{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T11:07:27Z","timestamp":1760267247178},"reference-count":54,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2013,9,19]],"date-time":"2013-09-19T00:00:00Z","timestamp":1379548800000},"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":[[2013,9,19]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>OS is a severe combined immunodeficiency characterized by erythrodermia and protracted diarrhea as a result of infiltration of oligoclonal-activated T cells, caused by hypomorphic mutations in RAGs. The RAG2R229Q mouse model fully recapitulates the clinical OS phenotype. We evaluated whether T and B cell defects, together with the abnormal lymphoid structure, could affect DC homeostasis and function. High density of LCs was observed in skin biopsies of Omenn patients and in the derma of RAG2R229Q mice, correlating with the presence of erythrodermia. In vivo models of cutaneous skin painting and CHS demonstrated a decreased migration of RAG2R229Q DCs\u2014in particular, LCs\u2014into draining LNs. Interestingly, at steady state, RAG2R229Q mice showed a reduction in DC number in all hematopoietic organs except LNs. Analysis of the MHCII marker revealed a diminished expression also upon the LPS-driven inflammatory condition. Despite the decreased number of peripheral DCs, BM pre-cDCs were present in normal number compared with RAG2+\/+ controls, whereas pDCs and monocytes were reduced significantly. Overall, these results point to a secondary defect in the DC compartment, which contributes to clinical manifestations and autoimmunity in OS.<\/jats:p>","DOI":"10.1189\/jlb.0713365","type":"journal-article","created":{"date-parts":[[2013,9,20]],"date-time":"2013-09-20T09:22:14Z","timestamp":1379668934000},"page":"1221-1230","source":"Crossref","is-referenced-by-count":8,"title":["Hypomorphic mutation in the RAG2 gene affects dendritic cell distribution and migration"],"prefix":"10.1093","volume":"94","author":[{"given":"Virginia","family":"Maina","sequence":"first","affiliation":[{"name":"Milan Unit, Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche , Milan, Italy"},{"name":"Humanitas Clinical and Research Center , Rozzano, Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Veronica","family":"Marrella","sequence":"additional","affiliation":[{"name":"Milan Unit, Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche , Milan, Italy"},{"name":"Humanitas Clinical and Research Center , Rozzano, Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefano","family":"Mantero","sequence":"additional","affiliation":[{"name":"Milan Unit, Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche , Milan, Italy"},{"name":"Humanitas Clinical and Research Center , Rozzano, Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barbara","family":"Cassani","sequence":"additional","affiliation":[{"name":"Milan Unit, Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche , Milan, Italy"},{"name":"Humanitas Clinical and Research Center , Rozzano, Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Fontana","sequence":"additional","affiliation":[{"name":"Department of Molecular and Translational Medicine, University of Brescia , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Achille","family":"Anselmo","sequence":"additional","affiliation":[{"name":"Humanitas Clinical and Research Center , Rozzano, Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annalisa","family":"Del Prete","sequence":"additional","affiliation":[{"name":"Humanitas Clinical and Research Center , Rozzano, Milan, Italy"},{"name":"Department of Molecular and Translational Medicine, University of Brescia , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvano","family":"Sozzani","sequence":"additional","affiliation":[{"name":"Humanitas Clinical and Research Center , Rozzano, Milan, Italy"},{"name":"Department of Molecular and Translational Medicine, University of Brescia , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paolo","family":"Vezzoni","sequence":"additional","affiliation":[{"name":"Milan Unit, Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche , Milan, Italy"},{"name":"Humanitas Clinical and Research Center , Rozzano, Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pietro Luigi","family":"Poliani","sequence":"additional","affiliation":[{"name":"Department of Molecular and Translational Medicine, University of Brescia , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Villa","sequence":"additional","affiliation":[{"name":"Milan Unit, Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche , Milan, Italy"},{"name":"Humanitas Clinical and Research Center , Rozzano, Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2013,9,19]]},"reference":[{"key":"2023032711165890800_","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.1016\/j.jaci.2008.09.037","article-title":"Omenn syndrome: inflammation in leaky severe combined immunodeficiency","volume":"122","author":"Villa","year":"2008","journal-title":"J. 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Invest."},{"key":"2023032711165890800_","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.jaci.2009.10.023","article-title":"Defect of regulatory T cells in patients with Omenn syndrome","volume":"125","author":"Cassani","year":"2010","journal-title":"J. Allergy Clin. Immunol."