{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T17:53:16Z","timestamp":1774893196240,"version":"3.50.1"},"reference-count":103,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2023,10,9]],"date-time":"2023-10-09T00:00:00Z","timestamp":1696809600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100015691","name":"HHS | NIH | NIAID | Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI 115452"],"award-info":[{"award-number":["AI 115452"]}],"id":[{"id":"10.13039\/100015691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000867","name":"Robert Wood Johnson Foundation","doi-asserted-by":"publisher","award":["67038"],"award-info":[{"award-number":["67038"]}],"id":[{"id":"10.13039\/100000867","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000867","name":"Barile Children\u2019s Medical Research Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000867","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000867","name":"Janssen Research and Development, LLC","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000867","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Peptide loading of MHC class II (MHCII) molecules is facilitated by HLA-DM (DM), which catalyzes CLIP release, stabilizes empty MHCII, and edits the MHCII-bound peptide repertoire. HLA-DO (DO) binds to DM and modulates its activity, resulting in an altered set of peptides presented at the cell surface. MHCII\u2013peptide presentation in individuals with type 1 diabetes (T1D) is abnormal, leading to a breakdown in tolerance; however, no direct measurement of the MHCII pathway activity in T1D patients has been performed. In this study, we measured MHCII Ag-processing pathway activity in humans by determining MHCII, MHCII\u2013CLIP, DM, and DO levels by flow cytometry for peripheral blood B cells, dendritic cells, and monocytes from 99 T1D patients and 97 controls. Results showed that MHCII levels were similar for all three APC subsets. In contrast, MHCII\u2013CLIP levels, independent of sex, age at blood draw, disease duration, and diagnosis age, were significantly increased for all three APCs, with B cells showing the largest increase (3.4-fold). DM and DO levels, which usually directly correlate with MHCII\u2013CLIP levels, were unexpectedly identical in T1D patients and controls. Gene expression profiling on PBMC RNA showed that DMB mRNA was significantly elevated in T1D patients with residual C-peptide. This resulted in higher levels of DM protein in B cells and dendritic cells. DO levels were also increased, suggesting that the MHCII pathway maybe differentially regulated in individuals with residual C-peptide. Collectively, these studies show a dysregulation of the MHCII Ag-processing pathway in patients with T1D.<\/jats:p>","DOI":"10.4049\/jimmunol.2300213","type":"journal-article","created":{"date-parts":[[2023,10,9]],"date-time":"2023-10-09T12:23:27Z","timestamp":1696854207000},"page":"1630-1642","source":"Crossref","is-referenced-by-count":4,"title":["The MHC Class II Antigen-Processing and Presentation Pathway Is Dysregulated in Type 1 Diabetes"],"prefix":"10.1093","volume":"211","author":[{"given":"Ambroise","family":"Gilles","sequence":"first","affiliation":[{"name":"Rutgers Robert Wood Johnson Medical School , New Brunswick, NJ"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lan","family":"Hu","sequence":"additional","affiliation":[{"name":"Oncology Informatics and Genomics, Philips North America , Cambridge, MA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesca","family":"Virdis","sequence":"additional","affiliation":[{"name":"Child Health Institute of New Jersey, Rutgers Robert Wood Johnson Medical School , New Brunswick, NJ"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5510-9367","authenticated-orcid":false,"given":"Derek B","family":"Sant\u2019Angelo","sequence":"additional","affiliation":[{"name":"Child Health Institute of New Jersey, Rutgers Robert Wood Johnson Medical School , New Brunswick, NJ"},{"name":"Rutgers Graduate School of Biomedical Sciences , Piscataway, NJ"},{"name":"Department of Pediatrics, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey , New Brunswick, NJ"},{"name":"Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey , New Brunswick, NJ"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nevenka","family":"Dimitrova","sequence":"additional","affiliation":[{"name":"Oncology Informatics and Genomics, Philips North America , Valhalla, NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1629-4907","authenticated-orcid":false,"given":"Joseph