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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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 5

Increased plasma BAFF concentrations, homeostatic naive B cell proliferation, and an impaired Treg compartment are features common to CVID patients with and without TACI mutations.

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Increased plasma BAFF concentrations, homeostatic naive B cell prolifera...
TACI mutations did not affect plasma BAFF concentrations (pg/ml) measured by ELISA (A) or mature naive B cell expansion detected by KREC analysis (B). Both were greater in CVID patients compared with healthy controls. (C–F) CVID status, but not TACI mutations, affected Treg frequency and function. (C) Dot plots represent CD4+ gated CD25hiFOXP3+ T cells of a healthy donor control and an age-matched CVID patient with one TACI mutation. Scatter plots reveal that decreased CD4+CD25hiCD127loFOXP3+ Treg frequency only correlated with CVID. yo, year-old. (D) Representative histograms of Treg-mediated suppression of autologous and heterologous CFSE-labeled Tresp cells on day 4.5 from a CVID patient and a healthy relative both carrying a TACI mutation were compared with a healthy control. Dashed lines display nonstimulated Tresp cells. The autologous and heterologous suppressive activities of Tregs from healthy donor controls, healthy carriers with a single TACI mutation, CVID patients with one or two mutated TACI alleles, as well as CVID patients without TACI mutations are summarized in E and F, respectively. Statistical significance is indicated by an unpaired Student’s t test.