CVID-associated TACI mutations affect autoreactive B cell selection and activation
Neil Romberg, … , Charlotte Cunningham-Rundles, Eric Meffre
Neil Romberg, … , Charlotte Cunningham-Rundles, Eric Meffre
Published September 24, 2013
Citation Information: J Clin Invest. 2013;123(10):4283-4293. https://doi.org/10.1172/JCI69854.
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Research Article

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

Abstract

Common variable immune deficiency (CVID) is an assorted group of primary diseases that clinically manifest with antibody deficiency, infection susceptibility, and autoimmunity. Heterozygous mutations in the gene encoding the tumor necrosis factor receptor superfamily member TACI are associated with CVID and autoimmune manifestations, whereas two mutated alleles prevent autoimmunity. To assess how the number of TACI mutations affects B cell activation and tolerance checkpoints, we analyzed healthy individuals and CVID patients carrying one or two TACI mutations. We found that TACI interacts with the cleaved, mature forms of TLR7 and TLR9 and plays an important role during B cell activation and the central removal of autoreactive B cells in healthy donors and CVID patients. However, only subjects with a single TACI mutation displayed a breached immune tolerance and secreted antinuclear antibodies (ANAs). These antibodies were associated with the presence of circulating B cell lymphoma 6–expressing T follicular helper (Tfh) cells, likely stimulating autoreactive B cells. Thus, TACI mutations may favor CVID by altering B cell activation with coincident impairment of central B cell tolerance, whereas residual B cell responsiveness in patients with one, but not two, TACI mutations enables autoimmune complications.

Authors

Neil Romberg, Nicolas Chamberlain, David Saadoun, Maurizio Gentile, Tuure Kinnunen, Yen Shing Ng, Manmeet Virdee, Laurence Menard, Tineke Cantaert, Henner Morbach, Rima Rachid, Natalia Martinez-Pomar, Nuria Matamoros, Raif Geha, Bodo Grimbacher, Andrea Cerutti, Charlotte Cunningham-Rundles, Eric Meffre

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Figure 2

TACI mutation(s) result in selective defects for in vitro naive B cell activation.

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TACI mutation(s) result in selective defects for in vitro naive B cell ...
Purified naive B cells from representative individuals with and without TACI mutation(s) (thick lines) displayed decreased CD86 (A) but mostly normal CD69 (B) induction compared with healthy controls (thin lines) after 48 hours of stimulation with F(ab′)2 anti-IgM, CpG, and gardiquimod, but not CD40L. CVID patients without TACI mutation(s) (thick lines) displayed more variable CD86 and CD69 induction under activating conditions. Unstimulated healthy controls (dashed line) are shown for comparison. CVID patients (n = 3) and healthy subjects (n = 5) with a single TACI mutation were pooled because they displayed similar decreased B cell responses. Bar graphs (right) represent the combined data from multiple B cell activation experiments. Error bars represent the mean ± SEM. Statistical significance is indicated by an unpaired Student’s t test.