB1*02 and DRB1*02-DQB1*06 haplotypes, whereas no associations have been described with any HLA class I allele. To define the impact of HLA class I alleles in predisposition to pSS, 46 patients responding to the European criteria and 222 healthy unrelated Caucasians were analyzed for their HLA class I and class II haplotypes. Our results confirm the association of the DRB1*03-DQB1*02 haplotype with SS-A/SS-B autoantibodies positive pSS and demonstrate a significant association of the HLA-A24 with the disease. Moreover, HLA-A24 is more often associated with DRB1*11-DQB1*0301 and/or DRB1*0301-DQB1*02 in pSS patients than in the controls. The novel association of HLA class I alleles with susceptibility to pSS provides new insights to the genetic predisposition to this disease and subsequently to its physiopathology.

Adult↗
PubMed2001

Influence of bone marrow graft lymphocyte subsets on outcome after HLA-identical sibling transplants.

OBJECTIVE: The aim of this study was to analyze bone marrow lymphocyte subsets and CD34 cell dose and their influence on the outcomes of bone marrow transplantation. MATERIALS AND METHODS: Forty-eight patients (median age 30 years, range 5-54) receiving HLA-identical sibling bone marrow transplantation for hematologic malignancies were analyzed. RESULTS: Median number (range) of nucleated cells and CD34+ cells infused were 2.4 (0.4-6.0) x 10(8)/kg and 3.5 (0.5-13.0) x 10(6)/kg, respectively. Probability of neutrophil recovery was 97%. In a multivariate analysis, time to neutrophil recovery was shortened when a higher number of CD3/CD8 cells was infused (> or =1.0 x 10(7)/kg) (hazard ratio [HR] = 2.13, p = 0.018); when the patient was female or had negative cytomegalovirus serology (HR = 2.03, p = 0.03; HR = 0.41, p = 0.009; respectively). The incidence of grade II to IV acute graft-vs-host disease (GVHD) was 47%. Infusion of >1 x 10(7) CD4 infused/kg increased the risk of acute GVHD (HR = 2.86, p = 0.03). Nineteen of 40 patients at risk experienced chronic GVHD, the risk of which was increased by diagnosis of chronic leukemia (p = 0.03), <2.0 x 10(8) nucleated cells infused/kg (p = 0.05), and a low number of all lymphocyte subsets, except CD19. Estimated 3-year survival rate was 54%. Risk of death was increased in patients receiving <3.5 x 10(6)CD34 infused/kg (HR = 0.37, p = 0.02). Only six patients relapsed. CONCLUSIONS: A high cell dose of CD3/CD8 is associated with faster neutrophil recovery, whereas a high cell dose of CD4+ cells increases the incidence of acute GVHD. A high number of nucleated cells and CD34+ cells infused was associated with decreased risk of chronic GVHD and improved survival, respectively.

Acute Disease↗
PubMed2001

Genomic diversity of natural killer cell receptor genes in three populations.

We report the distribution of genes encoding 11 killer cell immunoglobulin-like receptors (KIR) and 2 CD94:NKG2 receptors, in 32 Caucasians, 67 Australian Aborigines and 59 Vietnamese. The inhibitory and the activating KIR genes were found at different frequency in the three populations. No correlation was found between the polymorphism of the KIR genes and the HLA specificities of the tested samples. The most significant KIR associations were 2DL2 with 2DS2; 2DL2 with 2DS3 and 3DL1 with 2DS4 in all three study groups. In Caucasians and Vietnamese 2DS2 was associated with 2DS3 and 2DS1with 3DS1. KIR 2DL1 was strongly associated with three other KIRs: 2DL3, 3DL1 and 2DS4 in Aborigines. The distribution of the KIR phenotypes was different in the three populations. The AA1 phenotype was frequent in Vietnamese (42.4%) and Caucasians (31.2%), but very rare in Aborigines (1.5%). In contrast, the BB7 phenotype was very common for Aborigines (22.4%) and was absent in the two other groups. Our data demonstrate that different associations and putative KIR haplotypes could be distinguished in different populations.

Gene Frequency↗
PubMed2001

A new HLA-B*27 allele (B*2719) identified in a Lebanese patient affected with ankylosing spondylitis.

Eighteen different HLA-B*27 alleles (B*2701-B2718) have so far been recognized by the WHO Nomenclature Committee for Factors of the HLA System. Frequency and disease association of these alleles with spondyloarthropathies differ among ethnic groups. We describe here a novel HLA-B*27 subtype identified in a Lebanese patient suffering from ankylosing spondylitis (AS). This new variant differs from the common HLA-B*2705 DNA sequence at five different nucleotide positions. These nucleotide changes lead to three amino acid differences in the alpha2 domain; Thr to Ile at position 94, Leu to Ile at position 95 and Asn to Arg at position 97. Since this novel allele is encountered in an AS patient, the associated sequence changes are not expected to affect significantly neither the presentation of a putative arthritogenic peptide nor the conformation-dependent recognition by effector cells.

Amino Acid Sequence↗
PubMed2001

A new HLA-Cw allele (Cw*1510), identified in a French Caucasian individual.

A novel HLA-Cw*15 allele, Cw*1510, found in a French Caucasian bone marrow recipient is described. Nucleotide sequence of the new variant is identical to the common Cw*15021 DNA sequences except nucleotides at positions 32 and 61 of exon 2. While the first difference is silent, the second cause substitution of an Histidine by an Arginine at amino acid position 21 of the alpha1 heavy chain domain.

Alleles↗
PubMed2001

HLA alleles in relation to specific immunity to liver stage antigen-1 from plasmodium falciparum in Gabon.

Cellular responses to synthetic peptides from the Liver Stage Antigen-1 (LSA-1) from Plasmodium falciparum were determined in 229 Gabonese children. HLA class I and II typing (by PCR-SSP and -RFLP, respectively) revealed that HLA-A*19, -B*17 (and -B*70), -DRB1*05, -DQA1*0102, -DQB1*0602 and -DPB1*0402 were the most frequent types or alleles at each locus. The DQB1*0201 and DQB1*0301 alleles were present at a higher frequency among IL-6 and IFN-gamma responders to the LSA-Rep and LSA-CTL peptides, respectively, and a higher proportion of these responders carried A*19 or B*53. The DRB1*06 type was positively related to the IL-10 production in response to the LSA-CTL peptide, and responders presented mainly A*2. The specificity A*10 was negatively associated with the cellular response to the LSA-J peptide. These results suggest a degree of genetic regulation of specific immune responses by HLA-A, operating at the pre-erythrocytic stage of development of P. falciparum in this Central African population.

Alleles↗