A","family":"Hedrick","sequence":"additional","affiliation":[{"name":"Janssen Research and Development, LLC , Raritan, NJ"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0554-4547","authenticated-orcid":false,"given":"Lisa K","family":"Denzin","sequence":"additional","affiliation":[{"name":"Child Health Institute of New Jersey, Rutgers Robert Wood Johnson Medical School , New Brunswick, NJ"},{"name":"Rutgers Graduate School of Biomedical Sciences , Piscataway, NJ"},{"name":"Department of Pediatrics, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey , New Brunswick, NJ"},{"name":"Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey , New Brunswick, NJ"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2023,10,9]]},"reference":[{"key":"2025020406200854900_r1","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/j.jpeds.2005.10.029","article-title":"Characteristics at diagnosis of type 1 diabetes in children younger than 6 years","volume":"148","author":"Quinn","year":"2006","journal-title":"J. Pediatr."},{"key":"2025020406200854900_r2","doi-asserted-by":"crossref","first-page":"e938","DOI":"10.1542\/peds.2013-2795","article-title":"Trends in the prevalence of ketoacidosis at diabetes diagnosis: the SEARCH for diabetes in youth study","volume":"133","author":"Dabelea","year":"2014","journal-title":"Pediatrics"},{"key":"2025020406200854900_r3","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1016\/j.jpeds.2012.06.058","article-title":"Diabetic ketoacidosis at diabetes onset: still an all too common threat in youth","volume":"162","author":"Klingensmith","year":"2013","journal-title":"J. Pediatr."},{"key":"2025020406200854900_r4","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1111\/j.1399-543X.2005.00110.x","article-title":"Clinical presentation of type 1 diabetes","volume":"6","author":"Roche","year":"2005","journal-title":"Pediatr. Diabetes"},{"key":"2025020406200854900_r5","doi-asserted-by":"crossref","first-page":"2449","DOI":"10.1016\/S0140-6736(18)31320-5","article-title":"Type 1 diabetes","volume":"391","author":"DiMeglio","year":"2018","journal-title":"Lancet"},{"key":"2025020406200854900_r6","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1007\/s00018-012-1042-1","article-title":"Prevention or acceleration of type 1 diabetes by viruses","volume":"70","author":"Ghazarian","year":"2013","journal-title":"Cell. Mol. Life Sci."},{"key":"2025020406200854900_r7","doi-asserted-by":"crossref","first-page":"e11501","DOI":"10.1371\/journal.pone.0011501","article-title":"Estimating the cost of type 1 diabetes in the U.S.: a propensity score matching method","volume":"5","author":"Tao","year":"2010","journal-title":"PLoS One"},{"key":"2025020406200854900_r8","doi-asserted-by":"crossref","first-page":"a007641","DOI":"10.1101\/cshperspect.a007641","article-title":"The pathogenesis and natural history of type 1 diabetes","volume":"2","author":"Atkinson","year":"2012","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"2025020406200854900_r9","doi-asserted-by":"crossref","first-page":"2331","DOI":"10.1016\/S0140-6736(16)30582-7","article-title":"Genetic risk factors for type 1 diabetes","volume":"387","author":"Pociot","year":"2016","journal-title":"Lancet"},{"key":"2025020406200854900_r10","doi-asserted-by":"crossref","first-page":"1698","DOI":"10.2337\/diacare.22.10.1698","article-title":"Perinatal risk factors for childhood type 1 diabetes in Europe. The EURODIAB Substudy 2 Study Group","volume":"22","author":"Dahlquist","year":"1999","journal-title":"Diabetes Care"},{"key":"2025020406200854900_r11","doi-asserted-by":"crossref","first-page":"382165","DOI":"10.1155\/2015\/382165","article-title":"Role of nutritional factors at the early life stages in the pathogenesis and clinical course of type 1 diabetes","volume":"2015","author":"Kagohashi","year":"2015","journal-title":"BioMed Res. Int."},{"key":"2025020406200854900_r12","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1152\/physrev.00003.2010","article-title":"Type 1 diabetes: etiology, immunology, and therapeutic strategies","volume":"91","author":"van Belle","year":"2011","journal-title":"Physiol. Rev."},{"key":"2025020406200854900_r13","doi-asserted-by":"crossref","first-page":"1964","DOI":"10.2337\/dc15-1419","article-title":"Staging presymptomatic type 1 diabetes: a scientific statement of JDRF, the Endocrine Society, and the American Diabetes Association","volume":"38","author":"Insel","year":"2015","journal-title":"Diabetes Care"},{"key":"2025020406200854900_r14","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1038\/ng.381","article-title":"Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes","volume":"41","author":"Barrett","year":"2009","journal-title":"Nat. Genet."