Germline CBM-opathies: From immunodeficiency to atopy

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 CBMopathies) 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,

CARD14E138A signalling in keratinocytes induces TNF-dependent skin and systemic inflammation

“…Gain-of-function, highly penetrant (>90%) and dominantly acting mutations within the CARD14 gene can trigger the development of PV or GPP ( Jordan et al, 2012b ). CARD14 (CARMA2) is a member of the CARMA family of scaffolding proteins that includes CARD11 (CARMA1) and CARD10 (CARMA3) ( Lu et al, 2019 ). Each of these proteins has a similar domain structure, comprising an N-terminal CARD domain, followed by a coiled-coil (CC) domain, and a C-terminal MAGUK domain (PDZ-SH3-GUK).…”

“…Each of these proteins has a similar domain structure, comprising an N-terminal CARD domain, followed by a coiled-coil (CC) domain, and a C-terminal MAGUK domain (PDZ-SH3-GUK). CARD11 and CARD10 play critical roles in the activation of NF-κB transcription factors following ligation of antigen receptors and G-protein-coupled receptors, respectively ( Lu et al, 2019 ). NF-κB, composed of dimers of Rel polypeptides, regulates gene expression by binding to κB elements in the promoters and enhancers of multiple target genes that control immune and inflammatory responses ( Zhang et al, 2017 ).…”

Coordinated regulation of scaffold opening and enzymatic activity during CARD11 signaling

“…CARD11 is a critical scaffold protein that operates in the adaptive immune system to relay antigen receptor engagement on B and T lymphocytes into the activation of NF-B, JNK, 4 and mTOR pathways (1)(2)(3)(4). CARD11 function is essential for the efficient elimination of multiple human pathogens.…”

“…1 Supported by National Institutes of Health Grant T32CA009110. 2 Recipient of a Leukemia and Lymphoma Society Fellow Award. 3 To whom correspondence should be addressed: engagement, the autoinhibitory action of the REs is neutralized in a poorly understood process that converts CARD11 into an open, active state that is receptive to the binding of cofactors including Bcl10, MALT1, and HOIP, the catalytic subunit of the linear ubiquitin chain assembly complex, as well as several other proteins (1).…”

The First Case of BENTA Disease (B Cell Expansion with NF-κB and T Cell Anergy) from Iran

“…The G123S germline mutation was first reported by Snow et al, in 2012 in an adapted 6-year-old girl from China [2] and later in two other patients from Europe and India [3,4]. Clinical presentations of all BENTA disease patients include earlyonset polyclonal B cell proliferation leading to peripheral blood lymphocytosis, splenomegaly, lymphadenopathy, recurrent upper respiratory tract infections, and susceptibility to other types of viral infections including Epstein-Barr virus (EBV) [5]. Autoimmunity with various severities has also been reported in some patients including two of the previously reported ones with G123S mutation [2,4,5].…”