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 1

Defective central B cell tolerance checkpoint in individuals carrying TACI mutation(s).

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Defective central B cell tolerance checkpoint in individuals carrying TA...
(A) Recombinant antibodies derived from new emigrant/transitional B cells from representative individuals were tested by ELISA for reactivity against dsDNA, insulin, and LPS (21). Antibodies were considered polyreactive when they reacted against all three antigens. Dashed lines show ED38 antibody–positive control, and solid lines show binding for each cloned recombinant antibody. Horizontal lines define the cutoff OD405 for positive reactivity. For each individual, the frequency of polyreactive and nonpolyreactive clones is summarized in pie charts, with the total number of antibodies tested indicated in the center. (B) The frequency of polyreactive new emigrant/transitional B cells increased in all individuals carrying TACI mutation(s) and most CVID patients without TACI mutations, whereas the frequency of HEp-2–reactive new emigrant/transitional B cells only increased in patients with two mutated TACI alleles. (C) Autoreactive antibodies expressed by new emigrant/transitional B cells from individuals carrying TACI mutation(s) included clones with various nuclear staining patterns on HEp-2 cells. Original magnification, ×40. (D) The frequency of antinuclear new emigrant/transitional B cells in individuals carrying TACI mutation(s) was elevated compared with healthy controls and is reminiscent of patients with MyD88 and IRAK4 deficiency (white squares) (23). Statistical significance by an unpaired Student’s t test is indicated.