Germline CBM-opathies: From immunodeficiency to atopy - 04/05/19

Doi : 10.1016/j.jaci.2019.03.009

Henry Y. Lu, BSc ^a,^b, Catherine M. Biggs, MD ^a,^b, Geraldine Blanchard-Rohner, MD, DPhil ^a, Shan-Yu Fung, PhD ^c,^d, Mehul Sharma, MSc ^a, Stuart E. Turvey, MBBS, DPhil ^a,^b,^⁎
^a Department of Pediatrics, British Columbia Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada
^b Experimental Medicine Program, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
^c Department of Immunology, Tianjin Medical University, Tianjin, China
^d Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Medical University, Tianjin, China

^∗Corresponding author: Stuart E. Turvey, MBBS, DPhil, FRCPC, BC Children's Hospital, 950 West 28th Ave, Vancouver, British Columbia V5Z 4H4, Canada.BC Children's Hospital950 West 28th AveVancouverBritish ColumbiaV5Z 4H4Canada

Abstract

Caspase recruitment domain (CARD) protein–B cell CLL/lymphoma 10 (BCL10)–MALT1 paracaspase (MALT1) [CBM] complexes are critical signaling adaptors that facilitate immune and inflammatory responses downstream of both cell surface and intracellular receptors. Germline mutations that alter the function of members of this complex (termed CBM-opathies) cause a broad array of clinical phenotypes, ranging from profound combined immunodeficiency to B-cell lymphocytosis. With an increasing number of patients being described in recent years, the clinical spectrum of diseases associated with CBM-opathies is rapidly expanding and becoming unexpectedly heterogeneous. Here we review major discoveries that have shaped our understanding of CBM complex biology, and we provide an overview of the clinical presentation, diagnostic approach, and treatment options for those carrying germline mutations affecting CARD9, CARD11, CARD14, BCL10, and MALT1.

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Key words : CBM-opathies, CARD9, CARD11, CARD14, BCL10, MALT1, primary immunodeficiencies, combined immunodeficiency, congenital B-cell lymphocytosis, primary atopic disease

Abbreviations used : BCL10, BCR, BENTA, CADINS, CARD, CBM, CC, CID, CNS, DN, DOCK8, GOF, HSCT, IFD, IκBα, IKK, IVIG, LOF, MALT1, mTOR, mTORC, NF-κB, NGS, NK, PDZ, PID, PJP, PRP, PsV, STAT, TCR, Treg

Plan

Signaling by the CBM complexes

Discovery of the CBM complexes and germline CBM-opathies

Spectrum of human disease caused by germline CARD11 mutations

Biallelic loss-of-function mutations in CARD11 cause profound combined immunodeficiency

Heterozygous dominant negative mutations in CARD11 cause CARD11-associated atopy with dominant interference of NF-κB signaling

Heterozygous gain-of-function mutations in CARD11 cause B-cell expansion with NF-κB and T-cell anergy

Spectrum of human disease caused by germline CARD9 mutations

Biallelic LOF mutations in CARD9 cause profound susceptibility to invasive fungal disease

Spectrum of human disease caused by germline CARD14 mutations

Heterozygous DN LOF mutations in CARD14 cause severe atopic dermatitis

Heterozygous GOF mutations in CARD14 cause psoriasis and pityriasis rubra pilaris

Human disease caused by germline BCL10 mutations

Biallelic LOF mutations in BCL10 cause CID

Human disease caused by germline MALT1 mutations

Biallelic LOF mutations in MALT1 cause CID

CBM-opathies: Therapeutic and clinical implications

Concluding remarks

Supported in part by the Canadian Institutes of Health Research (CIHR); Genome British Columbia (SIP007 to S.E.T.); the Canadian Allergy, Asthma and Immunology Foundation; and the British Columbia Children's Hospital Foundation. S.E.T. holds the Canada Research Chair in Pediatric Precision Health and the Aubrey J. Tingle Professorship in Pediatric Immunology. C.M.B. is a Health Professional-Investigator of the Michael Smith Foundation for Health Research and is supported by the AllerGen Emerging Clinician-Scientist Research Fellowship. H.Y.L. is funded by a University of British Columbia Four Year Doctoral Fellowship.