title: The CARD11-BCL10-MALT1 (CBM) signalosome complex: Stepping into the limelight of human primary immunodeficiency.
abstract: Next-generation DNA sequencing has accelerated the genetic characterization of many human primary immunodeficiency diseases (PIDs). These discoveries can be lifesaving for the affected patients and also provide a unique opportunity to study the effect of specific genes on human immune function. In the past 18 months, a number of independent groups have begun to define novel PIDs caused by defects in the caspase recruitment domain family, member 11 (CARD11)-B-cell chronic lymphocytic leukemia/lymphoma 10 (BCL10)-mucosa-associated lymphoid tissue lymphoma translocation gene 1 (MALT1 [CBM]) signalosome complex. The CBM complex forms an essential molecular link between the triggering of cell-surface antigen receptors and nuclear factor κB activation. Germline mutations affecting the CBM complex are now recognized as the cause of novel combined immunodeficiency phenotypes, which all share abnormal nuclear factor κB activation and dysregulated B-cell development as defining features. For this "Current perspectives" article, we have engaged experts in both basic biology and clinical immunology to capture the worldwide experience in recognizing and managing patients with PIDs caused by CBM complex mutations.
authors.affiliation: Department of Pediatrics, Child & Family Research Institute, and BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address: sturvey@cw.bc.ca.
authors.forename: Stuart E
authors.initials: SE
authors.lastname: Turvey
authors.affiliation: National Institute of Health and Medical Research and the Department of Immunology and Hematology, Assistance Publique-Hopitaux de Paris, Necker Children's Hospital, Paris, and Descartes-Sorbonne Paris Cité University of Paris, Imagine Institute, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Durandy
authors.affiliation: National Institute of Health and Medical Research and the Department of Immunology and Hematology, Assistance Publique-Hopitaux de Paris, Necker Children's Hospital, Paris, and Descartes-Sorbonne Paris Cité University of Paris, Imagine Institute, Paris, France; Unité d'immuno-hématologie pédiatrique, Hôpital Necker-Enfant Malades, Assistance Publique des Hôpitaux de Paris (APHP), Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.affiliation: Department of Pediatrics, Child & Family Research Institute, and BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Shan-Yu
authors.initials: SY
authors.lastname: Fung
authors.affiliation: Division of Immunology, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Mass.
authors.forename: Raif S
authors.initials: RS
authors.lastname: Geha
authors.affiliation: German Cancer Consortium (DKTK), partner site Munich at the Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München, Munich, and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Gewies
authors.affiliation: Institute for Immunology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Giese
authors.affiliation: Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Johann
authors.initials: J
authors.lastname: Greil
authors.affiliation: Centre for Chronic Immunodeficiency (CCI), University Medical Center Freiburg and University of Freiburg, Freiburg, Germany.
authors.forename: Bärbel
authors.initials: B
authors.lastname: Keller
authors.affiliation: Department of Medical Genetics, Child & Family Research Institute and BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Margaret L
authors.initials: ML
authors.lastname: McKinnon
authors.affiliation: Unité d'immuno-hématologie pédiatrique, Hôpital Necker-Enfant Malades, Assistance Publique des Hôpitaux de Paris (APHP), Paris, France.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Neven
authors.affiliation: Department of Pediatrics, Child & Family Research Institute, and BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Jacob
authors.initials: J
authors.lastname: Rozmus
authors.affiliation: Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Ruland
authors.affiliation: Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, Md.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Snow
authors.affiliation: Pediatric Hematology-Oncology and Bone Marrow Transplantation, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Polina
authors.initials: P
authors.lastname: Stepensky
authors.affiliation: Centre for Chronic Immunodeficiency (CCI), University Medical Center Freiburg and University of Freiburg, Freiburg, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Warnatz
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000276:immunology; D000074018:B-Cell CLL-Lymphoma 10 Protein; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology*; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics* / Q000276:immunology; D020169:Caspases / Q000235:genetics* / Q000276:immunology; D005786:Gene Expression Regulation; D018095:Germ-Line Mutation; D006162:Guanylate Cyclase / Q000235:genetics* / Q000276:immunology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D009363:Neoplasm Proteins / Q000235:genetics* / Q000276:immunology; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; C118591:BCL10 protein, human; D053468:CARD Signaling Adaptor Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D011947:Receptors, Antigen, B-Cell; D020169:Caspases; C400109:MALT1 protein, human; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; C426242:CARD11 protein, human; D006162:Guanylate Cyclase
keywords: CARD11-BCL10-MALT1 signalosome complex; CARMA1; combined immunodeficiency; congenital B-cell lymphocytosis; next-generation sequencing; nuclear factor κB; paracaspase; primary immunodeficiency diseases
