{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T18:43:36Z","timestamp":1790621016339,"version":"4.1.0"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2015,11,1]],"date-time":"2015-11-01T00:00:00Z","timestamp":1446336000000},"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":[[2015,11,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>We showed previously that C57BL\/6 congenic mice with an introgressed homozygous 70 cM (125.6 Mb) to 100 cM (179.8 Mb) interval on c1 from the lupus-prone New Zealand Black (NZB) mouse develop high titers of antinuclear Abs and severe glomerulonephritis. Using subcongenic mice, we found that a genetic locus in the 88\u201396 cM region was associated with altered dendritic cell (DC) function and synergized with T cell functional defects to promote expansion of pathogenic proinflammatory T cell subsets. In this article, we show that the promoter region of the NZB gene encoding the SLAM signaling pathway adapter molecule EWS-activated transcript 2 (EAT-2) is polymorphic, which results in an \u223c70% reduction in EAT-2 in DC. Silencing of the EAT-2 gene in DC that lacked this polymorphism led to increased production of IL-12 and enhanced differentiation of T cells to a Th1 phenotype in T cell\u2013DC cocultures, reproducing the phenotype observed for DC from congenic mice with the NZB c1 70\u2013100 cM interval. SLAM signaling was shown to inhibit production of IL-12 by CD40L-activated DCs. Consistent with a role for EAT-2 in this inhibition, knockdown of EAT-2 resulted in increased production of IL-12 by CD40-stimulated DC. Assessment of downstream signaling following CD40 cross-linking in the presence or absence of SLAM cross-linking revealed that SLAM coengagement blocked activation of p38 MAPK and JNK signaling pathways in DC, which was reversed in DC with the NZB EAT-2 allele. We conclude that EAT-2 negatively regulates cytokine production in DC downstream of SLAM engagement and that a genetic polymorphism that disturbs this process promotes the development of lupus.<\/jats:p>","DOI":"10.4049\/jimmunol.1500552","type":"journal-article","created":{"date-parts":[[2015,10,3]],"date-time":"2015-10-03T00:32:52Z","timestamp":1443832372000},"page":"4623-4631","source":"Crossref","is-referenced-by-count":6,"title":["Identification of the SLAM Adapter Molecule EAT-2 as a Lupus-Susceptibility Gene That Acts through Impaired Negative Regulation of Dendritic Cell Signaling"],"prefix":"10.1093","volume":"195","author":[{"given":"Nafiseh","family":"Talaei","sequence":"first","affiliation":[{"name":"Arthritis Centre of Excellence, Toronto Western Research Institute, University Health Network , Toronto, Ontario M5T 2S8 ,","place":["Canada"]},{"name":"Department of Immunology, University of Toronto , Toronto, Ontario M5S 1A8 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Yu","sequence":"additional","affiliation":[{"name":"Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital , Toronto, Ontario M5G 1X5 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kieran","family":"Manion","sequence":"additional","affiliation":[{"name":"Arthritis Centre of Excellence, Toronto Western Research Institute, University Health Network , Toronto, Ontario M5T 2S8 ,","place":["Canada"]},{"name":"Department of Immunology, University of Toronto , Toronto, Ontario M5S 1A8 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rod","family":"Bremner","sequence":"additional","affiliation":[{"name":"Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital , Toronto, Ontario M5G 1X5 ,","place":["Canada"]},{"name":"Department of Laboratory Medicine and Pathology, University of Toronto , Toronto, Ontario M5S 1A1 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joan E","family":"Wither","sequence":"additional","affiliation":[{"name":"Arthritis Centre of Excellence, Toronto Western Research Institute, University Health Network , Toronto, Ontario M5T 2S8 ,","place":["Canada"]},{"name":"Department of Immunology, University of Toronto , Toronto, Ontario M5S 1A8 ,","place":["Canada"]},{"name":"Department of Medicine, University of Toronto , Toronto, Ontario M5S 1A8 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2015,11,15]]},"reference":[{"key":"2025030704235690500_r1","doi-asserted-by":"crossref","first-page":"ii56","DOI":"10.1136\/annrheumdis-2012-202351","article-title":"Recent insights into the genetic basis of systemic lupus erythematosus","volume":"72","author":"Rullo","year":"2013","journal-title":"Ann. 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