},{"key":"2023032711165890800_","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1146\/annurev.immunol.20.100301.064828","article-title":"Antigen presentation and T cell stimulation by dendritic cells","volume":"20","author":"Guermonprez","year":"2002","journal-title":"Ann. Rev. Immun."},{"key":"2023032711165890800_","doi-asserted-by":"crossref","first-page":"1853","DOI":"10.1084\/jem.20090746","article-title":"Feedback control of regulatory T cell homeostasis by dendritic cells in vivo","volume":"206","author":"Darrasse-Jeze","year":"2009","journal-title":"J. Exp. 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Pathol."},{"key":"2023032711165890800_","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1007\/BF00792602","article-title":"Lymph node pathology in primary combined immunodeficiency diseases","volume":"19","author":"Facchetti","year":"1998","journal-title":"Springer Semin. Immunopathol."},{"key":"2023032711165890800_","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1016\/S0092-8674(00)81448-8","article-title":"Partial V(D)J recombination activity leads to Omenn syndrome","volume":"93","author":"Villa","year":"1998","journal-title":"Cell"},{"key":"2023032711165890800_","doi-asserted-by":"crossref","first-page":"3468","DOI":"10.1182\/blood.V94.10.3468.422k34_3468_3478","article-title":"Intrathymic restriction and peripheral expansion of the T-cell repertoire in Omenn syndrome","volume":"94","author":"Signorini","year":"1999","journal-title":"Blood"},{"key":"2023032711165890800_","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.jim.2007.05.001","article-title":"Production of monoclonal antibodies that recognize the extracellular domain of mouse langerin\/CD207","volume":"324","author":"Cheong","year":"2007","journal-title":"J. Immunol. 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Med."},{"key":"2023032711165890800_","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1038\/nri2455","article-title":"Origin, homeostasis and function of Langerhans cells and other Langerin-expressing dendritic cells","volume":"8","author":"Merad","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"2023032711165890800_","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1111\/j.0105-2896.2009.00877.x","article-title":"Instructive cytokine signals in dendritic cell lineage commitment","volume":"234","author":"Schmid","year":"2010","journal-title":"Immunol. Rev."},{"key":"2023032711165890800_","doi-asserted-by":"crossref","first-page":"4829","DOI":"10.1182\/blood-2011-03-344960","article-title":"Bone marrow dendritic cell progenitors sense pathogens via Toll-like receptors and subsequently migrate to inflamed lymph nodes","volume":"118","author":"Schmid","year":"2011","journal-title":"Blood"},{"key":"2023032711165890800_","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1146\/annurev.immunol.21.120601.141007","article-title":"Biology of hematopoietic stem cells and progenitors: implications for clinical application","volume":"21","author":"Kondo","year":"2003","journal-title":"Ann. Rev. Immunol."},{"key":"2023032711165890800_","volume-title":"Curr. Protoc. Cytom.","author":"Roederer","year":"2002"},{"key":"2023032711165890800_","doi-asserted-by":"crossref","first-page":"3505","DOI":"10.1038\/sj.emboj.7600361","article-title":"Defective dendritic cell migration and activation of adaptive immunity in PI3K\u03b3-deficient mice","volume":"23","author":"Del Prete","year":"2004","journal-title":"EMBO J."},{"key":"2023032711165890800_","doi-asserted-by":"crossref","first-page":"7468","DOI":"10.4049\/jimmunol.181.11.7468","article-title":"Cutting edge: migration of Langerhans dendritic cells is impaired in autoimmune dermatitis","volume":"181","author":"Eriksson","year":"2008","journal-title":"J. Immunol."},{"key":"2023032711165890800_","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/S1074-7613(03)00230-9","article-title":"TRAF6 is a critical factor for dendritic cell maturation and development","volume":"19","author":"Kobayashi","year":"2003","journal-title":"Immunity"},{"key":"2023032711165890800_","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1038\/nature08118","article-title":"CD14 regulates the dendritic cell life cycle after LPS exposure through NFAT activation","volume":"460","author":"Zanoni","year":"2009","journal-title":"Nature"},{"key":"2023032711165890800_","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1038\/nm1038","article-title":"Depletion of host Langerhans cells before transplantation of donor alloreactive T cells prevents skin graft-versus-host disease","volume":"10","author":"Merad","year":"2004","journal-title":"Nat. Med."},{"key":"2023032711165890800_","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/j.immuni.2004.07.019","article-title":"Langerhans cells activate naive self-antigen-specific CD8 T cells in the steady state","volume":"21","author":"Mayerova","year":"2004","journal-title":"Immunity"},{"key":"2023032711165890800_","doi-asserted-by":"crossref","first-page":"114","DOI":"10.3109\/10520299509108327","article-title":"Differentiation of Langerhans cells from interdigitating cells using CD1a and S-100 protein antibodies","volume":"70","author":"Shinzato","year":"1995","journal-title":"Biotech. Histochem."