CD19 controls Toll-like receptor 9 responses in human B cells

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dc.contributor.authorMorbach, Henner
dc.contributor.authorSchickel, Jean-Nicolas
dc.contributor.authorCunningham-Rundles, Charlotte
dc.contributor.authorConley, Mary Ellen
dc.contributor.authorReisli, İsmail
dc.contributor.authorLuis Franco, Jose
dc.contributor.authorMeffre, Eric
dc.date.accessioned2020-03-26T19:23:16Z
dc.date.available2020-03-26T19:23:16Z
dc.date.issued2016
dc.departmentSelçuk Üniversitesien_US
dc.description.abstractBackground: CD19 is a B cell-specific molecule that serves as a major costimulatory molecule for amplifying B-cell receptor (BCR) responses. Biallelic CD19 gene mutations cause common variable immunodeficiency in human subjects. BCR- and Toll-like receptor (TLR) 9-induced B-cell responses are impaired in most patients with common variable immunodeficiency. Objective: We sought to analyze whether CD19 is required for TLR9 function in human B cells. Methods: Expression of surface activation markers was assessed after anti-IgM or CpG stimulation by using flow cytometry on B cells from patients with 1 or 2 defective CD19 alleles, which decrease or abrogate CD19 expression, respectively. The phosphorylation or interaction of signaling molecules was analyzed by using phospho flow cytometry, immunoblotting, or co-immunoprecipitation in CD19-deficient or control B cells and in a B-cell line in which CD19 has been knocked down with lentivirus-transduced short hairpin RNA. Results: B cells from subjects with 1 or 2 defective CD19 alleles showed defective upregulation in vitro of CD86, transmembrane activator and CAML interactor (TACI), and CD23 activation markers after TLR9 stimulation. TLR9 ligands normally induce phosphorylation of CD19 through myeloid differentiation primary response gene-88 (MYD88)/proline-rich tyrosine kinase 2 (PYK2)/LYN complexes, which allows recruitment of phosphoinositide 3-kinase (PI3K) and phosphorylation of Bruton tyrosine kinase (BTK) and AKT in human B cells with a different kinetic than that of BCRs. In addition, inhibition of PI3K, AKT, or BTK, as well as BTK deficiency, also resulted in TLR9 activation defects in B cells similar to those in patients with CD19 deficiency. Conclusion: CD19 is required for TLR9-induced B-cell activation. Hence CD19/PI3K/AKT/BTK is an essential axis integrating BCRs and TLR9 signaling in human B cells.en_US
dc.description.sponsorshipNational Institute of Health (NIH)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [AI061093, AI071087, AI082713, AI095848]; German Research FoundationGerman Research Foundation (DFG) [MO 2160/2-1]en_US
dc.description.sponsorshipSupported by National Institute of Health (NIH) grants AI061093, AI071087, AI082713, and AI095848 (to E.M.) and German Research Foundation grant MO 2160/2-1 (to H.M.).en_US
dc.identifier.doi10.1016/j.jaci.2015.08.040en_US
dc.identifier.endpage+en_US
dc.identifier.issn0091-6749en_US
dc.identifier.issn1097-6825en_US
dc.identifier.issue3en_US
dc.identifier.pmid26478008en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage889en_US
dc.identifier.urihttps://dx.doi.org/10.1016/j.jaci.2015.08.040
dc.identifier.urihttps://hdl.handle.net/20.500.12395/33334
dc.identifier.volume137en_US
dc.identifier.wosWOS:000371897500033en_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.selcuk20240510_oaigen_US
dc.subjectB cellsen_US
dc.subjectToll-like receptor 9en_US
dc.subjectCD19en_US
dc.subjectphosphoinositide 3-kinaseen_US
dc.subjectBruton tyrosine kinaseen_US
dc.subjectAKTen_US
dc.subjectcommon variable immunodeficiencyen_US
dc.titleCD19 controls Toll-like receptor 9 responses in human B cellsen_US
dc.typeArticleen_US

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