Dedicator of cytokinesis 8-deficient patients have a breakdown in peripheral B-cell tolerance and defective regulatory T cells

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dc.contributor.authorJanssen, Erin
dc.contributor.authorMorbach, Henner
dc.contributor.authorUllas, Sumana
dc.contributor.authorBannock, Jason M.
dc.contributor.authorMassad, Christopher
dc.contributor.authorMenard, Laurence
dc.contributor.authorBarlan, Isil
dc.date.accessioned2024-02-23T14:12:29Z
dc.date.available2024-02-23T14:12:29Z
dc.date.issued2014
dc.departmentNEÜen_US
dc.description.abstractBackground: Dedicator of cytokinesis 8 (DOCK8) deficiency is typified by recurrent infections, increased serum IgE levels, eosinophilia, and a high incidence of allergic and autoimmune manifestations. Objective: We sought to determine the role of DOCK8 in the establishment and maintenance of human B-cell tolerance. Methods: Autoantibodies were measured in the plasma of DOCK8-deficient patients. The antibody-coding genes from new emigrant/transitional and mature naive B cells were cloned and assessed for their ability to bind self-antigens. RegulatoryT(Treg) cells in the blood were analyzed by means of flow cytometry, and their function was tested by examining their capacity to inhibit the proliferation of CD4(+)CD25(-) effector T cells. Results: DOCK8-deficient patients had increased levels of autoantibodies in their plasma. We determined that central B-cell tolerance did not require DOCK8, as evidenced by the normally low frequency of polyreactive new emigrant/transitional B cells in DOCK8-deficient patients. In contrast, autoreactive B cells were enriched in the mature naive B-cell compartment, revealing a defective peripheral B-cell tolerance checkpoint. In addition, we found that Treg cells were decreased and exhibited impaired suppressive activity in DOCK8-deficient patients. Conclusions: Our data support a critical role for DOCK8 in Treg cell homeostasis and function and the enforcement of peripheral B-cell tolerance.en_US
dc.description.sponsorshipNational Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID) [AI061093, AI071087, AI082713, AI095848, AI100315, HL059561, 5K 12HD052896]; Manton Foundation; German Research Foundation [DFG MO2160/2-1]; Dubai-Harvard Foundation for Medical Research; Jeffrey Modell Foundation; Intramural Research Program of the NIH; NIAID; Kuwait Foundation for the Advancement of Sciences [2010-1302-05]en_US
dc.description.sponsorshipSupported by National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID) grants AI061093, AI071087, AI082713, and AI095848 (to E.M.); AI100315 and HL059561 (to R.S.G.); and 5K 12HD052896 (to E.J.), as well as by grants from the Manton Foundation (to E.J.), German Research Foundation grant DFG MO2160/2-1 (to H.M.), the Dubai-Harvard Foundation for Medical Research and the Jeffrey Modell Foundation (to R.S.G.), the Intramural Research Program of the NIH, NIAID (to H.S.), and the Kuwait Foundation for the Advancement of Sciences 2010-1302-05 (to W.A.-H.).en_US
dc.identifier.doi10.1016/j.jaci.2014.07.042
dc.identifier.endpage1374en_US
dc.identifier.issn0091-6749
dc.identifier.issn1097-6825
dc.identifier.issue6en_US
dc.identifier.pmid25218284en_US
dc.identifier.scopus2-s2.0-84908440532en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage1365en_US
dc.identifier.urihttps://doi.org/10.1016/j.jaci.2014.07.042
dc.identifier.urihttps://hdl.handle.net/20.500.12452/12074
dc.identifier.volume134en_US
dc.identifier.wosWOS:000346075400019en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherMosby-Elsevieren_US
dc.relation.ispartofJournal Of Allergy And Clinical Immunologyen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectDedicator Of Cytokinesis 8en_US
dc.subjectAutoimmunityen_US
dc.subjectB-Cell Toleranceen_US
dc.subjectRegulatory T Cellsen_US
dc.titleDedicator of cytokinesis 8-deficient patients have a breakdown in peripheral B-cell tolerance and defective regulatory T cellsen_US
dc.typeArticleen_US

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