Epistatic interactions between mutations of TACI (TNFRSF13B) and TCF3 result in a severe primary immunodeficiency disorder and systemic lupus erythematosus

Common variable immunodeficiency disorders (CVID) are a group of primary immunodeficiencies where monogenetic causes account for only a fraction of cases. On this evidence, CVID is potentially polygenic and epistatic although there are, as yet, no examples to support this hypothesis. We have identified a non-consanguineous family, who carry the C104R (c.310T>C) mutation of the Transmembrane Activator Calcium-modulator and cyclophilin ligand Interactor (TACI, TNFRSF13B) gene. Variants in TNFRSF13B/TACI are identified in up to 10% of CVID patients, and are associated with, but not solely causative of CVID. The proband is heterozygous for the TNFRSF13B/TACI C104R mutation and meets the Ameratunga et al. diagnostic criteria for CVID and the American College of Rheumatology criteria for systemic lupus erythematosus (SLE). Her son has type 1 diabetes, arthritis, reduced IgG levels and IgA deficiency, but has not inherited the TNFRSF13B/TACI mutation. Her brother, homozygous for the TNFRSF13B/TACI mutation, is in good health despite profound hypogammaglobulinemia and mild cytopenias. We hypothesised that a second unidentified mutation contributed to the symptomatic phenotype of the proband and her son. Whole-exome sequencing of the family revealed a de novo nonsense mutation (T168fsX191) in the Transcription Factor 3 (TCF3) gene encoding the E2A transcription factors, present only in the proband and her son. We demonstrate mutations of TNFRSF13B/TACI impair immunoglobulin isotype switching and antibody production predominantly via T-cell-independent signalling, while mutations of TCF3 impair both T-cell-dependent and -independent pathways of B-cell activation and differentiation. We conclude that epistatic interactions between mutations of the TNFRSF13B/TACI and TCF3 signalling networks lead to the severe CVID-like disorder and SLE in the proband.We thank AMRF, A+ Trust, IDFNZ, ASCIA and the Australian National Health and Medical Research Council (NHMRC, Program Grant 1054925, Project Grant 1127198 and Independent Research Institutes Infrastructure Support Scheme Grant 361646) for grant support. We also received support from Bloody Long Way (BLW) the Victorian State Government Operational Infrastructure scheme and Walter and Eliza Hall Institute (WEHI) Innovation Grant. CAS is supported by NHMRC postgraduate scholarship 1075666

Epistatic interactions between mutations of TACI (TNFRSF13B) and TCF3 result in a severe primary immunodeficiency disorder and systemic lupus erythematosus

Common variable immunodeficiency disorders (CVID) are a group of primary immunodeficiencies where monogenetic causes account for only a fraction of cases. On this evidence, CVID is potentially polygenic and epistatic although there are, as yet, no examples to support this hypothesis. We have identified a non‐consanguineous family, who carry the C104R (c.310T>C) mutation of the Transmembrane Activator Calcium‐modulator and cyclophilin ligand Interactor (TACI, TNFRSF13B) gene. Variants in TNFRSF13B/TACI are identified in up to 10% of CVID patients, and are associated with, but not solely causative of CVID. The proband is heterozygous for the TNFRSF13B/TACI C104R mutation and meets the Ameratunga et al. diagnostic criteria for CVID and the American College of Rheumatology criteria for systemic lupus erythematosus (SLE). Her son has type 1 diabetes, arthritis, reduced IgG levels and IgA deficiency, but has not inherited the TNFRSF13B/TACI mutation. Her brother, homozygous for the TNFRSF13B/TACI mutation, is in good health despite profound hypogammaglobulinemia and mild cytopenias. We hypothesised that a second unidentified mutation contributed to the symptomatic phenotype of the proband and her son. Whole‐exome sequencing of the family revealed a de novo nonsense mutation (T168fsX191) in the Transcription Factor 3 (TCF3) gene encoding the E2A transcription factors, present only in the proband and her son. We demonstrate mutations of TNFRSF13B/TACI impair immunoglobulin isotype switching and antibody production predominantly via T‐cell‐independent signalling, while mutations of TCF3 impair both T‐cell‐dependent and ‐independent pathways of B‐cell activation and differentiation. We conclude that epistatic interactions between mutations of the TNFRSF13B/TACI and TCF3 signalling networks lead to the severe CVID‐like disorder and SLE in the proband.We thank AMRF, A+ Trust, IDFNZ,ASCIA and the Australian National Health and Medical Research Council(NHMRC, Program Grant 1054925, Project Grant 1127198 and IndependentResearch Institutes Infrastructure Support Scheme Grant 361646) for grantsupport. We also received support from Bloody Long Way (BLW) the VictorianState Government Operational Infrastructure scheme and Walter and Eliza HallInstitute (WEHI) Innovation Grant. CAS is supported by NHMRCpostgraduate scholarship 107566

French J: Cellular and Molecular Characterisation of the Hyper Immunoglobulin M Syndrome Associated with Congenital Rubella Infection

Abstract Introduction The hyper-immunoglobulin M syndrome (HIM) is a rare group of immune deficiency disorders characterised by normal or increased serum IgM with normal or reduced IgG, IgA and IgE. Materials and Methods We have undertaken detailed cellular and molecular studies in a 53-year-old man with HIM as a result of congenital rubella. Results No mutations were detected in the CD40 ligand, activation-induced cytidine deaminase and uracil DNA glycosylase. His T-cell responses to lectins and antigens were normal. Flow cytometry confirmed the presence of CD40 ligand on activated T cells. Most CD40-dependent functions that were tested, including B-cell proliferation, isotype switching and production of memory B cells, were normal. CD40/IL4 dependent rescue from anti-IgMinduced apoptosis was impaired. Conclusion The detection of cell-surface IgG but lack of serum IgG indicated that he may have an antibody secretion defect