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Transmembrane activator and calcium-modulating cyclophilin ligand interactor mutations in common variable
Li Zhang1, Lin Radigan, Ulrich Salzer
1Department of Medicine, Pediatrics and the Immunobiology Center, Mount Sinai Medical School, New York, NY, USA.
Insights
Mutations in the transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) gene are linked to autoimmune issues and lymphoid hyperplasia in common variable immunodeficiency (CVID). However, additional factors are needed to cause the actual immune deficiency.
Area of Science:
- Immunology
- Genetics
Background:
- Mutations in the TACI gene are associated with common variable immunodeficiency (CVID).
- These mutations often appear to be inherited in a dominant pattern within families.
Purpose of the Study:
- To investigate the role of TACI mutations in sporadic CVID, given that most patients lack affected family members.
- To analyze the clinical relevance of TACI mutations in CVID.
Main Methods:
- Sequencing of the TACI gene in 176 CVID subjects and their families.
- Assessing B cell binding to APRIL, proliferation, and immunoglobulin production after ligand stimulation.
- Analyzing clinical data to determine the significance of TACI mutations.
Main Results:
- Heterozygous TACI mutations were identified in 7.3% of CVID subjects.
- Subjects with TACI mutations showed a higher incidence of autoimmune thrombocytopenia, splenomegaly, and splenectomy.
- While some B cells exhibited impaired APRIL binding and function, this was not significantly different from subjects without mutations. Relatives with mutations were not immune-deficient.
Conclusions:
- TACI mutations are significant risk factors for autoimmunity and lymphoid hyperplasia in CVID.
- Additional genetic or environmental factors are necessary for the development of immune deficiency in CVID.
- The precise causes of this common immune deficiency syndrome require further investigation.
Background:
Mutations in the gene coding for transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) have been identified in common variable immunodeficiency (CVID). Mutations coincided with immunodeficiency in families, suggesting dominant inheritance.
Objective:
Because most subjects with CVID have no immunodeficient family members and heterozygous mutations predominate, the role of TACI mutations in sporadic CVID is unclear.
Methods:
TACI was sequenced from the genomic DNA of 176 subjects with CVID and family members. B cells of subjects with or without mutations were examined for binding to the ligand, a proliferation inducing ligand (APRIL), and for proliferation and immunoglobulin production after ligand stimulation. Data analysis was performed to assess the clinical relevance of TACI mutations.
Results:
Heterozygous TACI mutations were found in 13 subjects (7.3%). Six with mutations (46%) had episodes of autoimmune thrombocytopenia, in contrast with 12% of 163 subjects without mutations; splenomegaly and splenectomy were significantly increased (P = .012; P = .001.) B cells of some had impaired binding of APRIL and on culture with this ligand were defective in proliferation and immunoglobulin production; however, this was not different from B cells of subjects without mutations. Eight first-degree relatives from 5 families had the same mutations but were not immune-deficient, and their B cells produced normal amounts of IgG and IgA after APRIL stimulation.
Conclusion:
Mutations in TACI significantly predispose to autoimmunity and lymphoid hyperplasia in CVID, but additional genetic or environmental factors are required to induce immune deficiency.
Clinical Implications:
Additional causes of this common immune deficiency syndrome remain to be determined.
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