{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T07:13:40Z","timestamp":1775978020496,"version":"3.50.1"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2012,9,1]],"date-time":"2012-09-01T00:00:00Z","timestamp":1346457600000},"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":[[2012,9,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The lupus-prone NZM2410 mice present an expanded B1a cell population that we have mapped to the Sle2c1 lupus susceptibility locus. The expression of Cdkn2c, a gene encoding for cyclin-dependent kinase inhibitor p18Ink4c and located within Sle2c1, is significantly lower in B6.Sle2c1 B cells than in B6 B cells. To test the hypothesis that the B1a cell expansion in B6.Sle2c1 mice was due to a defective p18 expression, we analyzed the B1a cell phenotypes of p18-deficient C57BL\/6 mice. We found a dose-dependent negative correlation between the number of B1a cells and p18 expression in B cells, with p18-deficient mice showing an early expansion of the peritoneal B1a cell pool. p18 deficiency enhanced the homeostatic expansion of B1a cells but not of splenic conventional B cells, and the elevated number of B6.Sle2c1 B1a cells was normalized by cyclin D2 deficiency. These data demonstrated that p18 is a key regulator of the size of the B1a cell pool. B6.p18\u2212\/\u2212 mice produced significant amounts of anti-DNA IgM and IgG, indicating that p18 deficiency contributes to humoral autoimmunity. Finally, we have shown that Sle2c1 increases lpr-associated lymphadenopathy and T cell\u2013mediated pathology. B6.p18\u2212\/\u2212.lpr mice showed a greater lymphadenopathy than B6.Sle2c1.lpr mice, but their renal pathology was intermediate between that of B6.lpr and B6.Sle2c1.lpr mice. This indicated that p18-deficiency synergizes, at least partially, with lpr-mediated pathology. These results show that Cdkn2c contributes to lupus susceptibility by regulating the size of the B1a cell compartment and hence their contribution to autoimmunity.<\/jats:p>","DOI":"10.4049\/jimmunol.1200556","type":"journal-article","created":{"date-parts":[[2012,8,16]],"date-time":"2012-08-16T02:05:57Z","timestamp":1345082757000},"page":"2931-2940","source":"Crossref","is-referenced-by-count":27,"title":["Cyclin-Dependent Kinase Inhibitor <i>Cdkn2c<\/i> Deficiency Promotes B1a Cell Expansion and Autoimmunity in a Mouse Model of Lupus"],"prefix":"10.1093","volume":"189","author":[{"given":"Hari-Hara S K","family":"Potula","sequence":"first","affiliation":[{"name":"Department of Pathology, Immunology, and Laboratory Medicine, University of Florida , Gainesville, FL 32610"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhiwei","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Pathology, Immunology, and Laboratory Medicine, University of Florida , Gainesville, FL 32610"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leilani","family":"Zeumer","sequence":"additional","affiliation":[{"name":"Department of Pathology, Immunology, and Laboratory Medicine, University of Florida , Gainesville, FL 32610"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Allison","family":"Sang","sequence":"additional","affiliation":[{"name":"Department of Pathology, Immunology, and Laboratory Medicine, University of Florida , Gainesville, FL 32610"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Byron P","family":"Croker","sequence":"additional","affiliation":[{"name":"Department of Pathology, Immunology, and Laboratory Medicine, University of Florida , Gainesville, FL 32610"},{"name":"North Florida South George Veterans Health System , Gainesville, FL 32608"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laurence","family":"Morel","sequence":"additional","affiliation":[{"name":"Department of Pathology, Immunology, and Laboratory Medicine, University of Florida , Gainesville, FL 32610"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2012,9,15]]},"reference":[{"key":"2025032409254754100_r1","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1146\/annurev.immunol.20.100301.064833","article-title":"Origins and functions of B-1 cells with notes on the role of CD5","volume":"20","author":"Berland","year":"2002","journal-title":"Annu. Rev. Immunol."},{"key":"2025032409254754100_r2","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1385\/IR:27:1:31","article-title":"Cell cycle control mechanisms in B-1 and B-2 lymphoid subsets","volume":"27","author":"Piatelli","year":"2003","journal-title":"Immunol. Res."