Exaggerated follicular helper T-cell responses in patients with LRBA deficiency caused by failure of CTLA4-mediated regulation

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dc.contributor.authorAlroqi, Fayhan J.
dc.contributor.authorCharbonnier, Louis-Marie
dc.contributor.authorBaris, Safa
dc.contributor.authorKiykim, Ayca
dc.contributor.authorChou, Janet
dc.contributor.authorPlatt, Craig D.
dc.contributor.authorAlgassim, Abdulrahman
dc.date.accessioned2024-02-23T14:12:29Z
dc.date.available2024-02-23T14:12:29Z
dc.date.issued2018
dc.departmentNEÜen_US
dc.description.abstractBackground: LPS-responsive beige-like anchor protein (LRBA) and cytotoxic T lymphocyte-associated antigen 4 (CTLA4) deficiencies give rise to overlapping phenotypes of immune dysregulation and autoimmunity, with dramatically increased frequencies of circulating follicular helper T (cTFH) cells. Objective: We sought to determine the mechanisms of cTFH cell dysregulation in patients with LRBA deficiency and the utility of monitoring cTFH cells as a correlate of clinical response to CTLA4-Ig therapy. Methods: cTFH cells and other lymphocyte subpopulations were characterized. Functional analyses included in vitro follicular helper T (TFH) cell differentiation and cTFH naive B-cell cocultures. Serum soluble IL-2 receptor a chain levels and in vitro immunoglobulin production by cultured B cells were quantified by using ELISA. Results: cTFH cell frequencies in patients with LRBA or CTLA4 deficiency sharply decreased with CTLA4-Ig therapy in parallel with other markers of immune dysregulation, including soluble IL-2 receptor a chain, CD45RO(+)CD4(+) effector T cells, and autoantibodies, and this was predictive of favorable clinical responses. cTFH cells in patients with LRBA deficiency were biased toward a TH1-like cell phenotype, which was partially reversed by CTLA4-Ig therapy. LRBA-sufficient but not LRBA-deficient regulatory T cells suppressed in vitro TFH cell differentiation in a CTLA4-dependent manner. LRBA-deficient TFH cells supported in vitro antibody production by naive LRBA-sufficient B cells. Conclusions: cTFH cell dysregulation in patients with LRBA deficiency reflects impaired control of TFH cell differentiation because of profoundly decreased CTLA4 expression on regulatory T cells and probably contributes to autoimmunity in patients with this disease. Serial monitoring of cTFH cell frequencies is highly useful in gauging the clinical response of LRBA-deficient patients to CTLA4-Ig therapy.en_US
dc.description.sponsorshipNational Institutes of Health [5R01AI065617, 4R01AI100315]; Scientific and Technological Research Council of Turkey [1059B191300622]en_US
dc.description.sponsorshipSupported by National Institutes of Health grants 5R01AI065617 (to T.A.C.) and 4R01AI100315 (to R.S.G.) and a grant from the Scientific and Technological Research Council of Turkey (1059B191300622; to S.K.).en_US
dc.identifier.doi10.1016/j.jaci.2017.05.022
dc.identifier.endpage+en_US
dc.identifier.issn0091-6749
dc.identifier.issn1097-6825
dc.identifier.issue3en_US
dc.identifier.pmid28601686en_US
dc.identifier.scopus2-s2.0-85023604425en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage1050en_US
dc.identifier.urihttps://doi.org/10.1016/j.jaci.2017.05.022
dc.identifier.urihttps://hdl.handle.net/20.500.12452/12079
dc.identifier.volume141en_US
dc.identifier.wosWOS:000426974800025en_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.subjectAutoantibodiesen_US
dc.subjectLps-Responsive Beige-Like Anchoren_US
dc.subjectCytotoxic T Lymphocyte-Associated Antigen 4en_US
dc.subjectRegulatory T Cellsen_US
dc.subjectFollicular Helper T Cellsen_US
dc.subjectFollicular Regulatory T Cellsen_US
dc.titleExaggerated follicular helper T-cell responses in patients with LRBA deficiency caused by failure of CTLA4-mediated regulationen_US
dc.typeArticleen_US

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