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.
Highlights
Inborn errors of immunity or primary immunodeficiency diseases (PIDs) are a group of ∼350 genetic disorders that are characterized by defects in immune system development and/or function [1]
Secretion in the presence of cytokines that trigger NF-κB (e.g., IL-1/TNF) and signal transducer and activator of transcription (STAT3) (e.g., IL-6) activation independent to the TCR [32]. These findings suggest that both NF-κB and mTORC1 signaling defects contribute to atopic predisposition and disease pathology, even though diagnostic readouts of impaired mTORC1 signaling can be variable and difficult to detect experimentally
Functional testing (e.g., Jurkat T cell transfections) is highly recommended to confirm DN LOF activity for any novel variants found. Based on these collective clinical and experimental findings, we propose to classify this disorder as CARD11-associated Atopy with Dominant Interference of NF-κB Signaling (CADINS) disease
Summary
Inborn errors of immunity or primary immunodeficiency diseases (PIDs) are a group of ∼350 genetic disorders that are characterized by defects in immune system development and/or function [1]. Summary of major clinical and immunological phenotypes associated with human germline GOF mutations in CARD11 causing B cell Expansion with NF-κB and T-cell Anergy (BENTA) disease. The ectopic expression of BENTA-associated CARD11 mutants in B and T cell lines results in the spontaneous assembly of large protein aggregates including CARD11, BCL10, MALT1, and phosphorylated IKKα/β, which induces constitutive NF-κB signaling independent of antigen receptor ligation [26, 28].
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