},{"key":"2025032409254754100_r3","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1093\/intimm\/12.5.631","article-title":"Cyclin D2 is essential for BCR-mediated proliferation and CD5 B cell development","volume":"12","author":"Solvason","year":"2000","journal-title":"Int. Immunol."},{"key":"2025032409254754100_r4","doi-asserted-by":"crossref","first-page":"787","DOI":"10.4049\/jimmunol.177.2.787","article-title":"Disruption of cyclin D3 blocks proliferation of normal B-1a cells, but loss of cyclin D3 is compensated by cyclin D2 in cyclin D3-deficient mice","volume":"177","author":"Mataraza","year":"2006","journal-title":"J. Immunol."},{"key":"2025032409254754100_r5","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1084\/jem.189.11.1685","article-title":"Early induction of cyclin D2 expression in phorbol ester-responsive B-1 lymphocytes","volume":"189","author":"Tanguay","year":"1999","journal-title":"J. Exp. Med."},{"key":"2025032409254754100_r6","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/j.autrev.2005.10.007","article-title":"Role of B-1a cells in autoimmunity","volume":"5","author":"Duan","year":"2006","journal-title":"Autoimmun. Rev."},{"key":"2025032409254754100_r7","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1002\/eji.200940050","article-title":"Class switching and consecutive loss of dsDNA-reactive B1a B cells from the peritoneal cavity during murine lupus development","volume":"40","author":"Enghard","year":"2010","journal-title":"Eur. J. Immunol."},{"key":"2025032409254754100_r8","doi-asserted-by":"crossref","first-page":"4251","DOI":"10.1172\/JCI42213","article-title":"The proteoglycan biglycan regulates expression of the B cell chemoattractant CXCL13 and aggravates murine lupus nephritis","volume":"120","author":"Moreth","year":"2010","journal-title":"J. Clin. Invest."},{"key":"2025032409254754100_r9","doi-asserted-by":"crossref","first-page":"1652","DOI":"10.1002\/1529-0131(199809)41:9<1652::AID-ART17>3.0.CO;2-W","article-title":"Accumulation of splenic B1a cells with potent antigen-presenting capability in NZM2410 lupus-prone mice","volume":"41","author":"Mohan","year":"1998","journal-title":"Arthritis Rheum."},{"key":"2025032409254754100_r10","doi-asserted-by":"crossref","first-page":"2400","DOI":"10.1002\/eji.200737296","article-title":"Reciprocal generation of Th1\/Th17 and T(reg) cells by B1 and B2 B cells","volume":"37","author":"Zhong","year":"2007","journal-title":"Eur. J. Immunol."},{"key":"2025032409254754100_r11","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1084\/jem.20101499","article-title":"Human B1 cells in umbilical cord and adult peripheral blood express the novel phenotype CD20+ CD27+ CD43+ CD70-","volume":"208","author":"Griffin","year":"2011","journal-title":"J. Exp. Med."},{"key":"2025032409254754100_r12","doi-asserted-by":"crossref","first-page":"2591","DOI":"10.1084\/jem.20110978","article-title":"A small CD11b(+) human B1 cell subpopulation stimulates T cells and is expanded in lupus","volume":"208","author":"Griffin","year":"2011","journal-title":"J. Exp. Med."},{"key":"2025032409254754100_r13","doi-asserted-by":"crossref","first-page":"6050","DOI":"10.4049\/jimmunol.173.10.6050","article-title":"Mechanisms of peritoneal B-1a cells accumulation induced by murine lupus susceptibility locus Sle2","volume":"173","author":"Xu","year":"2004","journal-title":"J. Immunol."},{"key":"2025032409254754100_r14","doi-asserted-by":"crossref","first-page":"936","DOI":"10.4049\/jimmunol.175.2.936","article-title":"Genetic dissection of the murine lupus susceptibility locus Sle2: contributions to increased peritoneal B-1a cells and lupus nephritis map to different loci","volume":"175","author":"Xu","year":"2005","journal-title":"J. Immunol."},{"key":"2025032409254754100_r15","doi-asserted-by":"crossref","first-page":"6673","DOI":"10.4049\/jimmunol.1002544","article-title":"Cyclin-dependent kinase inhibitor Cdkn2c regulates B cell homeostasis and function in the NZM2410-derived murine lupus susceptibility locus Sle2c1","volume":"186","author":"Xu","year":"2011","journal-title":"J. Immunol."