Transmembrane activator and calcium-modulating cyclophilin ligand interactor mutations in common variable immunodeficiency: clinical and immunologic outcomes in heterozygotes

Abstract

Background: Mutations in the gene coding for transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) have been identified in common variable immunodeficiency (CVID). Mutations coincided with immunodeficiency in families, suggesting dominant inheritance.

Objective: Because most subjects with CVID have no immunodeficient family members and heterozygous mutations predominate, the role of TACI mutations in sporadic CVID is unclear.

Methods: TACI was sequenced from the genomic DNA of 176 subjects with CVID and family members. B cells of subjects with or without mutations were examined for binding to the ligand, a proliferation inducing ligand (APRIL), and for proliferation and immunoglobulin production after ligand stimulation. Data analysis was performed to assess the clinical relevance of TACI mutations.

Results: Heterozygous TACI mutations were found in 13 subjects (7.3%). Six with mutations (46%) had episodes of autoimmune thrombocytopenia, in contrast with 12% of 163 subjects without mutations; splenomegaly and splenectomy were significantly increased (P = .012; P = .001.) B cells of some had impaired binding of APRIL and on culture with this ligand were defective in proliferation and immunoglobulin production; however, this was not different from B cells of subjects without mutations. Eight first-degree relatives from 5 families had the same mutations but were not immune-deficient, and their B cells produced normal amounts of IgG and IgA after APRIL stimulation.

Conclusion: Mutations in TACI significantly predispose to autoimmunity and lymphoid hyperplasia in CVID, but additional genetic or environmental factors are required to induce immune deficiency.

Clinical implications: Additional causes of this common immune deficiency syndrome remain to be determined.

FIG 1

Heterozygous mutations may lead to reduced ligand binding. B cells (EBV cell lines) of subjects with TACI mutations indicated were tested to determine the binding of APRIL in comparison with the controls indicated. The mean fluorescence intensity (MFI, x-axis) for B cells (cell counts, y-axis) is shown. Isotype controls are marked in closed areas, surface APRIL fluorescence in open areas. NL, Normal.

FIG 2

APRIL-induced proliferation of B cells. Cells were stained with CFSE (log scale, x-axis, wavelength, 492 nm) and cultured with indicated stimulators for 6 days; y-axis = cell counts. A and B, Non-B and nondividing cells = dense population at the lower right of each panel. The CD19⁺ B-cell population is indicated (top pink rectangle). C and D, CFSE-stained B-cell populations.

FIG 3

Proliferation of B cells of subjects with C104R TACI mutations. As for Fig 2, proliferation of CFSE (x-axis)–labeled B cells of 3 unrelated subjects with CVID with C104R mutations were compared by using stimulators shown. y-axis = cell counts. A, APRIL alone. B, APRIL + IL-10. C, CD40 ligand + IL-10. D, CpG.

FIG 4

IgG and IgA production. Peripheral blood cells of subjects were cultured as shown to assess IgG (A) or IgA (B) production (ng/mL); values minus baseline levels. Four subjects with CVID (no mutations) and 8 subjects with the heterozygous mutations shown are compared or are indicated, ng/mL (y-axis). Results for 8 normal controls are given as means (± SEs). NL, Normal; Pt, patient.

FIG 5

Immunoglobulin production for normal relatives. As for Fig 4, peripheral blood cells of subjects (#3 C104R patient [Pt], and #10 C104R Pt 2) and their first-degree relatives with the same mutation (C104R Rel-1, C104R Rel-2) were tested for IgG (A) and IgA (B) production. The amounts of IgG or IgA over baseline are given in ng/mL (y-axis). The median (± SE) is shown for 8 normal controls.