title: Comparing HLA shared epitopes in French Caucasian patients with scleroderma.
abstract: Although many studies have analyzed HLA allele frequencies in several ethnic groups in patients with scleroderma (SSc), none has been done in French Caucasian patients and none has evaluated which one of the common amino acid sequences, (67)FLEDR(71), shared by HLA-DRB susceptibility alleles, or (71)TRAELDT(77), shared by HLA-DQB1 susceptibility alleles in SSc, was the most important to develop the disease. HLA-DRB and DQB typing was performed for a total of 468 healthy controls and 282 patients with SSc allowing FLEDR and TRAELDT analyses. Results were stratified according to patient's clinical subtypes and autoantibody status. Moreover, standardized HLA-DRß1 and DRß5 reverse transcriptase Taqman PCR assays were developed to quantify ß1 and ß5 mRNA in 20 subjects with HLA-DRB1*15 and/or DRB1*11 haplotypes. FLEDR motif is highly associated with diffuse SSc (χ(2) = 28.4, p<10-6) and with anti-topoisomerase antibody (ATA) production (χ(2) = 43.9, p<10-9) whereas TRAELDT association is weaker in both subgroups (χ(2) = 7.2, p = 0.027 and χ(2) = 14.6, p = 0.0007 respectively). Moreover, FLEDR motif- association among patients with diffuse SSc remains significant only in ATA subgroup. The risk to develop ATA positive SSc is higher with double dose FLEDR than single dose with respectively, adjusted standardised residuals of 5.1 and 2.6. The increase in FLEDR motif is mostly due to the higher frequency of HLA-DRB1*11 and DRB1*15 haplotypes. Furthermore, FLEDR is always carried by the most abundantly expressed ß chain: ß1 in HLA DRB1*11 haplotypes and ß5 in HLA-DRB1*15 haplotypes.In French Caucasian patients with SSc, FLEDR is the main presenting motif influencing ATA production in dcSSc. These results open a new field of potential therapeutic applications to interact with the FLEDR peptide binding groove and prevent ATA production, a hallmark of severity in SSc.
authors.affiliation: Laboratoire d'Immunogénétique de la Polyarthrite Rhumatoïde, INSERM UMRs1097, Marseille, France.
authors.forename: Doua F
authors.initials: DF
authors.lastname: Azzouz
authors.forename: Justyna M
authors.initials: JM
authors.lastname: Rak
authors.forename: Isabelle
authors.initials: I
authors.lastname: Fajardy
authors.forename: Yannick
authors.initials: Y
authors.lastname: Allanore
authors.forename: Kiet Phong
authors.initials: KP
authors.lastname: Tiev
authors.forename: Dominique
authors.initials: D
authors.lastname: Farge-Bancel
authors.forename: Marielle
authors.initials: M
authors.lastname: Martin
authors.forename: Sami B
authors.initials: SB
authors.lastname: Kanaan
authors.forename: Philippe P
authors.initials: PP
authors.lastname: Pagni
authors.forename: Eric
authors.initials: E
authors.lastname: Hachulla
authors.forename: Jean Robert
authors.initials: JR
authors.lastname: Harlé
authors.forename: Rémi
authors.initials: R
authors.lastname: Didelot
authors.forename: Brigitte
authors.initials: B
authors.lastname: Granel
authors.forename: Jean
authors.initials: J
authors.lastname: Cabane
authors.forename: Jean
authors.initials: J
authors.lastname: Roudier
authors.forename: Nathalie C
authors.initials: NC
authors.lastname: Lambert
mesh_terms: D000483:Alleles; D000939:Epitopes / Q000235:genetics* / Q000276:immunology; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006680:HLA Antigens / Q000235:genetics* / Q000276:immunology*; D059866:HLA-DQ beta-Chains / Q000235:genetics / Q000276:immunology; D059811:HLA-DRB1 Chains / Q000235:genetics / Q000276:immunology; D059847:HLA-DRB5 Chains / Q000235:genetics / Q000276:immunology; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics; D012595:Scleroderma, Systemic / Q000235:genetics* / Q000276:immunology*; D044465:White People / Q000235:genetics*
chemical_list: D000939:Epitopes; D006680:HLA Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D059811:HLA-DRB1 Chains; D059847:HLA-DRB5 Chains; D012333:RNA, Messenger