},{"key":"2023032711165890800_","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1097\/PAI.0b013e31822053a7","article-title":"Do indeterminate cells follow the footsteps of Langerhans cells and migrate from the skin to the lymph node?","volume":"20","author":"Rezk","year":"2012","journal-title":"Appl. Immunohistochem. Mol. Morphol."},{"key":"2023032711165890800_","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1111\/j.0303-6987.2005.00382.x","article-title":"Indeterminate cell histiocytosis: fact or fiction?","volume":"32","author":"Ratzinger","year":"2005","journal-title":"J. Cutan. Pathol."},{"key":"2023032711165890800_","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1038\/jid.2012.284","article-title":"Update of immune events in the murine contact hypersensitivity model: toward the understanding of allergic contact dermatitis","volume":"133","author":"Honda","year":"2013","journal-title":"J. Invest. Dermatol."},{"key":"2023032711165890800_","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1084\/jem.20052367","article-title":"Impaired Langerhans cell migration in psoriasis","volume":"203","author":"Cumberbatch","year":"2006","journal-title":"J. Exp. Med."},{"key":"2023032711165890800_","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1084\/jem.20030448","article-title":"Regulation of dendritic cell migration to the draining lymph node: impact on T lymphocyte traffic and priming","volume":"198","author":"MartIn-Fontecha","year":"2003","journal-title":"J. Exp. Med."},{"key":"2023032711165890800_","doi-asserted-by":"crossref","first-page":"1903","DOI":"10.1084\/jem.20052272","article-title":"Regulation of lymph node vascular growth by dendritic cells","volume":"203","author":"Webster","year":"2006","journal-title":"J. Exp. Med."},{"key":"2023032711165890800_","doi-asserted-by":"crossref","first-page":"8736","DOI":"10.1073\/pnas.0906126107","article-title":"Requirement of CCL17 for CCR7- and CXCR4-dependent migration of cutaneous dendritic cells","volume":"107","author":"Stutte","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023032711165890800_","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1038\/icb.2008.86","article-title":"The impact of circulating dendritic cells on the development and differentiation of thymocytes","volume":"87","author":"Proietto","year":"2009","journal-title":"Immunol. Cell. Biol."},{"key":"2023032711165890800_","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1126\/science.1178331","article-title":"Development of monocytes, macrophages, and dendritic cells","volume":"327","author":"Geissmann","year":"2010","journal-title":"Science"},{"key":"2023032711165890800_","doi-asserted-by":"crossref","first-page":"4535","DOI":"10.4049\/jimmunol.179.7.4535","article-title":"Skin-derived dendritic cells can mediate deletional tolerance of class I-restricted self-reactive T cells","volume":"179","author":"Waithman","year":"2007","journal-title":"J. Immunol."},{"key":"2023032711165890800_","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1084\/jem.20020018","article-title":"Accumulation of immature Langerhans cells in human lymph nodes draining chronically inflamed skin","volume":"196","author":"Geissmann","year":"2002","journal-title":"J. Exp. Med."},{"key":"2023032711165890800_","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1038\/nri1964","article-title":"Tuning inflammation and immunity by chemokine sequestration: decoys and more","volume":"6","author":"Mantovani","year":"2006","journal-title":"Nat. Rev. Immunol."},{"key":"2023032711165890800_","doi-asserted-by":"crossref","first-page":"2340","DOI":"10.4049\/jimmunol.157.6.2340","article-title":"T cell-mediated terminal maturation of dendritic cells: loss of adhesive and phagocytotic capacities","volume":"157","author":"Kitajima","year":"1996","journal-title":"J. Immunol."},{"key":"2023032711165890800_","doi-asserted-by":"crossref","first-page":"3430","DOI":"10.4049\/jimmunol.151.7.3430","article-title":"Deficient antigen presentation by Langerhans cells from athymic (nu\/nu) mice. Restoration with thymic transplantation or administration of cytokines","volume":"151","author":"Grabbe","year":"1993","journal-title":"J. Immunol."},{"key":"2023032711165890800_","doi-asserted-by":"crossref","first-page":"1662","DOI":"10.1002\/eji.201142338","article-title":"Thymocyte death by neglect: contribution of engulfing macrophages","volume":"42","author":"Szondy","year":"2012","journal-title":"Eur. J. Immunol."},{"key":"2023032711165890800_","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1038\/372100a0","article-title":"T-cell apoptosis detected in situ during positive and negative selection in the thymus","volume":"372","author":"Surh","year":"1994","journal-title":"Nature"},{"key":"2023032711165890800_","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1126\/science.1122545","article-title":"Dendritic cell apoptosis in the maintenance of immune tolerance","volume":"311","author":"Chen","year":"2006","journal-title":"Science"},{"key":"2023032711165890800_","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1084\/jem.20030422","article-title":"Direct expansion of functional CD25+ CD4+ regulatory T cells by antigen-processing dendritic cells","volume":"198","author":"Yamazaki","year":"2003","journal-title":"J. Exp. 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