},{"key":"2025020406200854900_r15","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1038\/nrg3069","article-title":"Understanding type 1 diabetes through genetics: advances and prospects","volume":"12","author":"Polychronakos","year":"2011","journal-title":"Nat. Rev. Genet."},{"key":"2025020406200854900_r16","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1111\/pedi.12597","article-title":"Genetics of type 1 diabetes","volume":"19","author":"Redondo","year":"2018","journal-title":"Pediatr. Diabetes"},{"key":"2025020406200854900_r17","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1016\/S1074-7613(04)00111-6","article-title":"Back to central tolerance","volume":"20","author":"Mathis","year":"2004","journal-title":"Immunity"},{"key":"2025020406200854900_r18","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1146\/annurev-immunol-032712-095910","article-title":"Pathways of antigen processing","volume":"31","author":"Blum","year":"2013","journal-title":"Annu. Rev. Immunol."},{"key":"2025020406200854900_r19","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1038\/378457a0","article-title":"The structure of an intermediate in class II MHC maturation: CLIP bound to HLA-DR3","volume":"378","author":"Ghosh","year":"1995","journal-title":"Nature"},{"key":"2025020406200854900_r20","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1038\/360474a0","article-title":"HLA-DR molecules from an antigen-processing mutant cell line are associated with invariant chain peptides","volume":"360","author":"Riberdy","year":"1992","journal-title":"Nature"},{"key":"2025020406200854900_r21","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/0092-8674(95)90061-6","article-title":"HLA-DM induces CLIP dissociation from MHC class II \u03b1\u03b2 dimers and facilitates peptide loading","volume":"82","author":"Denzin","year":"1995","journal-title":"Cell"},{"key":"2025020406200854900_r22","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1038\/375802a0","article-title":"Mediation by HLA-DM of dissociation of peptides from HLA-DR","volume":"375","author":"Sloan","year":"1995","journal-title":"Nature"},{"key":"2025020406200854900_r23","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1126\/science.274.5287.618","article-title":"Enhanced dissociation of HLA-DR-bound peptides in the presence of HLA-DM","volume":"274","author":"Weber","year":"1996","journal-title":"Science"},{"key":"2025020406200854900_r24","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.1126\/science.271.5253.1278","article-title":"Antigen presentation and T cell development in H2-M-deficient mice","volume":"271","author":"Fung-Leung","year":"1996","journal-title":"Science"},{"key":"2025020406200854900_r25","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/S1074-7613(00)80332-5","article-title":"HLA-DM acts as a molecular chaperone and rescues empty HLA-DR molecules at lysosomal pH","volume":"6","author":"Kropshofer","year":"1997","journal-title":"Immunity"},{"key":"2025020406200854900_r26","doi-asserted-by":"crossref","first-page":"6144","DOI":"10.1002\/j.1460-2075.1996.tb01002.x","article-title":"Editing of the HLA-DR-peptide repertoire by HLA-DM","volume":"15","author":"Kropshofer","year":"1996","journal-title":"EMBO J."},{"key":"2025020406200854900_r27","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1016\/S0092-8674(00)81030-2","article-title":"H2-M mutant mice are defective in the peptide loading of class II molecules, antigen presentation, and T cell repertoire selection","volume":"84","author":"Martin","year":"1996","journal-title":"Cell"},{"key":"2025020406200854900_r28","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1016\/S0092-8674(00)81029-6","article-title":"Mice lacking H2-M complexes, enigmatic elements of the MHC class II peptide-loading pathway","volume":"84","author":"Miyazaki","year":"1996","journal-title":"Cell"},{"key":"2025020406200854900_r29","doi-asserted-by":"crossref","first-page":"2153","DOI":"10.1084\/jem.184.6.2153","article-title":"HLA-DM interactions with intermediates in HLA-DR maturation and a role for HLA-DM in stabilizing empty HLA-DR molecules","volume":"184","author":"Denzin","year":"1996","journal-title":"J. Exp. Med."