title: Naturally occurring mutation affecting the MyD88-binding site of TNFRSF13B impairs triggering of class switch recombination.
abstract: Mutations in the transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) were previously found to be associated with hypogammaglobulinemia in humans. It has been shown that proliferation inducing ligand (APRIL) elicits class switch recombination (CSR) by inducing recruitment of MyD88 to a TACI highly conserved cytoplasmic domain (THC). We have identified a patient with hypogammaglobulinemia carrying a missense mutation (S231R) predicted to affect the THC. Aiming to evaluate the relevance of this novel mutation of TACI in CSR induction, we tested the ability of TACI, TLR9, or/and CD40 ligands to trigger CSR in naive B cells and B-cell lines carrying S231R. IgG secretion was impaired when triggered by TACI or/and TLR9 ligands on S231R-naive B cells. Likewise, these stimuli induced less expression of activation-induced cytidine deaminase, I(γ)1-C(μ), and I(γ)1-C(μ), while induction by optimal CD40 stimulation was indistinguishable from controls. These cells also showed an impaired cooperation between TACI and TLR9 pathways, as well as a lack of APRIL-mediated enhancement of CD40 activation in suboptimal conditions. Finally, after APRIL ligation, S231R-mutated TACI failed to colocalize with MyD88. Collectively, these results highlight the requirement of an intact MyD88-binding site in TACI to trigger CSR.
authors.affiliation: Servicio de Inmunología y Reumatología, Hospital Nacional de Pediatría Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina.
authors.forename: Maria B
authors.initials: MB
authors.lastname: Almejun
authors.forename: Montserrat
authors.initials: M
authors.lastname: Cols
authors.forename: Marta
authors.initials: M
authors.lastname: Zelazko
authors.forename: Matias
authors.initials: M
authors.lastname: Oleastro
authors.forename: Andrea
authors.initials: A
authors.lastname: Cerutti
authors.forename: Pablo
authors.initials: P
authors.lastname: Oppezzo
authors.forename: Charlotte
authors.initials: C
authors.lastname: Cunningham-Rundles
authors.forename: Silvia
authors.initials: S
authors.lastname: Danielian
mesh_terms: D000293:Adolescent; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D001665:Binding Sites; D019013:CD40 Antigens / Q000378:metabolism; D002478:Cells, Cultured; D017074:Common Variable Immunodeficiency / Q000235:genetics / Q000276:immunology; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000235:genetics*; D009154:Mutation; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D011485:Protein Binding; D015398:Signal Transduction; D053303:Transmembrane Activator and CAML Interactor Protein / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D060152:V(D)J Recombination
chemical_list: D019013:CD40 Antigens; D053594:Myeloid Differentiation Factor 88; C108467:TNFRSF13B protein, human; D053303:Transmembrane Activator and CAML Interactor Protein