Combined immunodeficiency and atopy caused by a dominant negative mutation in caspase activation and recruitment domain family member 11 (CARD11) - 04/05/18

Doi : 10.1016/j.jaci.2017.06.047

Harjit Dadi, PhD ^a,^b,^{^{∗
These authors contributed equally to this work.}}, Tyler A. Jones, BS ^c,^{^{∗
These authors contributed equally to this work.}}, Daniele Merico, PhD ^d,^{^{∗
These authors contributed equally to this work.}}, Nigel Sharfe, PhD ^a,^b, Adi Ovadia, MD ^a,^b, Yael Schejter, MD ^a,^b, Brenda Reid, MN ^a,^b, Mark Sun, PhD ^d, Linda Vong, PhD ^a,^b, Adelle Atkinson, MD ^a, Sasson Lavi, MD ^a, Joel L. Pomerantz, PhD ^c,^{‡
These authors contributed equally to this work.}, Chaim M. Roifman, MD ^a,^b,^⁎,^{‡
These authors contributed equally to this work.}
^a Division of Immunology and Allergy, Department of Pediatrics, Hospital for Sick Children and the University of Toronto, Toronto, Ontario, Canada
^b Canadian Centre for Primary Immunodeficiency and the Jeffrey Modell Research Laboratory for the Diagnosis of Primary Immunodeficiency, Hospital for Sick Children, Toronto, Ontario, Canada
^c Department of Biological Chemistry and Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Md
^d Deep Genomics, Toronto, Ontario, Canada

^∗Corresponding author: Chaim M. Roifman, MD, Division of Immunology & Allergy, Hospital for Sick Children, 555 University Ave, Toronto, Ontario M5G 1X8, Canada.Division of Immunology & AllergyHospital for Sick Children555 University AveTorontoOntarioM5G 1X8Canada

Abstract

Background

Combined immunodeficiency (CID) is a T-cell defect frequently presenting with recurrent infections, as well as associated immune dysregulation manifesting as autoimmunity or allergic inflammation.

Objective

We sought to identify the genetic aberration in 4 related patients with CID, early-onset asthma, eczema, and food allergies, as well as autoimmunity.

Methods

We performed whole-exome sequencing, followed by Sanger confirmation, assessment of the genetic variant effect on cell signaling, and evaluation of the resultant immune function.

Results

A heterozygous novel c.C88T 1-bp substitution resulting in amino acid change R30W in caspase activation and recruitment domain family member 11 (CARD11) was identified by using whole-exome sequencing and segregated perfectly to family members with severe atopy only but was not found in healthy subjects. We demonstrate that the R30W mutation results in loss of function while also exerting a dominant negative effect on wild-type CARD11. The CARD11 defect altered the classical nuclear factor κB pathway, resulting in poor in vitro T-cell responses to mitogens and antigens caused by reduced secretion of IFN-γ and IL-2.

Conclusion

Unlike patients with biallelic mutations in CARD11 causing severe CID, the R30W defect results in a less profound yet prominent susceptibility to infections, as well as multiorgan atopy and autoimmunity.

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Key words : Caspase activation and recruitment domain family member 11, combined immunodeficiency, hypogammaglobulinemia, nuclear factor κB, cytokine secretion, T-cell repertoire, T-cell mitogen and antigen responses, autoimmunity, asthma, eczema and food allergies, atopy

Abbreviations used : BCL10, CARD11, CID, ID, MALT1, NF-κB, PE, PKC, PMA, SCID, TCR, WES

Plan

Supported by Immunodeficiency Canada's Distinguished Professorship in Immunology (to C.M.R.), the Program for Immunogenomics and the Canadian Centre for Primary Immunodeficiency (to C.M.R.), the Jeffrey Modell Foundation and Immunodeficiency Canada (to C.M.R.), and RO1CA177600 from the National Institutes of Health (to J.L.P.).

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Vol 141 - N° 5

P. 1818 - mai 2018 Retour au numéro

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Combined immunodeficiency and atopy caused by a dominant negative mutation in caspase activation and recruitment domain family member 11 (CARD11) - 04/05/18

Abstract

Background

Objective

Methods

Results

Conclusion

Plan

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