},{"key":"2025020406200854900_r30","doi-asserted-by":"crossref","first-page":"125","DOI":"10.2337\/diab.44.1.125","article-title":"Polymorphic amino acid variations in HLA-DQ are associated with systematic physical property changes and occurrence of IDDM. Members of the Swedish Childhood Diabetes Study","volume":"44","author":"Sanjeevi","year":"1995","journal-title":"Diabetes"},{"key":"2025020406200854900_r31","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1038\/nsmb.2460","article-title":"HLA-DO acts as a substrate mimic to inhibit HLA-DM by a competitive mechanism","volume":"20","author":"Guce","year":"2013","journal-title":"Nat. Struct. Mol. Biol."},{"key":"2025020406200854900_r32","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1126\/science.278.5335.106","article-title":"Negative regulation by HLA-DO of MHC class II-restricted antigen processing","volume":"278","author":"Denzin","year":"1997","journal-title":"Science"},{"key":"2025020406200854900_r33","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1084\/jem.20012066","article-title":"Regulated expression of human histocompatibility leukocyte antigen (HLA)-DO during antigen-dependent and antigen-independent phases of B cell development","volume":"195","author":"Chen","year":"2002","journal-title":"J. Exp. Med."},{"key":"2025020406200854900_r34","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1084\/jem.20012059","article-title":"Germinal center B cells regulate their capability to present antigen by modulation of HLA-DO","volume":"195","author":"Glazier","year":"2002","journal-title":"J. Exp. Med."},{"key":"2025020406200854900_r35","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1074\/mcp.RA118.000956","article-title":"HLA-DO modulates the diversity of the MHCII self-peptidome","volume":"18","author":"Nanaware","year":"2019","journal-title":"Mol. Cell. Proteomics"},{"key":"2025020406200854900_r36","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1172\/JCI40220","article-title":"Targeted regulation of self-peptide presentation prevents type I diabetes in mice without disrupting general immunocompetence","volume":"120","author":"Yi","year":"2010","journal-title":"J. Clin. Invest."},{"key":"2025020406200854900_r37","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1038\/nature06406","article-title":"Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A","volume":"450","author":"Nejentsev","year":"2007","journal-title":"Nature"},{"key":"2025020406200854900_r38","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1111\/j.1463-1326.2008.01002.x","article-title":"Several loci in the HLA class III region are associated with T1D risk after adjusting for DRB1-DQB1","volume":"11","author":"Valdes","year":"2009","journal-title":"Diabetes Obes. Metab."},{"key":"2025020406200854900_r39","doi-asserted-by":"crossref","first-page":"2967","DOI":"10.1093\/hmg\/9.20.2967","article-title":"Confirmation of the DRB1-DQB1 loci as the major component of IDDM1 in the isolated founder population of Sardinia","volume":"9","author":"Zavattari","year":"2000","journal-title":"Hum. Mol. Genet."},{"key":"2025020406200854900_r40","doi-asserted-by":"crossref","first-page":"1516","DOI":"10.2337\/diacare.23.10.1516","article-title":"Incidence of childhood type 1 diabetes worldwide. Diabetes Mondiale (DiaMond) Project Group","volume":"23","author":"Karvonen","year":"2000","journal-title":"Diabetes Care"},{"key":"2025020406200854900_r41","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1093\/hmg\/10.8.881","article-title":"Conditional linkage disequilibrium analysis of a complex disease superlocus, IDDM1 in the HLA region, reveals the presence of independent modifying gene effects influencing the type 1 diabetes risk encoded by the major HLA-DQB1, -DRB1 disease loci","volume":"10","author":"Zavattari","year":"2001","journal-title":"Hum. Mol. Genet."},{"key":"2025020406200854900_r42","doi-asserted-by":"crossref","first-page":"476","DOI":"10.2337\/dc14-1952","article-title":"Prevalence of detectable C-peptide according to age at diagnosis and duration of type 1 diabetes","volume":"38","author":"Davis","year":"2015","journal-title":"Diabetes Care"},{"key":"2025020406200854900_r43","doi-asserted-by":"crossref","first-page":"293","DOI":"10.4049\/jimmunol.125.1.293","article-title":"Two populations of Ia-like molecules on a human B cell line","volume":"125","author":"Lampson","year":"1980","journal-title":"J. Immunol."},{"key":"2025020406200854900_r44","doi-asserted-by":"crossref","first-page":"3282","DOI":"10.4049\/jimmunol.161.7.3282","article-title":"The tetraspan protein CD82 is a resident of MHC class II compartments where it associates with HLA-DR, -DM, and -DO molecules","volume":"161","author":"Hammond","year":"1998","journal-title":"J. Immunol."