Naturally occurring mutation affecting the MyD88-binding site ofTNFRSF13Bimpairs triggering of class switch recombination
| Autor: | Montserrat Cols, Pablo Oppezzo, María Belén Almejún, Charlotte Cunningham-Rundles, Andrea Cerutti, Marta Zelazko, Matías Oleastro, Silvia Danielian |
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| Rok vydání: | 2013 |
| Předmět: |
0303 health sciences
CD40 Common variable immunodeficiency Immunology V(D)J recombination Naive B cell chemical and pharmacologic phenomena Cytidine deaminase Biology medicine.disease Cell biology 03 medical and health sciences 0302 clinical medicine Immunoglobulin class switching medicine biology.protein Immunology and Allergy Binding site Signal transduction 030304 developmental biology 030215 immunology |
| Zdroj: | European Journal of Immunology. 43:805-814 |
| ISSN: | 0014-2980 |
| DOI: | 10.1002/eji.201242945 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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