Mechanistic understanding of the combined immunodeficiency in complete human CARD11 deficiency

Lu, Henry Y.; Sharma, Mehul; Sharma, Ashish; Lacson, Atilano; Szpurko, Ashley; Luider, Joanne; Dharmani‐Khan, Poonam; Shameli, Afshin; Bell, Peter A.; Guilcher, Gregory M.T.; Lewis, Victor; Vasquez, Marta Rojas; Desai, Sunil; McGonigle, Lyle; Murguía-Favela, Luis; Wright, Nicola; Sergi, Consolato; Wine, Eytan; Overall, Christopher M.; Suresh, Sneha; Turvey, Stuart E.

doi:10.1016/j.jaci.2021.04.006

Cited by 23 publications

(28 citation statements)

References 87 publications

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“…It remains to be determined what threshold of CARD11 dominant-negative activity is required to elicit CADINS disease in patients. The increasing identification and study of LOF CARD11 mutations in patients ( Dadi et al., 2018 ; Dorjbal et al., 2019 ; Greil et al., 2013 ; Izadi et al., 2021 ; Lu et al., 2019 , 2021 ; Ma et al., 2017 ; Stepensky et al., 2013 ), in model systems ( Meitlis et al., 2020 ), and mice ( Hutcherson et al., 2021 ) promise to accelerate our understanding of the different clinical syndromes associated with different classes of CARD11 mutations.…”

Section: Discussionmentioning

confidence: 99%

“…These three diseases, caused by different classes of CARD11 mutations, are referred to as CARD11 deficiency, B cell Expansion with NF-κB and T cell Anergy (BENTA), and CARD11-associated Atopy with Dominant Interference of NF-κB Signaling (CADINS). CARD11 deficiency is caused by homozygous LOF mutations in CARD11 and is associated with severe Pneumocystis jirovecii infections, hypogammaglobulinemia, deficits in mature or differentiated B and T cells, and defective B and T cell activation in vitro ( Greil et al., 2013 ; Lu et al., 2021 ; Stepensky et al., 2013 ). BENTA disease is caused by heterozygous GOF CARD11 mutations ( Snow et al., 2012 ).…”

Section: Introductionmentioning

confidence: 99%

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Mechanistic impact of oligomer poisoning by dominant-negative CARD11 variants

et al. 2022

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mechanistic impact of oligomer poisoning by dominant-negative CARD11 variants

et al. 2022

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“…Inherited mutations in CARD11 are associated with different diseases. Thus, heterozygous dominant-negative variants of CARD11 result in combined immunodeficiency with, or without atopy, high IgE levels and other autoimmune features [reviewed in (85,86)]. Germline GoF CARD11 mutations instead cause B cell expansion with NF-kB and T cell anergy (BENTA), accompanied by elevated NF-kB activity and hyperproliferative B cells (87).…”

Section: Card11 (Carma1) Resistance Mutations For Btkimentioning

confidence: 99%

“…Mutations in components of the CARD11-BCL10-MALT1 complex affect the development of the B cell lineage but also give rise to other phenotypes (86,89). CARD11 is so far unique in that both GoF and LoF germline mutations have been identified in humans, with LoF causing a combined immunodeficiency affecting both B-and T-cells (86,89,145). The inhibitory IkBa can be affected with GoF variations, whereas NF-kB only shows LoF and these cause B cell deficiency (145).…”

Section: Phenotype Of Germline Loss-of-function Mutations Affecting Components Of the Bcr Pathwaymentioning

confidence: 99%

Resistance Mutations to BTK Inhibitors Originate From the NF-κB but Not From the PI3K-RAS-MAPK Arm of the B Cell Receptor Signaling Pathway

Smith

Burger

2021

Front. Immunol.

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Since the first clinical report in 2013, inhibitors of the intracellular kinase BTK (BTKi) have profoundly altered the treatment paradigm of B cell malignancies, replacing chemotherapy with targeted agents in patients with chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and Waldenström’s macroglobulinemia. There are over 20 BTKi, both irreversible and reversible, in clinical development. While loss-of-function (LoF) mutations in the BTK gene cause the immunodeficiency X-linked agammaglobulinemia, neither inherited, nor somatic BTK driver mutations are known. Instead, BTKi-sensitive malignancies are addicted to BTK. BTK is activated by upstream surface receptors, especially the B cell receptor (BCR) but also by chemokine receptors, and adhesion molecules regulating B cell homing. Consequently, BTKi therapy abrogates BCR-driven proliferation and the tissue homing capacity of the malignant cells, which are being redistributed into peripheral blood. BTKi resistance can develop over time, especially in MCL and high-risk CLL patients. Frequently, resistance mutations affect the BTKi binding-site, cysteine 481, thereby reducing drug binding. Less common are gain-of-function (GoF) mutations in downstream signaling components, including phospholipase Cγ2 (PLCγ2). In a subset of patients, mechanisms outside of the BCR pathway, related e.g. to resistance to apoptosis were described. BCR signaling depends on many proteins including SYK, BTK, PI3K; still based on the resistance pattern, BTKi therapy only selects GoF alterations in the NF-κB arm, whereas an inhibitor of the p110δ subunit of PI3K instead selects resistance mutations in the RAS-MAP kinase pathway. BTK and PLCγ2 resistance mutations highlight BTK’s non-redundant role in BCR-mediated NF-κB activation. Of note, mutations affecting BTK tend to generate clone sizes larger than alterations in PLCγ2. This infers that BTK signaling may go beyond the PLCγ2-regulated NF-κB and NFAT arms. Collectively, when comparing the primary and acquired mutation spectrum in BTKi-sensitive malignancies with the phenotype of the corresponding germline alterations, we find that certain observations do not readily fit with the existing models of BCR signaling.

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“…In our opinion, there is some evidence that Zn may be of benefit to patients receiving HSCT and in individuals affected with other immunologic deficiencies, such as CARD11 deficiency (25,33). However, randomized clinical trials with numerous patients and animal models for mechanistic data are warranted.…”

mentioning

confidence: 99%

The Role of Zinc in the T-Cell Metabolism in Infection Requires Further Investigation - An Opinion

Sergi

2022

Front. Immunol.

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Mechanistic understanding of the combined immunodeficiency in complete human CARD11 deficiency

Cited by 23 publications

References 87 publications

Mechanistic impact of oligomer poisoning by dominant-negative CARD11 variants

Mechanistic impact of oligomer poisoning by dominant-negative CARD11 variants

Resistance Mutations to BTK Inhibitors Originate From the NF-κB but Not From the PI3K-RAS-MAPK Arm of the B Cell Receptor Signaling Pathway

The Role of Zinc in the T-Cell Metabolism in Infection Requires Further Investigation - An Opinion

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