},{"key":"2025020406200854900_r45","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1038\/nbt.3519","article-title":"Near-optimal probabilistic RNA-seq quantification. [Published erratum appears in 2016 Nat. Biotechnol. 34: 888.]","volume":"34","author":"Bray","year":"2016","journal-title":"Nat. Biotechnol."},{"key":"2025020406200854900_r46","doi-asserted-by":"crossref","first-page":"e47","DOI":"10.1093\/nar\/gkv007","article-title":"limma powers differential expression analyses for RNA-sequencing and microarray studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"2025020406200854900_r47","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.1093\/bioinformatics\/btr260","article-title":"Molecular signatures database (MSigDB) 3.0","volume":"27","author":"Liberzon","year":"2011","journal-title":"Bioinformatics"},{"key":"2025020406200854900_r48","doi-asserted-by":"crossref","first-page":"3536","DOI":"10.4049\/jimmunol.176.6.3536","article-title":"Human dendritic cell expression of HLA-DO is subset specific and regulated by maturation","volume":"176","author":"Hornell","year":"2006","journal-title":"J. Immunol."},{"key":"2025020406200854900_r49","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1084\/jem.181.2.527","article-title":"Supermotifs enable natural invariant chain-derived peptides to interact with many major histocompatibility complex-class II molecules","volume":"181","author":"Malcherek","year":"1995","journal-title":"J. Exp. Med."},{"key":"2025020406200854900_r50","doi-asserted-by":"crossref","first-page":"950","DOI":"10.1016\/S0960-9822(06)00414-3","article-title":"HLA-DO is a negative modulator of HLA-DM-mediated MHC class II peptide loading","volume":"7","author":"van Ham","year":"1997","journal-title":"Curr. Biol."},{"key":"2025020406200854900_r51","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/s001250051573","article-title":"Diabetes and gender","volume":"44","author":"Gale","year":"2001","journal-title":"Diabetologia"},{"key":"2025020406200854900_r52","doi-asserted-by":"crossref","first-page":"1947","DOI":"10.1002\/pro.3715","article-title":"Toward understanding the origin and evolution of cellular organisms","volume":"28","author":"Kanehisa","year":"2019","journal-title":"Protein Sci."},{"issue":"D1","key":"2025020406200854900_r53","doi-asserted-by":"crossref","first-page":"D545","DOI":"10.1093\/nar\/gkaa970","article-title":"KEGG: integrating viruses and cellular organisms","volume":"49","author":"Kanehisa","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"2025020406200854900_r54","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/nar\/28.1.27","article-title":"KEGG: Kyoto Encyclopedia of Genes and Genomes","volume":"28","author":"Kanehisa","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"2025020406200854900_r55","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1002\/(SICI)1096-9136(199810)15:10<844::AID-DIA679>3.0.CO;2-A","article-title":"Parameters associated with residual insulin secretion during the first year of disease in children and adolescents with type 1 diabetes mellitus","volume":"15","author":"Bonfanti","year":"1998","journal-title":"Diabet. Med."},{"key":"2025020406200854900_r56","doi-asserted-by":"crossref","first-page":"1664","DOI":"10.2337\/dc16-0360","article-title":"Fall in C-peptide during first 4 years from diagnosis of type 1 diabetes: variable relation to age, HbA1c, and insulin dose","volume":"39","author":"Hao","year":"2016","journal-title":"Diabetes Care"},{"key":"2025020406200854900_r57","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.4049\/jimmunol.173.3.1549","article-title":"Ectopic expression of HLA-DO in mouse dendritic cells diminishes MHC class II antigen presentation","volume":"173","author":"Fallas","year":"2004","journal-title":"J. Immunol."},{"key":"2025020406200854900_r58","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/S2213-8587(18)30112-8","article-title":"The challenge of modulating \u03b2-cell autoimmunity in type 1 diabetes","volume":"7","author":"Atkinson","year":"2019","journal-title":"Lancet Diabetes Endocrinol."},{"key":"2025020406200854900_r59","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1056\/NEJMoa1902226","article-title":"An anti-CD3 antibody, teplizumab, in relatives at risk for type 1 diabetes","volume":"381","author":"Herold","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"2025020406200854900_r60","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/S2213-8587(22)00351-5","article-title":"FDA approves teplizumab: a milestone in type 1 diabetes","volume":"11","author":"Hirsch","year":"2023","journal-title":"Lancet Diabetes Endocrinol."