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

Anaphylaxis to hyperallergenic functional foods

<p>Abstract</p> <p>Background</p> <p>Food allergy can cause life threatening reactions. Currently, patients with severe food allergy are advised to avoid foods which provoke allergic reactions. This has become increasingly difficult as food proteins are being added to a broader range of consumer products.</p> <p>Patients and methods</p> <p>Here we describe our investigations into the allergenicity of a new drink when two cow's milk allergic children suffered anaphylaxis after consuming <it>Wh</it>_<it>2</it><it>ole</it>^®.</p> <p>Results</p> <p>Our studies have shown that in comparison with cow's milk, <it>Wh</it>_<it>2</it><it>ole</it>^®contains at least three times the concentration of β-lactoglobulin. β-lactoglobulin is one of the dominant allergens in bovine milk.</p> <p>Conclusions</p> <p>These studies have shown that modern technology allows the creation of "hyperallergenic" foods. These products have the potential to cause severe reactions in milk allergic persons. Avoiding inadvertent exposure is the shared responsibility of allergic consumers, regulatory authorities and the food industry.</p

The clinical utility of molecular diagnostic testing for primary immune deficiency disorders: a case based review

Primary immune deficiency disorders (PIDs) are a group of diseases associated with a genetic predisposition to recurrent infections, malignancy, autoimmunity and allergy. The molecular basis of many of these disorders has been identified in the last two decades. Most are inherited as single gene defects. Identifying the underlying genetic defect plays a critical role in patient management including diagnosis, family studies, prognostic information, prenatal diagnosis and is useful in defining new diseases. In this review we outline the clinical utility of molecular testing for these disorders using clinical cases referred to Auckland Hospital. It is written from the perspective of a laboratory offering a wide range of tests for a small developed country

Characterization of the clinical and immunologic phenotype and management of 157 individuals with 56 distinct heterozygous NFKB1 mutations

Background: An increasing number of NFKB1 variants are being identified in patients with heterogeneous immunologic phenotypes. Objective: To characterize the clinical and cellular phenotype as well as the management of patients with heterozygous NFKB1 mutations. Methods: In a worldwide collaborative effort, we evaluated 231 individuals harboring 105 distinct heterozygous NFKB1 variants. To provide evidence for pathogenicity, each variant was assessed in silico; in addition, 32 variants were assessed by functional in vitro testing of nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-kappa B) signaling. Results: We classified 56 of the 105 distinct NFKB1 variants in 157 individuals from 68 unrelated families as pathogenic. Incomplete clinical penetrance (70%) and age-dependent severity of NFKB1-related phenotypes were observed. The phenotype included hypogammaglobulinemia (88.9%), reduced switched memory B cells (60.3%), and respiratory (83%) and gastrointestinal (28.6%) infections, thus characterizing the disorder as primary immunodeficiency. However, the high frequency of autoimmunity (57.4%), lymphoproliferation (52.4%), noninfectious enteropathy (23.1%), opportunistic infections (15.7%), autoinflammation (29.6%), and malignancy (16.8%) identified NF-kappa B1-related disease as an inborn error of immunity with immune dysregulation, rather than a mere primary immunodeficiency. Current treatment includes immunoglobulin replacement and immunosuppressive agents. Conclusions: We present a comprehensive clinical overview of the NF-kappa B1-related phenotype, which includes immunodeficiency, autoimmunity, autoinflammation, and cancer. Because of its multisystem involvement, clinicians from each and every medical discipline need to be made aware of this autosomal-dominant disease. Hematopoietic stem cell transplantation and NF-kappa B1 pathway-targeted therapeutic strategies should be considered in the future.Peer reviewe

Initial intravenous immunoglobulin doses should be based on adjusted body weight in obese patients with primary immunodeficiency disorders

Abstract Background Immunoglobulin therapy plays a critical role in the treatment of immunodeficiency disorders as well as autoimmune and inflammatory conditions. In immunodeficient patients, there has been controversy whether initial loading doses of intravenous (IVIG) should be based on actual body weight or a calculated parameter such as adjusted body weight in obese patients. Case presentation I describe a patient with Common Variable Immunodeficiency disorder (CVID) who underwent bariatric surgery for morbid obesity. Her weight decreased by 50% to below her calculated ideal body weight (IBW) while her immunoglobulin requirement fell by approximately 20%. Her steady state serum IgG increased from approximately 7 g/l to 11.7 g/l concomitant with weight loss. Conclusions I present this observation as support for the recommendation that initial loading doses of SCIG/IVIG in immunodeficiency should be based on adjusted body weight (AjBW) and not actual body weight in obese patients. This has important fiscal implications for treating obese patients with immunodeficiency disorders