Journal
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume 136, Issue 5, Pages 1139-1149Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2015.06.031
Keywords
Primaryimmunodeficiency; combined immunodeficiency; B-cell lymphoma 10; mucosa-associated lymphoid tissue lymphoma-translocation gene 1; CARMA1; caspase recruitment domain 9
Categories
Funding
- Ramon Areces Foundation, grant XVII Concurso Nacional de Ayudas a la Investigacion
- FIS grant [PI14/00616]
- St. Giles Foundation
- Rockefeller University
- Jeffrey Modell Foundation
- Institut National de la Sante et de la Recherche Medicale, University Paris Descartes
- French National Research Agency (ANR) under the Investments for the future'' program [ANR-10-IAHU-01]
- National Center for Research Resources [8 UL1 TR000043]
- National Center for Advancing Sciences (NCATS), National Institutes of Health
- EMBO long-term fellowship
- Ramon y Cajal'' program (MINECO, Spain) [RYC-2011-07597]
- EMBO short-term fellowship ASTF [119-2013]
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Three members of the caspase recruitment domain (CARD) family of adaptors (CARD9, CARD10, and CARD11) are known to form heterotrimers with B-cell lymphoma 10 (BCL10) and mucosa-associated lymphoid tissue lymphoma-translocation gene 1 (MALT1). These 3 CARD-BCL10-MALT1 (CBM) complexes activate nuclear factor kappa B in both the innate and adaptive arms of immunity. Human inherited defects of the 3 components of the CBM complex, including the 2 adaptors CARD9 and CARD11 and the 2 core components BCL10 and MALT1, have recently been reported. Biallelic loss-of-function mutant alleles underlie several different immunologic and clinical phenotypes, which can be assigned to 2 distinct categories. Isolated invasive fungal infections of unclear cellular basis are associated with CARD9 deficiency, whereas a broad range of clinical manifestations, including those characteristic of T-and B-lymphocyte defects, are associated with CARD11, MALT1, and BCL10 deficiencies. Interestingly, human subjects corresponding knockout mice, but other features are different between human subjects and mice. Moreover, germline and somatic gain-of-function mutations of MALT1, BCL10, and CARD11 have also been found in patients with other lymphoproliferative disorders. This broad range of germline and somatic CBM lesions, including loss-of-function and gain-of-function mutations, highlights the contribution of each of the components of the CBM complex to human immunity.
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