},{"key":"2025020406200854900_r61","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1126\/science.abh1654","article-title":"Immunotherapy: building a bridge to a cure for type 1 diabetes","volume":"373","author":"Bluestone","year":"2021","journal-title":"Science"},{"key":"2025020406200854900_r62","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1097\/MED.0000000000000647","article-title":"Current state of antigen-specific immunotherapy for type 1 diabetes","volume":"28","author":"Kreiner","year":"2021","journal-title":"Curr. Opin. Endocrinol. Diabetes Obes."},{"key":"2025020406200854900_r63","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1097\/MED.0000000000000646","article-title":"Breaking and restoring immune tolerance to pancreatic beta-cells in type 1 diabetes","volume":"28","author":"Erdem","year":"2021","journal-title":"Curr. Opin. Endocrinol. Diabetes Obes."},{"key":"2025020406200854900_r64","doi-asserted-by":"crossref","first-page":"2617","DOI":"10.1084\/jem.20180300","article-title":"Rapid CLIP dissociation from MHC II promotes an unusual antigen presentation pathway in autoimmunity","volume":"215","author":"Ito","year":"2018","journal-title":"J. Exp. Med."},{"key":"2025020406200854900_r65","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1002\/eji.201545942","article-title":"Type 1 diabetes associated HLA-DQ2 and DQ8 molecules are relatively resistant to HLA-DM mediated release of invariant chain-derived CLIP peptides","volume":"46","author":"Zhou","year":"2016","journal-title":"Eur. J. Immunol."},{"key":"2025020406200854900_r66","doi-asserted-by":"crossref","first-page":"314","DOI":"10.3390\/cells12020314","article-title":"MHC class II presentation in autoimmunity","volume":"12","author":"Ishina","year":"2023","journal-title":"Cells"},{"key":"2025020406200854900_r67","doi-asserted-by":"crossref","first-page":"5451","DOI":"10.4049\/jimmunol.181.8.5451","article-title":"Complexes of two cohorts of CLIP peptides and HLA-DQ2 of the autoimmune DR3-DQ2 haplotype are poor substrates for HLA-DM","volume":"181","author":"Fallang","year":"2008","journal-title":"J. Immunol."},{"key":"2025020406200854900_r68","doi-asserted-by":"crossref","first-page":"2442","DOI":"10.4049\/jimmunol.1100255","article-title":"An insertion mutant in DQA1*0501 restores susceptibility to HLA-DM: implications for disease associations","volume":"187","author":"Hou","year":"2011","journal-title":"J. Immunol."},{"key":"2025020406200854900_r69","doi-asserted-by":"crossref","first-page":"5","DOI":"10.4049\/jimmunol.2100061","article-title":"MHC class II presentation is affected by polymorphism in the H2-Ob gene and additional loci","volume":"207","author":"Cullum","year":"2021","journal-title":"J. Immunol."},{"key":"2025020406200854900_r70","doi-asserted-by":"crossref","first-page":"3548","DOI":"10.4049\/jimmunol.176.6.3548","article-title":"H2-O expression in primary dendritic cells","volume":"176","author":"Chen","year":"2006","journal-title":"J. Immunol."},{"key":"2025020406200854900_r71","doi-asserted-by":"crossref","first-page":"923","DOI":"10.4049\/jimmunol.2000476","article-title":"Human hepatitis B viral infection outcomes are linked to naturally occurring variants of HLA-DOA that have altered function","volume":"205","author":"Graves","year":"2020","journal-title":"J. Immunol."},{"key":"2025020406200854900_r72","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1016\/j.immuni.2017.07.013","article-title":"Neutralizing antibody responses to viral infections are linked to the non-classical MHC class II gene H2-Ob","volume":"47","author":"Denzin","year":"2017","journal-title":"Immunity"},{"key":"2025020406200854900_r73","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/s41423-018-0181-1","article-title":"Distinct editing functions of natural HLA-DM allotypes impact antigen presentation and CD4+ T cell activation","volume":"17","author":"\u00c1lvaro-Benito","year":"2020","journal-title":"Cell. Mol. Immunol."},{"key":"2025020406200854900_r74","doi-asserted-by":"crossref","first-page":"803","DOI":"10.4049\/jimmunol.1401389","article-title":"HLA-DMA polymorphisms differentially affect MHC class II peptide loading","volume":"194","author":"\u00c1lvaro-Benito","year":"2015","journal-title":"J. Immunol."},{"key":"2025020406200854900_r75","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1038\/s41577-022-00707-2","article-title":"A guide to antigen processing and presentation","volume":"22","author":"Pishesha","year":"2022","journal-title":"Nat. Rev. Immunol."