references.citation: Immunity. 2003 Jun;18(6):763-75
references.pmid: 12818158
references.citation: J Allergy Clin Immunol. 2013 Feb;131(2):477-85.e1
references.pmid: 23374270
references.citation: J Biol Chem. 2001 Jun 1;276(22):19012-9
references.pmid: 11262391
references.citation: Cell. 2001 Jan 12;104(1):33-42
references.pmid: 11163238
references.citation: Blood. 2014 Apr 3;123(14):2199-203
references.pmid: 24497531
references.citation: Clin Cancer Res. 2011 Mar 15;17(6):1440-51
references.pmid: 21266526
references.citation: Nat Immunol. 2008 Mar;9(3):263-71
references.pmid: 18223652
references.citation: Microbes Infect. 2006 Apr;8(4):1151-6
references.pmid: 16517203
references.citation: Science. 2008 Mar 21;319(5870):1676-9
references.pmid: 18323416
references.citation: Cell Cycle. 2011 Aug 1;10(15):2485-96
references.pmid: 21750409
references.citation: Proc Natl Acad Sci U S A. 2012 Mar 6;109(10):3879-84
references.pmid: 22343534
references.citation: Mol Cell. 2013 Sep 26;51(6):766-79
references.pmid: 24074955
references.citation: J Exp Med. 2012 Nov 19;209(12):2247-61
references.pmid: 23129749
references.citation: Cancer Cell. 2012 Dec 11;22(6):706-7
references.pmid: 23238011
references.citation: Immunol Rev. 2012 Mar;246(1):141-53
references.pmid: 22435552
references.citation: Nat Genet. 1997 Dec;17(4):393-8
references.pmid: 9398839
references.citation: J Allergy Clin Immunol. 2013 Jul;132(1):151-8
references.pmid: 23727036
references.citation: Immunity. 2006 Nov;25(5):701-15
references.pmid: 17098202
references.citation: Nat Genet. 2001 Jan;27(1):20-1
references.pmid: 11137993
references.citation: Mol Cell. 2010 Dec 10;40(5):798-809
references.pmid: 21145487
references.citation: Subcell Biochem. 2010;54:88-99
references.pmid: 21222275
references.citation: Cold Spring Harb Perspect Biol. 2010 Jun;2(6):a002485
references.pmid: 20516133
references.citation: EMBO J. 2011 May 4;30(9):1742-52
references.pmid: 21448133
references.citation: Pediatr Dent. 2005 Jan-Feb;27(1):68-73
references.pmid: 15839398
references.citation: Cancer Discov. 2014 Apr;4(4):480-93
references.pmid: 24491438
references.citation: Nat Immunol. 2003 Sep;4(9):857-65
references.pmid: 12910267
references.citation: Acta Neuropathol. 2010 Oct;120(4):529-35
references.pmid: 20544211
references.citation: N Engl J Med. 2013 Dec 26;369(26):2504-14
references.pmid: 24369075
references.citation: Annu Rev Immunol. 2013;31:195-225
references.pmid: 23298211
references.citation: Nat Immunol. 2008 Mar;9(3):272-81
references.pmid: 18264101
references.citation: Front Immunol. 2011 Nov 08;2:54
references.pmid: 22566844
references.citation: Cold Spring Harb Perspect Biol. 2010 Sep;2(9):a003004
references.pmid: 20685844
references.citation: J Clin Invest. 2003 Oct;112(7):1108-15
references.pmid: 14523047
references.citation: Immunol Rev. 2009 Mar;228(1):93-114
references.pmid: 19290923
references.citation: J Allergy Clin Immunol. 2012 Jul;130(1):177-83
references.pmid: 22664165
references.citation: Immunity. 2003 Nov;19(5):749-58
references.pmid: 14614861
references.citation: Nature. 2006 May 11;441(7090):179-85
references.pmid: 16582901
references.citation: J Exp Med. 2005 Nov 21;202(10):1423-31
references.pmid: 16301747
references.citation: J Allergy Clin Immunol. 2014 Apr;133(4):1092-8
references.pmid: 24290292
references.citation: Annu Rev Immunol. 2009;27:693-733
references.pmid: 19302050
references.citation: Mol Cell. 2000 Oct;6(4):961-7
references.pmid: 11090634
references.citation: J Allergy Clin Immunol. 2014 Aug;134(2):262-8
references.pmid: 24100122
references.citation: Cell. 2013 May 23;153(5):1036-49
references.pmid: 23706741
references.citation: Immunity. 2005 Dec;23(6):561-74
references.pmid: 16356855
references.citation: Mol Cell Biol. 2013 Jan;33(2):429-43
references.pmid: 23149938
references.citation: Nat Genet. 2001 Jan;27(1):18-20
references.pmid: 11137992
references.citation: J Immunol. 2009 Jun 1;182(11):6736-43
references.pmid: 19454668
references.citation: Trends Immunol. 2013 May;34(5):234-42
references.pmid: 23428395
references.citation: Science. 2003 Nov 28;302(5650):1581-4
references.pmid: 14576442
references.citation: EMBO J. 2007 Nov 14;26(22):4634-45
references.pmid: 17948050
references.citation: Nat Immunol. 2011 Jul 19;12(8):715-23
references.pmid: 21772280
references.citation: Clin Exp Immunol. 2006 Dec;146(3):486-92
references.pmid: 17100769
references.citation: Nat Genet. 1997 Dec;17(4):399-403
references.pmid: 9398840
references.citation: Immunol Rev. 2009 Mar;228(1):199-211
references.pmid: 19290929
references.citation: Immunol Rev. 2012 Mar;246(1):379-400
references.pmid: 22435567
references.citation: J Biol Chem. 2004 Apr 16;279(16):15870-6
references.pmid: 14754896
references.citation: J Allergy Clin Immunol. 2013 May;131(5):1376-83.e3
references.pmid: 23561803
references.citation: FEBS Lett. 2001 May 11;496(2-3):121-7
references.pmid: 11356195
references.citation: Proc Natl Acad Sci U S A. 2011 Aug 30;108(35):14596-601
references.pmid: 21873235
references.citation: Biochim Biophys Acta. 2009 Jul;1793(7):1115-27
references.pmid: 19306898
references.citation: Am J Hum Genet. 2000 Dec;67(6):1555-62
references.pmid: 11047757
references.citation: Biochem J. 2012 Jun 1;444(2):e3-5
references.pmid: 22574776
references.citation: Annu Rev Immunol. 2012;30:565-610
references.pmid: 22224767
references.citation: Crit Rev Immunol. 2013;33(3):219-43
references.pmid: 23756245
references.citation: J Allergy Clin Immunol. 2014 May;133(5):1458-62, 1462.e1-7
references.pmid: 24332264