Human CD19 and CD40L deficiencies impair antibody selection and differentially affect somatic hypermutation

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dc.contributor.authorvan Zelm, Menno C.
dc.contributor.authorBartol, Sophinus J. W.
dc.contributor.authorDriessen, Gertjan J.
dc.contributor.authorMascart, Francoise
dc.contributor.authorReisli, Ismail
dc.contributor.authorFranco, Jose L.
dc.contributor.authorWolska-Kusnierz, Beata
dc.date.accessioned2024-02-23T14:12:29Z
dc.date.available2024-02-23T14:12:29Z
dc.date.issued2014
dc.departmentNEÜen_US
dc.description.abstractBackground: Individuals with genetic defects in CD40 ligand (CD40L) or B-cell antigen receptor coreceptor molecules CD19 and CD81 suffer from an antibody deficiency. Still, these patients carry low levels of memory B cells and serum antibodies. Objective: We sought to assess why the remaining memory B cells and antibodies in the blood of these patients do not provide functional immunity. Methods: We included CD19-deficient patients (n = 8), CD40L-deficient patients (n = 8), and healthy controls (n = 50) to perform detailed flow cytometry on blood B cells, molecular analysis of IgA and IgG transcripts, as well as functional analysis of B-cell activation. Results: CD19-deficient and CD40L-deficient patients carried reduced numbers of all memory B-cell subsets except CD27(-) IgA(+) B cells. Their immunoglobulin heavy chain class-switched transcripts contained less somatic mutations and reduced usage of IgM-distal IgG2 and IgA2 subclasses. The selection strength of mutations for antigen binding was significantly lower than in controls, whereas selection to maintain superantigen binding was normal. Furthermore, the patients showed impaired selection against inherently autoreactive properties of their immunoglobulins. Somatic hypermutation analysis revealed decreased activation-induced cytidine deaminase and uracil-DNA glycosylase 2 activity in CD40L deficiency and increased uracil-DNA glycosylase 2 but decreased mismatch repair in CD19 deficiency. B-cell activation studies revealed that this was at least in part due to transcriptional regulation of DNA repair genes. Conclusions: This study on CD19 and CD40L deficiencies illustrates that both the B-cell antigen receptor and CD40 signaling pathways are required for the selection of immunoglobulin reactivity. Still, they differentially mediate DNA repair pathways during somatic hypermutation, thereby together shaping the human in vivo antigen-experienced B-cell repertoire.en_US
dc.description.sponsorshipErasmus University Rotterdam (EUR-Fellowship); ZonMW Vidi grant [015.008.046]en_US
dc.description.sponsorshipThis work was supported by a grant from Erasmus University Rotterdam (EUR-Fellowship) to M.C.v.Z., and ZonMW Vidi grant 015.008.046 to M.v.d.B.en_US
dc.identifier.doi10.1016/j.jaci.2013.11.015
dc.identifier.endpage+en_US
dc.identifier.issn0091-6749
dc.identifier.issn1097-6825
dc.identifier.issue1en_US
dc.identifier.pmid24418477en_US
dc.identifier.scopus2-s2.0-84903730984en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage135en_US
dc.identifier.urihttps://doi.org/10.1016/j.jaci.2013.11.015
dc.identifier.urihttps://hdl.handle.net/20.500.12452/12072
dc.identifier.volume134en_US
dc.identifier.wosWOS:000338930300018en_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.subjectCd19en_US
dc.subjectCd40len_US
dc.subjectSomatic Hypermutationen_US
dc.subjectSelectionen_US
dc.subjectImmunoglobulinen_US
dc.subjectAutoreactivityen_US
dc.titleHuman CD19 and CD40L deficiencies impair antibody selection and differentially affect somatic hypermutationen_US
dc.typeArticleen_US

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