},{"key":"2025020406200854900_r76","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1016\/j.immuni.2021.02.019","article-title":"Pleiotropic consequences of metabolic stress for the major histocompatibility complex class II molecule antigen processing and presentation machinery","volume":"54","author":"Clement","year":"2021","journal-title":"Immunity"},{"key":"2025020406200854900_r77","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1016\/S0140-6736(77)90237-9","article-title":"Haemoglobin A1: an indicator of the metabolic control of diabetic patients","volume":"2","author":"Gonen","year":"1977","journal-title":"Lancet"},{"key":"2025020406200854900_r78","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1146\/annurev.iy.09.040191.002425","article-title":"MHC class-II molecules and autoimmunity","volume":"9","author":"Nepom","year":"1991","journal-title":"Annu. Rev. Immunol."},{"key":"2025020406200854900_r79","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0198-8859(97)00024-4","article-title":"Invited anniversary review: HLA associated diseases","volume":"53","author":"Thorsby","year":"1997","journal-title":"Hum. Immunol."},{"key":"2025020406200854900_r80","doi-asserted-by":"crossref","first-page":"e15","DOI":"10.1017\/erm.2012.9","article-title":"On the perils of poor editing: regulation of peptide loading by HLA-DQ and H2-A molecules associated with celiac disease and type 1 diabetes","volume":"14","author":"Busch","year":"2012","journal-title":"Expert Rev. Mol. Med."},{"key":"2025020406200854900_r81","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1038\/88694","article-title":"Structure of a human insulin peptide-HLA-DQ8 complex and susceptibility to type 1 diabetes","volume":"2","author":"Lee","year":"2001","journal-title":"Nat. Immunol."},{"key":"2025020406200854900_r82","doi-asserted-by":"crossref","first-page":"3155","DOI":"10.3390\/ijms23063155","article-title":"Self-antigens targeted by regulatory T cells in type 1 diabetes","volume":"23","author":"Mitchell","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"2025020406200854900_r83","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.jaut.2016.05.009","article-title":"Maintenance of peripheral tolerance to islet antigens","volume":"72","author":"Hamilton-Williams","year":"2016","journal-title":"J. Autoimmun."},{"key":"2025020406200854900_r84","doi-asserted-by":"crossref","first-page":"100204","DOI":"10.1016\/j.mcpro.2022.100204","article-title":"Tuning DO:DM ratios modulates MHC class II immunopeptidomes","volume":"21","author":"Olsson","year":"2022","journal-title":"Mol. Cell. Proteomics"},{"key":"2025020406200854900_r85","doi-asserted-by":"crossref","first-page":"e3000590","DOI":"10.1371\/journal.pbio.3000590","article-title":"Lack of the MHC class II chaperone H2-O causes susceptibility to autoimmune diseases","volume":"18","author":"Welsh","year":"2020","journal-title":"PLoS Biol."},{"key":"2025020406200854900_r86","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1021\/acs.jproteome.1c00842","article-title":"HLA allele-specific quantitative profiling of type 1 diabetic B lymphocyte immunopeptidome","volume":"21","author":"Sudhir","year":"2022","journal-title":"J. Proteome Res."},{"key":"2025020406200854900_r87","doi-asserted-by":"crossref","first-page":"453","DOI":"10.2337\/dc13-0626","article-title":"B-lymphocyte depletion with rituximab and \u03b2-cell function: two-year results","volume":"37","author":"Pescovitz","year":"2014","journal-title":"Diabetes Care"},{"key":"2025020406200854900_r88","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1007\/s11892-014-0543-8","article-title":"Role of B lymphocytes in the pathogenesis of type 1 diabetes","volume":"14","author":"Hinman","year":"2014","journal-title":"Curr. Diab. Rep."},{"key":"2025020406200854900_r89","doi-asserted-by":"crossref","first-page":"617437","DOI":"10.3389\/fendo.2021.617437","article-title":"Footprints of immune cells in the pancreas in type 1 diabetes; to \u201cB\u201d or not to \u201cB\u201d: is that still the question?","volume":"12","author":"Leete","year":"2021","journal-title":"Front. Endocrinol. (Lausanne)"},{"key":"2025020406200854900_r90","doi-asserted-by":"crossref","first-page":"988","DOI":"10.2337\/db18-0686","article-title":"HLA class II antigen processing and presentation pathway components demonstrated by transcriptome and protein analyses of islet \u03b2-cells from donors with type 1 diabetes","volume":"68","author":"Russell","year":"2019","journal-title":"Diabetes"},{"key":"2025020406200854900_r91","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1006\/jaut.1996.0053","article-title":"Islet-infiltrating T lymphocytes in insulin-dependent diabetic patients express CD80 (B7-1) and CD86 (B7-2)","volume":"9","author":"Imagawa","year":"1996","journal-title":"J. Autoimmun."