{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T21:52:07Z","timestamp":1790373127482,"version":"4.1.0"},"reference-count":0,"publisher":"National Academy of Sciences","issue":"25","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[1995,12,5]]},"abstract":"<jats:p>Human T-cell-mediated autoimmune diseases are genetically linked to particular alleles of MHC class II genes. Susceptibility to pemphigus vulgaris (PV), an autoimmune disease of the skin, is linked to a rare subtype of HLA-DR4 (DRB1*0402, 1 of 22 known DR4 subtypes). The PV-linked DR4 subtype differs from a rheumatoid arthritis-associated DR4 subtype (DRB1*0404) only at three residues (DR beta 67, 70, and 71). The disease is caused by autoantibodies against desmoglein 3 (DG), and T cells are thought to trigger the autoantibody production against this keratinocyte adhesion molecule. Based on the DRB1*0402 binding motif, seven candidate peptides of the DG autoantigen were identified. T cells from four PV patients with active disease responded to one of these DG peptides (residues 190-204); two patients also responded to DG-(206-220). T-cell clones specific for DG-(190-204) secreted high levels of interleukins 4 and 10, indicating that they may be important in triggering the production of DG-specific autoantibodies. The DG-(190-204) peptide was presented by the disease-linked DRB1*0402 molecule but not by other DR4 subtypes. Site-directed mutagenesis of DRB1*0402 demonstrated that selective presentation of DG-(190-204), which carries a positive charge at the P4 position, was due to the negatively charged residues of the P4 pocket (DR beta 70 and 71). DR beta 71 has a negative charge in DRB1*0402 but a positive charge in other DR4 subtypes, including the DR4 subtypes linked to rheumatoid arthritis. The charge of the P4 pocket in the DR4 peptide binding site therefore appears to be a critical determinant of MHC-linked susceptibility to PV and rheumatoid arthritis.<\/jats:p>","DOI":"10.1073\/pnas.92.25.11935","type":"journal-article","created":{"date-parts":[[2006,5,31]],"date-time":"2006-05-31T09:24:38Z","timestamp":1149067478000},"page":"11935-11939","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":193,"title":["Structural basis for major histocompatibility complex (MHC)-linked susceptibility to autoimmunity: charged residues of a single MHC binding pocket confer selective presentation of self-peptides in pemphigus vulgaris."],"prefix":"10.1073","volume":"92","author":[{"given":"K W","family":"Wucherpfennig","sequence":"first","affiliation":[{"name":"Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B","family":"Yu","sequence":"additional","affiliation":[{"name":"Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K","family":"Bhol","sequence":"additional","affiliation":[{"name":"Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D S","family":"Monos","sequence":"additional","affiliation":[{"name":"Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E","family":"Argyris","sequence":"additional","affiliation":[{"name":"Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R W","family":"Karr","sequence":"additional","affiliation":[{"name":"Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A R","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J L","family":"Strominger","sequence":"additional","affiliation":[{"name":"Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[1995,12,5]]},"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.92.25.11935","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,13]],"date-time":"2022-04-13T13:56:57Z","timestamp":1649858217000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.92.25.11935"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1995,12,5]]},"references-count":0,"journal-issue":{"issue":"25","published-print":{"date-parts":[[1995,12,5]]}},"alternative-id":["10.1073\/pnas.92.25.11935"],"URL":"https:\/\/doi.org\/10.1073\/pnas.92.25.11935","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[1995,12,5]]},"assertion":[{"value":"1995-12-05","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}