The CBM-opathies-A Rapidly Expanding Spectrum of Human Inborn Errors of Immunity Caused by Mutations in the CARD11-BCL10-MALT1 Complex

Henry Y Lu; Bradly M Bauman; Swadhinya Arjunaraja; Batsukh Dorjbal; Joshua D Milner; Andrew L Snow; Stuart E Turvey

doi:10.3389/fimmu.2018.02078

The CBM-opathies-A Rapidly Expanding Spectrum of Human Inborn Errors of Immunity Caused by Mutations in the CARD11-BCL10-MALT1 Complex

Front Immunol. 2018 Sep 19:9:2078. doi: 10.3389/fimmu.2018.02078. eCollection 2018.

Authors

Henry Y Lu^{1

2}, Bradly M Bauman³, Swadhinya Arjunaraja³, Batsukh Dorjbal³, Joshua D Milner⁴, Andrew L Snow³, Stuart E Turvey^{1

2}

Affiliations

¹ Department of Pediatrics, British Columbia Children's Hospital, The University of British Columbia, Vancouver, BC, Canada.
² Experimental Medicine Program, Faculty of Medicine, The University of British Columbia, Vancouver, BC, Canada.
³ Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD, United States.
⁴ Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States.

Abstract

The caspase recruitment domain family member 11 (CARD11 or CARMA1)-B cell CLL/lymphoma 10 (BCL10)-MALT1 paracaspase (MALT1) [CBM] signalosome complex serves as a molecular bridge between cell surface antigen receptor signaling and the activation of the NF-κB, JNK, and mTORC1 signaling axes. This positions the CBM complex as a critical regulator of lymphocyte activation, proliferation, survival, and metabolism. Inborn errors in each of the CBM components have now been linked to a diverse group of human primary immunodeficiency diseases termed "CBM-opathies." Clinical manifestations range from severe combined immunodeficiency to selective B cell lymphocytosis, atopic disease, and specific humoral defects. This surprisingly broad spectrum of phenotypes underscores the importance of "tuning" CBM signaling to preserve immune homeostasis. Here, we review the distinct clinical and immunological phenotypes associated with human CBM complex mutations and introduce new avenues for targeted therapeutic intervention.

Keywords: BCL10; BENTA; CARD11; CBM complex; MALT1; combined immunodeficiency; primary atopic disease; severe combined immunodeficiency.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review

MeSH terms

B-Cell CLL-Lymphoma 10 Protein / genetics
B-Cell CLL-Lymphoma 10 Protein / immunology*
B-Cell CLL-Lymphoma 10 Protein / metabolism
CARD Signaling Adaptor Proteins / genetics
CARD Signaling Adaptor Proteins / immunology*
CARD Signaling Adaptor Proteins / metabolism
Guanylate Cyclase / genetics
Guanylate Cyclase / immunology*
Guanylate Cyclase / metabolism
Homeostasis / genetics
Homeostasis / immunology
Humans
Lymphocyte Activation / genetics
Lymphocyte Activation / immunology
Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein / genetics
Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein / immunology*
Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein / metabolism
Mutation / immunology
Protein Binding
Severe Combined Immunodeficiency / genetics
Severe Combined Immunodeficiency / immunology*
Severe Combined Immunodeficiency / metabolism
Signal Transduction / genetics
Signal Transduction / immunology*

Substances

B-Cell CLL-Lymphoma 10 Protein
BCL10 protein, human
CARD Signaling Adaptor Proteins
MALT1 protein, human
Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
CARD11 protein, human
Guanylate Cyclase

Grants and funding

R21 AI109187/AI/NIAID NIH HHS/United States