TACI mutations and impaired B-cell function in subjects with CVID and healthy heterozygotes - 30/01/13
Corresponding author: Charlotte Cunningham-Rundles, MD, PhD, Department of Medicine, Mount Sinai Medical Center, 1425 Madison Ave, New York City, NY 10029.Abstract |
Background |
Mutations in the gene coding for the transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) are found in 8% to 10% of subjects with common variable immunodeficiency (CVID). Although heterozygous mutations may coincide with immunodeficiency in a few families, most mutation-bearing relatives are not hypogammaglobulinemic. Thus, the role of TACI mutations in producing the immune defect remains unclear.
Objective |
This study examined the expression and function of TACI mutations in healthy heterozygous relatives.
Methods |
We examined the surface and intracellular expression of TACI protein in EBV-transformed B cells of patients and relatives with mutations in 7 families, binding of a proliferation-inducing ligand, and secretion of IgG and IgA by ligand-activated B cells. We tested whether Toll-like receptor 9 agonists increased TACI expression and whether an agonistic anti-TACI antibody could induce activation-induced cytidine deaminase mRNA in those with mutations.
Results |
Intracellular and extracellular TACI expression was defective for B cells of all subjects with mutations, including subjects with CVID and relatives. Although Toll-like receptor 9 triggering normally up-regulates B-cell TACI expression, this was defective for all subjects with mutations. Triggering TACI by an agonistic antibody showed loss of activation-induced cytidine deaminase mRNA induction in all mutation-bearing B cells. However, ligand-induced IgG and IgA production was normal for healthy relatives but not for subjects with CVID.
Conclusion |
Thus, B cells of relatives of subjects with CVID who have mutations in TACI but normal immune globulin levels still have detectable in vitro B-cell defects.
Le texte complet de cet article est disponible en PDF.Key words : CVID, TACI, hypogammaglobulinemia, activation-induced cytidine deaminase, Toll-like receptor 9
Abbreviations used : AID, APRIL, BAFF, BCMA, CpG, CRD1, CVID, FACS, FCS, PBMC, TACI, TLR
Plan
| Supported by the National Institutes of Health AI-101093, AI-467320, and AI-48693 and National Institute of Allergy and Infectious Diseases Contract 03-22 (C.C.-R.). M.M.-G. was recipient of a fellowship (CM05/00145) from the Ministerio de Sanidad y Consumo of Spain. |
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| Disclosure of potential conflict of interest: C. Cunningham-Rundles has received grants from the National Institutes of Health and has received royalties from UpToDate. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 131 - N° 2
P. 468-476 - février 2013 Retour au numéro
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