},{"key":"2025032409254754100_r16","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1002\/art.30146","article-title":"The NZM2410-derived lupus susceptibility locus Sle2c1 increases Th17 polarization and induces nephritis in fas-deficient mice","volume":"63","author":"Xu","year":"2011","journal-title":"Arthritis Rheum."},{"key":"2025032409254754100_r17","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.1101\/gad.13.12.1501","article-title":"CDK inhibitors: positive and negative regulators of G1-phase progression","volume":"13","author":"Sherr","year":"1999","journal-title":"Genes Dev."},{"key":"2025032409254754100_r18","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1093\/jmcb\/mjq013","article-title":"RNA interference reveals a requirement for both p18INK4c and p27Kip1 in B lymphopoiesis","volume":"2","author":"Wang","year":"2010","journal-title":"J Mol Cell Biol"},{"key":"2025032409254754100_r19","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/S1074-7613(00)80241-1","article-title":"Induction of cell cycle arrest and B cell terminal differentiation by CDK inhibitor p18(INK4c) and IL-6","volume":"6","author":"Morse","year":"1997","journal-title":"Immunity"},{"key":"2025032409254754100_r20","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/S1074-7613(02)00364-3","article-title":"CDK inhibitor p18(INK4c) is required for the generation of functional plasma cells","volume":"17","author":"Tourigny","year":"2002","journal-title":"Immunity"},{"key":"2025032409254754100_r21","doi-asserted-by":"crossref","first-page":"4992","DOI":"10.4049\/jimmunol.1101992","article-title":"Genetic variation at a Yin-Yang 1 response site regulates the transcription of cyclin-dependent kinase inhibitor p18(INK4C) transcript in lupus-prone mice","volume":"188","author":"Potula","year":"2012","journal-title":"J. Immunol."},{"key":"2025032409254754100_r22","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1038\/384470a0","article-title":"Cyclin D2 is an FSH-responsive gene involved in gonadal cell proliferation and oncogenesis","volume":"384","author":"Sicinski","year":"1996","journal-title":"Nature"},{"key":"2025032409254754100_r23","doi-asserted-by":"crossref","first-page":"6670","DOI":"10.1073\/pnas.97.12.6670","article-title":"Genetic reconstitution of systemic lupus erythematosus immunopathology with polycongenic murine strains","volume":"97","author":"Morel","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032409254754100_r24","doi-asserted-by":"crossref","first-page":"3028","DOI":"10.1002\/eji.200838417","article-title":"Defective B-cell response to T-dependent immunization in lupus-prone mice","volume":"38","author":"Niu","year":"2008","journal-title":"Eur. J. Immunol."},{"key":"2025032409254754100_r25","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1016\/j.immuni.2006.10.017","article-title":"Identification of anergic B cells within a wild-type repertoire","volume":"25","author":"Merrell","year":"2006","journal-title":"Immunity"},{"key":"2025032409254754100_r26","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.clim.2006.03.009","article-title":"STAT4 deficiency reduces autoantibody production and glomerulonephritis in a mouse model of lupus","volume":"120","author":"Xu","year":"2006","journal-title":"Clin. Immunol."},{"key":"2025032409254754100_r27","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1016\/j.biocel.2009.10.011","article-title":"The role of B cells in lupus pathogenesis","volume":"42","author":"Nashi","year":"2010","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"2025032409254754100_r28","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.immuni.2005.04.011","article-title":"B-1a and B-1b cells exhibit distinct developmental requirements and have unique functional roles in innate and adaptive immunity to S. pneumoniae","volume":"23","author":"Haas","year":"2005","journal-title":"Immunity"},{"key":"2025032409254754100_r29","doi-asserted-by":"crossref","first-page":"454","DOI":"10.4049\/jimmunol.159.1.454","article-title":"Genetic dissection of systemic lupus erythematosus pathogenesis: Sle2 on murine chromosome 4 leads to B cell hyperactivity","volume":"159","author":"Mohan","year":"1997","journal-title":"J. Immunol."},{"key":"2025032409254754100_r30","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1038\/sj.gene.6364335","article-title":"Identification of chromosome intervals from 129 and C57BL\/6 mouse strains linked to the development of systemic lupus erythematosus","volume":"7","author":"Heidari","year":"2006","journal-title":"Genes Immun."