},{"key":"2025020406200854900_r92","doi-asserted-by":"crossref","first-page":"690783","DOI":"10.3389\/fimmu.2021.690783","article-title":"Revisiting the antigen-presenting function of \u03b2 cells in T1D pathogenesis","volume":"12","author":"Li","year":"2021","journal-title":"Front. Immunol."},{"key":"2025020406200854900_r93","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.immuni.2005.05.009","article-title":"The kinetic stability of MHC class II:peptide complexes is a key parameter that dictates immunodominance","volume":"23","author":"Lazarski","year":"2005","journal-title":"Immunity"},{"key":"2025020406200854900_r94","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1038\/42030","article-title":"Inflammatory stimuli induce accumulation of MHC class II complexes on dendritic cells","volume":"388","author":"Cella","year":"1997","journal-title":"Nature"},{"key":"2025020406200854900_r95","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1016\/1074-7613(94)90049-3","article-title":"Assembly and intracellular transport of HLA-DM and correction of the class II antigen-processing defect in T2 cells","volume":"1","author":"Denzin","year":"1994","journal-title":"Immunity"},{"key":"2025020406200854900_r96","doi-asserted-by":"crossref","first-page":"434","DOI":"10.2337\/dc15-1765","article-title":"Altered peripheral B-lymphocyte subsets in type 1 diabetes and latent autoimmune diabetes in adults","volume":"39","author":"Deng","year":"2016","journal-title":"Diabetes Care"},{"key":"2025020406200854900_r97","doi-asserted-by":"crossref","first-page":"487","DOI":"10.4049\/jimmunol.1102176","article-title":"Altered B cell homeostasis is associated with type I diabetes and carriers of the PTPN22 allelic variant","volume":"188","author":"Habib","year":"2012","journal-title":"J. Immunol."},{"key":"2025020406200854900_r98","doi-asserted-by":"crossref","first-page":"2303","DOI":"10.2337\/dc11-2460","article-title":"Altered phenotype of peripheral blood dendritic cells in pediatric type 1 diabetes","volume":"35","author":"Nieminen","year":"2012","journal-title":"Diabetes Care"},{"key":"2025020406200854900_r99","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1111\/cei.13332","article-title":"A study of 51 subtypes of peripheral blood immune cells in newly diagnosed young type 1 diabetes patients","volume":"198","author":"Oras","year":"2019","journal-title":"Clin. Exp. Immunol."},{"key":"2025020406200854900_r100","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1111\/cei.12362","article-title":"Multi-parametric flow cytometric and genetic investigation of the peripheral B cell compartment in human type 1 diabetes","volume":"177","author":"Thompson","year":"2014","journal-title":"Clin. Exp. Immunol."},{"key":"2025020406200854900_r101","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.clim.2007.03.002","article-title":"Decreased blood dendritic cell counts in type 1 diabetic children","volume":"123","author":"Vuckovic","year":"2007","journal-title":"Clin. Immunol."},{"key":"2025020406200854900_r102","doi-asserted-by":"crossref","first-page":"302","DOI":"10.3389\/fimmu.2012.00302","article-title":"Advances in human B cell phenotypic profiling","volume":"3","author":"Kaminski","year":"2012","journal-title":"Front. Immunol."},{"key":"2025020406200854900_r103","doi-asserted-by":"crossref","first-page":"945","DOI":"10.4049\/jimmunol.1901409","article-title":"The role of autoimmunity-related gene CLEC16A in the B cell receptor-mediated HLA class II pathway","volume":"205","author":"Rijvers","year":"2020","journal-title":"J. Immunol."}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/211\/11\/1630\/61473247\/ji2300213.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/211\/11\/1630\/61473247\/ji2300213.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,4]],"date-time":"2025-02-04T06:20:35Z","timestamp":1738650035000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/211\/11\/1630\/7925096"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,9]]},"references-count":103,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2023,12,1]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.2300213","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,12]]},"published":{"date-parts":[[2023,10,9]]}}}