TACI mutations and impaired B-cell function in subjects with CVID and healthy heterozygotes

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.

CVID-associated TACI mutations affect autoreactive B cell selection and activation

“…Previously, the association between TACI mutation(s) and CVID was unclear because many people carrying TACI mutations are healthy and without infectious susceptibility or decreased serum immunoglobulins (18,41). However, we found that all individuals with TACI mutations failed to remove developing autoreactive B cells in the marrow.…”

Differential induction of plasma cells by isoforms of human TACI

“…6 To assess the ability of the TACI to bind BAFF and APRIL in the presence of Fc block, cells were incubated with 100 ng/mL of FLAG-tagged BAFF or FLAG-tagged APRIL (Axxora, San Diego, CA). The cells were washed and examined with streptavidinphycoerythrin by FACS.…”

“…2,4 Although first-degree relatives of CVID subjects who have the same mutations are not commonly hypogammaglobulinemic, 5 activation of the mutant TACI on their B cells still fails to upregulate AICDA mRNA, revealing selective immune defects in these subjects. 6,7 Although TACI activation leads to B-cell activation, it also exerts selected inhibitory functions on B-cell expansion, best studied in mouse models. TACI 2/2 mice are deficient in antibody production to polysaccharide antigens but commonly develop severe lymphoproliferation, with increased numbers of B cells, enlarged spleens, and expanded peripheral B-cell populations leading to autoimmunity 1,8 and, in aging mice, lymphocytic infiltration of organs, membranoproliferative glomerulonephritis, and lymphoma.…”

Anti-B-Cell Therapies in Autoimmune Neurological Diseases: Rationale and Efficacy Trials

“…BAFF-R expression is absent during the early stages of the B-cell lineage; its expression coincides with functional BCR expression by immature B cells in the bone marrow and is essential for Bcell survival and maturation [13,14,26,27]. TACI is mainly expressed on memory B cells and BCMA on plasmablasts and plasma cells [28][29][30]. A number of these molecules are therapeutic targets, as discussed later.…”