},{"key":"2025032409254754100_r31","doi-asserted-by":"crossref","first-page":"6256","DOI":"10.4049\/jimmunol.0901463","article-title":"Identification and characterization of a lupus suppressor 129 locus on chromosome 3","volume":"184","author":"Carlucci","year":"2010","journal-title":"J. Immunol."},{"key":"2025032409254754100_r32","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/0167-5699(92)90066-G","article-title":"The lpr and gld genes in systemic autoimmunity: life and death in the Fas lane","volume":"13","author":"Cohen","year":"1992","journal-title":"Immunol. Today"},{"key":"2025032409254754100_r33","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1097\/BOR.0b013e32833c62b0","article-title":"Interleukin-17-producing T cells in lupus","volume":"22","author":"Crisp\u00edn","year":"2010","journal-title":"Curr. Opin. Rheumatol."},{"key":"2025032409254754100_r34","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/j.cell.2004.08.002","article-title":"Mammalian cells cycle without the D-type cyclin-dependent kinases Cdk4 and Cdk6","volume":"118","author":"Malumbres","year":"2004","journal-title":"Cell"},{"key":"2025032409254754100_r35","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/1747-1028-1-10","article-title":"Cdk2 and Cdk4 cooperatively control the expression of Cdc2","volume":"1","author":"Berthet","year":"2006","journal-title":"Cell Div."},{"key":"2025032409254754100_r36","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1038\/ni.1741","article-title":"Interleukin 17 acts in synergy with B cell-activating factor to influence B cell biology and the pathophysiology of systemic lupus erythematosus","volume":"10","author":"Doreau","year":"2009","journal-title":"Nat. Immunol."},{"key":"2025032409254754100_r37","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.immuni.2009.01.001","article-title":"The many roles of FAS receptor signaling in the immune system","volume":"30","author":"Strasser","year":"2009","journal-title":"Immunity"},{"key":"2025032409254754100_r38","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1006\/bbrc.1993.1262","article-title":"Transcriptional repression and differential splicing of Fas mRNA by early transposon (ETn) insertion in autoimmune lpr mice","volume":"191","author":"Kobayashi","year":"1993","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2025032409254754100_r39","doi-asserted-by":"crossref","first-page":"3285","DOI":"10.4049\/jimmunol.167.6.3285","article-title":"An important role of CDK inhibitor p18(INK4c) in modulating antigen receptor-mediated T cell proliferation","volume":"167","author":"Kovalev","year":"2001","journal-title":"J. Immunol."},{"key":"2025032409254754100_r40","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1038\/gene.2009.5","article-title":"A regulatory SNP at position -899 in CDKN1A is associated with systemic lupus erythematosus and lupus nephritis","volume":"10","author":"Kim","year":"2009","journal-title":"Genes Immun."},{"key":"2025032409254754100_r41","doi-asserted-by":"crossref","first-page":"2296","DOI":"10.4049\/jimmunol.178.4.2296","article-title":"p21CIP1\/WAF1 controls proliferation of activated\/memory T cells and affects homeostasis and memory T cell responses","volume":"178","author":"Arias","year":"2007","journal-title":"J. Immunol."},{"key":"2025032409254754100_r42","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.immuni.2010.12.010","article-title":"Deficiency of Rap1-binding protein RAPL causes lymphoproliferative disorders through mislocalization of p27kip1","volume":"34","author":"Katagiri","year":"2011","journal-title":"Immunity"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/189\/6\/2931\/61715532\/1200556.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/189\/6\/2931\/61715532\/1200556.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,27]],"date-time":"2025-03-27T06:56:35Z","timestamp":1743058595000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/189\/6\/2931\/7993757"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,9]]},"references-count":42,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2012,9,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1200556","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2012,9]]},"published":{"date-parts":[[2012,9]]}}}