{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,4,26]],"date-time":"2025-04-26T04:11:35Z","timestamp":1745640695697,"version":"3.38.0"},"reference-count":78,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2015,6,1]],"date-time":"2015-06-01T00:00:00Z","timestamp":1433116800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,6,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Type 1 diabetes in the NOD mouse model has been linked to &amp;gt;30 insulin-dependent diabetes (Idd) susceptibility loci. Idd4 on chromosome 11 consists of two subloci, Idd4.1 and Idd4.2. Using congenic analysis of alleles in NOD and NOD-resistant (NOR) mice, we previously defined Idd4.1 as an interval containing &amp;gt;50 genes that controlled expression of genes in the type 1 IFN pathway. In this study, we report refined mapping of Idd4.1 to a 1.1-Mb chromosomal region and provide genomic sequence analysis and mechanistic evidence supporting its role in innate immune regulation of islet-directed autoimmunity. Genetic variation at Idd4.1 was mediated by radiation-sensitive hematopoietic cells, and type 1 diabetes protection conferred by the NOR allele was abrogated in mice treated with exogenous type 1 IFN-\u03b2. Next generation sequence analysis of the full Idd4.1 genomic interval in NOD and NOR strains supported Nlrp1b as a strong candidate gene for Idd4.1. Nlrp1b belongs to the Nod-like receptor (NLR) gene family and contributes to inflammasome assembly, caspase-1 recruitment, and release of IL-1\u03b2. The Nlrp1b of NOR was expressed as an alternative spliced isoform that skips exon 9, resulting in a premature stop codon predicted to encode a truncated protein. Functional analysis of the truncated NOR Nlrp1b protein demonstrated that it was unable to recruit caspase-1 and process IL-1\u03b2. Our data suggest that Idd4.1-dependent protection from islet autoimmunity is mediated by differences in type 1 IFN\u2013 and IL-1\u03b2\u2013dependent immune responses resulting from genetic variation in Nlrp1b.<\/jats:p>","DOI":"10.4049\/jimmunol.1400913","type":"journal-article","created":{"date-parts":[[2015,5,12]],"date-time":"2015-05-12T02:21:36Z","timestamp":1431397296000},"page":"5663-5673","source":"Crossref","is-referenced-by-count":7,"title":["Identification of the Inflammasome <i>Nlrp1b<\/i> as the Candidate Gene Conferring Diabetes Risk at the <i>Idd4.1<\/i> Locus in the Nonobese Diabetic Mouse"],"prefix":"10.1093","volume":"194","author":[{"given":"Vinicius N","family":"Motta","sequence":"first","affiliation":[{"name":"Genetics and Genome Biology, Hospital for Sick Children , Toronto, Ontario M5G 0A4 ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janet G M","family":"Markle","sequence":"additional","affiliation":[{"name":"Genetics and Genome Biology, Hospital for Sick Children , Toronto, Ontario M5G 0A4 ,","place":["Canada"]},{"name":"Department of Immunology, University of Toronto , Toronto, Ontario M5S 1A8 ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Omid","family":"Gulban","sequence":"additional","affiliation":[{"name":"Genetics and Genome Biology, Hospital for Sick Children , Toronto, Ontario M5G 0A4 ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven","family":"Mortin-Toth","sequence":"additional","affiliation":[{"name":"Genetics and Genome Biology, Hospital for Sick Children , Toronto, Ontario M5G 0A4 ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kuo-Chien","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathobiology, University of Toronto , Toronto, Ontario M5S 1A8 ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeremy","family":"Mogridge","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathobiology, University of Toronto , Toronto, Ontario M5S 1A8 ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles A","family":"Steward","sequence":"additional","affiliation":[{"name":"Wellcome Trust Sanger Institute , Cambridge CB10 1SA ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jayne S","family":"Danska","sequence":"additional","affiliation":[{"name":"Genetics and Genome Biology, Hospital for Sick Children , Toronto, Ontario M5G 0A4 ,","place":["Canada"]},{"name":"Department of Immunology, University of Toronto , Toronto, Ontario M5S 1A8 ,","place":["Canada"]},{"name":"Department of Medical Biophysics, University of Toronto , Toronto, Ontario M5G 1L7 ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2015,6,15]]},"reference":[{"key":"2025030706510865400_r1","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1146\/annurev.iy.13.040195.001143","article-title":"Genetic control of autoimmune diabetes in the NOD mouse","volume":"13","author":"Wicker","year":"1995","journal-title":"Annu. 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