CVID-associated TACI mutations affect autoreactive B cell selection and activation.
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.
Neil
N
Romberg
Nicolas
N
Chamberlain
David
D
Saadoun
Maurizio
M
Gentile
Tuure
T
Kinnunen
Yen Shing
YS
Ng
Manmeet
M
Virdee
Laurence
L
Menard
Tineke
T
Cantaert
Henner
H
Morbach
Rima
R
Rachid
Natalia
N
Martinez-Pomar
Nuria
N
Matamoros
Raif
R
Geha
Bodo
B
Grimbacher
Andrea
A
Cerutti
Charlotte
C
Cunningham-Rundles
Eric
E
Meffre
D000328:Adult; D000974:Antibodies, Antinuclear / Q000378:metabolism; D001323:Autoantibodies / Q000378:metabolism; D053264:B-Cell Activating Factor / Q000097:blood; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016022:Case-Control Studies; D049109:Cell Proliferation; D002478:Cells, Cultured; D061167:Central Tolerance; D017074:Common Variable Immunodeficiency / Q000097:blood / Q000235:genetics* / Q000276:immunology; D004268:DNA-Binding Proteins / Q000378:metabolism; D018628:Gene Dosage; D006579:Heterozygote; D006801:Humans; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D009154:Mutation; D061166:Peripheral Tolerance; D051560:Proto-Oncogene Proteins c-bcl-6; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000378:metabolism; D053303:Transmembrane Activator and CAML Interactor Protein / Q000235:genetics*
D000974:Antibodies, Antinuclear; D001323:Autoantibodies; D053264:B-Cell Activating Factor; C084103:BCL6 protein, human; D004268:DNA-Binding Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; C495348:TLR7 protein, human; C495371:TLR9 protein, human; C108467:TNFRSF13B protein, human; C505719:TNFSF13B protein, human; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D053303:Transmembrane Activator and CAML Interactor Protein