Trans heterodimer between two non-arthritis-associated HLA alleles can predispose to arthritis in humanized mice

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dc.contributor.authorBehrens, M.en
dc.contributor.authorPapadopoulos, G. K.en
dc.contributor.authorMoustakas, A.en
dc.contributor.authorSmart, M.en
dc.contributor.authorLuthra, H.en
dc.contributor.authorDavid, C. S.en
dc.contributor.authorTaneja, V.en
dc.date.accessioned2015-11-24T19:12:00Z
dc.date.available2015-11-24T19:12:00Z
dc.identifier.issn1529-0131-
dc.identifier.urihttps://olympias.lib.uoi.gr/jspui/handle/123456789/20998
dc.rightsDefault Licence-
dc.subjectAnimalsen
dc.subjectArthritis/*genetics/*immunologyen
dc.subjectCollagen Type II/immunology/metabolismen
dc.subjectDisease Models, Animalen
dc.subjectFemaleen
dc.subject*Genetic Predisposition to Diseaseen
dc.subjectHLA-DQ Antigens/*geneticsen
dc.subjectHLA-DQ beta-Chainsen
dc.subjectHaplotypes/geneticsen
dc.subjectHumansen
dc.subjectMaleen
dc.subjectMembrane Glycoproteins/*geneticsen
dc.subjectMiceen
dc.subjectMice, Transgenicen
dc.subjectModels, Molecularen
dc.subjectSeverity of Illness Indexen
dc.titleTrans heterodimer between two non-arthritis-associated HLA alleles can predispose to arthritis in humanized miceen
heal.abstractOBJECTIVE: Certain HLA class II alleles are associated with susceptibility to the development of arthritis. However, the development of arthritis in some persons carrying non-rheumatoid arthritis (RA)-associated alleles remains unexplained. An individual who is heterozygous for the DQA1 and DQB1 genes can express the DQ molecule in cis or trans heterodimers. In a cis heterodimer, the alpha-chain interacts with the beta-chain coded by the same chromosome, while in a trans heterodimer it interacts with the beta-chain on the other chromosome. In this study, we used a humanized mouse model of arthritis in an attempt to determine whether a trans heterodimer of 2 nonassociated alleles, DQB1*0601 and DQB1*0604, can predispose to arthritis. METHODS: DQB1*0601 and *0604 occur in linkage with DQA1*0103 and *0102, respectively. To understand the role of trans heterodimers, we generated DQB1*0604/DQA1*0103-transgenic mice lacking endogenous HLA class II molecules. RESULTS: Severe arthritis developed in the DQB1*0604/A1*0103-trangenic mice, and an antigen-specific response was generated in vitro. DQB1*0604/DQA1*0103 presented type II collagen-derived peptides that were not presented by the arthritis-resistant DQB1*0601 allele, suggesting that trans heterodimer molecules between 2 DQB1 and DQA1 molecules may result in the presentation of unique antigens and susceptibility to the development of arthritis. Molecular modeling of type II collagen peptides showed that DQB1*0604/DQA1*0103 shares a p4 pocket with the arthritis-susceptible DQB1*0302 allele, suggesting a critical role of the p4 and p9 pockets in susceptibility to arthritis. CONCLUSION: These results provide a possible explanation for the parental inheritance of nonsusceptibility alleles in some patients with RA and a mechanism by which they can predispose to the development of arthritis.en
heal.accesscampus-
heal.fullTextAvailabilityTRUE-
heal.identifier.primary10.1002/art.30260-
heal.identifier.secondaryhttp://www.ncbi.nlm.nih.gov/pubmed/21305521-
heal.identifier.secondaryhttp://onlinelibrary.wiley.com/store/10.1002/art.30260/asset/30260_ftp.pdf?v=1&t=h0w0a7wb&s=5d4d0fd9dae94aea46702df6cf48584a7931a490-
heal.journalNameArthritis Rheumen
heal.journalTypepeer-reviewed-
heal.languageen-
heal.publicationDate2011-
heal.recordProviderΠανεπιστήμιο Ιωαννίνων. Σχολή Επιστημών Υγείας. Τμήμα Ιατρικήςel
heal.typejournalArticle-
heal.type.elΆρθρο Περιοδικούel
heal.type.enJournal articleen

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