{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:26:56Z","timestamp":1785432416064,"version":"3.56.0"},"posted":{"date-parts":[[2026,7,7]]},"group-title":"Immunology","reference-count":40,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T00:00:00Z","timestamp":1783382400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["AI084914"],"award-info":[{"award-number":["AI084914"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001021","name":"Damon Runyon Cancer Research Foundation","doi-asserted-by":"crossref","award":["DRG-2483-23"],"award-info":[{"award-number":["DRG-2483-23"]}],"id":[{"id":"10.13039\/100001021","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Type I diabetes (T1D) is an autoimmune disorder in which the insulin producing cells of the pancreas are attacked and destroyed by autoreactive T cells. The innate immune mechanisms that contribute to T1D remain incompletely defined. Genome-wide association studies in humans have identified alleles of the\n                  <jats:italic>IFIH1<\/jats:italic>\n                  gene, which encodes the intracellular RNA sensor MDA5, that are strongly associated with development of T1D. We previously found that MDA5 signaling drives disease and mortality in a mouse model of Aicardi-Goutieres Syndrome (AGS) caused by mutations in the ADAR1 RNA editing enzyme. Genetic dissection of disease in this ADAR1 mutant mouse model revealed that the double stranded RNA-activated kinase PKR and the RNA sensor ZBP1 are also essential for disease. To test the role of intracellular RNA detection in T1D in the nonobese diabetic (NOD) mouse model, we used CRISPR targeting to generate NOD mice targeted for\n                  <jats:italic>Ifih1, Eif2ak2<\/jats:italic>\n                  (PKR) and\n                  <jats:italic>Zbp1<\/jats:italic>\n                  . We found that haploinsufficiency for\n                  <jats:italic>Ifih1<\/jats:italic>\n                  resulted in modest but significant protection from T1D only in male NOD mice, but neither PKR nor ZBP1 contributed to T1D onset or incidence. Moreover, treatment of NOD mice with a pharmacological inhibitor of the integrated stress response (ISR) had no effect on T1D incidence in female NOD mice, but accelerated and exacerbated disease in male NOD mice. Together, our findings demonstrate that MDA5 and the ISR contribute to sex-specific disease incidence in NOD mice.\n                <\/jats:p>","DOI":"10.64898\/2026.07.02.736190","type":"posted-content","created":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T04:30:12Z","timestamp":1783485012000},"source":"Crossref","is-referenced-by-count":0,"title":["MDA5 and the integrated stress response control sex-specific type 1 diabetes onset in NOD mice"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4773-379X","authenticated-orcid":false,"given":"Erik","family":"Van Dis","sequence":"first","affiliation":[{"name":"Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra T.","family":"DeGidio","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lara","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damion","family":"Winship","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmela","family":"Sidrauski","sequence":"additional","affiliation":[{"name":"Calico Life Sciences LLC, South San Francisco, CA 94080, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacquelyn A.","family":"Gorman","sequence":"additional","affiliation":[{"name":"Oklahoma Medical Research Foundation, Arthritis & Clinical Immunology, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel B.","family":"Stetson","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026071003000556000_2026.07.02.736190v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/nature08933"},{"key":"2026071003000556000_2026.07.02.736190v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)80392-1"},{"key":"2026071003000556000_2026.07.02.736190v1.3","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.23.021704.115643"},{"key":"2026071003000556000_2026.07.02.736190v1.4","doi-asserted-by":"crossref","first-page":"e162","DOI":"10.1038\/cti.2017.51","article-title":"Type 1 diabetes genome-wide association studies: not to be lost in translation","volume":"6","year":"2017","journal-title":"Clin Transl Immunology"},{"key":"2026071003000556000_2026.07.02.736190v1.5","doi-asserted-by":"crossref","unstructured":"Storling, J. & Pociot, F. 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