Neil Romberg1, Manmeet Virdee2, Nicolas Chamberlain3, Tyler Oe3, Jean-Nicolas Schickel3, Tiffany Perkins2, Tineke Cantaert3, Rima Rachid4, Sally Rosengren5, Regina Palazzo2, Raif Geha4, Charlotte Cunningham-Rundles6, Eric Meffre7. 1. Department of Pediatrics, Yale University School of Medicine, New Haven, Conn. Electronic address: neil.romberg@yale.edu. 2. Department of Pediatrics, Yale University School of Medicine, New Haven, Conn. 3. Department of Immunobiology, Yale University School of Medicine, New Haven, Conn. 4. Division of Immunology, Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, Mass. 5. Department of Pediatrics, University of Connecticut School of Medicine, Hartford, Conn. 6. Department of Medicine, Mount Sinai Medical Center, New York, NY. 7. Department of Immunobiology, Yale University School of Medicine, New Haven, Conn; Department of Internal Medicine, Yale University School of Medicine, New Haven, Conn. Electronic address: eric.meffre@yale.edu.
Abstract
BACKGROUND: Heterozygous C104R or A181E TNF receptor superfamily member 13b (TNFRSF13B) mutations impair removal of autoreactive B cells, weaken B-cell activation, and convey to patients with common variable immune deficiency (CVID) an increased risk for autoimmunity. How mutant transmembrane activator and CAML interactor (TACI) influences wild-type TACI function is unclear; different models suggest either a dominant negative effect or haploinsufficiency. OBJECTIVE: We investigated potential TACI haploinsufficiency by analyzing patients with antibody-deficient Smith-Magenis syndrome (SMS) who possess only 1 TNFRSF13B allele and antibody-deficient patients carrying one c.204insA TNFRSF13B null mutation. METHODS: We tested the reactivity of antibodies isolated from single B cells from patients with SMS and patients with a c.204insA TNFRSF13B mutation and compared them with counterparts from patients with CVID with heterozygous C104R or A181E TNFRSF13B missense mutations. We also assessed whether loss of a TNFRSF13B allele induced haploinsufficiency in naive and memory B cells and recapitulated abnormal immunologic features typical of patients with CVID with heterozygous TNFRSF13B missense mutations. RESULTS: We found that loss of a TNFRSF13B allele does not affect TACI expression, activation responses, or establishment of central B-cell tolerance in naive B cells. Additionally, patients with SMS and those with a c.204insA TNFRSF13B mutation display normal regulatory T-cell function and peripheral B-cell tolerance. The lack of a TNFRSF13B allele did result in decreased TACI expression on memory B cells, resulting in impaired activation and antibody secretion. CONCLUSION: TNFRSF13B hemizygosity does not recapitulate autoimmune features of CVID-associated C104R and A181E TNFRSF13B mutations, which likely encode dominant negative products, but instead reveals selective TACI haploinsufficiency at later stages of B-cell development.
BACKGROUND: Heterozygous C104R or A181ETNF receptor superfamily member 13b (TNFRSF13B) mutations impair removal of autoreactive B cells, weaken B-cell activation, and convey to patients with common variable immune deficiency (CVID) an increased risk for autoimmunity. How mutant transmembrane activator and CAML interactor (TACI) influences wild-type TACI function is unclear; different models suggest either a dominant negative effect or haploinsufficiency. OBJECTIVE: We investigated potential TACIhaploinsufficiency by analyzing patients with antibody-deficient Smith-Magenis syndrome (SMS) who possess only 1 TNFRSF13B allele and antibody-deficientpatients carrying one c.204insATNFRSF13B null mutation. METHODS: We tested the reactivity of antibodies isolated from single B cells from patients with SMS and patients with a c.204insATNFRSF13B mutation and compared them with counterparts from patients with CVID with heterozygous C104R or A181ETNFRSF13B missense mutations. We also assessed whether loss of a TNFRSF13B allele induced haploinsufficiency in naive and memory B cells and recapitulated abnormal immunologic features typical of patients with CVID with heterozygous TNFRSF13B missense mutations. RESULTS: We found that loss of a TNFRSF13B allele does not affect TACI expression, activation responses, or establishment of central B-cell tolerance in naive B cells. Additionally, patients with SMS and those with a c.204insATNFRSF13B mutation display normal regulatory T-cell function and peripheral B-cell tolerance. The lack of a TNFRSF13B allele did result in decreased TACI expression on memory B cells, resulting in impaired activation and antibody secretion. CONCLUSION:TNFRSF13B hemizygosity does not recapitulate autoimmune features of CVID-associated C104R and A181ETNFRSF13B mutations, which likely encode dominant negative products, but instead reveals selective TACIhaploinsufficiency at later stages of B-cell development.
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