The CBM-opathies-A Rapidly Expanding Spectrum of Human Inborn Errors of Immunity Caused by Mutations in the CARD11-BCL10-MALT1 Complex

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.

Keywords: BCL10; BENTA; CARD11; CBM complex; MALT1; combined immunodeficiency; primary atopic disease; severe combined immunodeficiency.

Figure 1

The landscape of human germline mutations causing CBM-opathies. Schematic representation of protein domains found in CARD11, BCL10, and MALT1. Red arrows indicate interactions between domains. Annotated are confirmed mutations causing CBM-opathies and where they localize to on the protein. CARD, caspase recruitment domain; RE, repressive element; L, linker; PDZ, postsynaptic density protein (PSD95), Drosophila disc large tumor suppressor (Dlg1), zonula occludens-1 protein (zo-1) domain; SH3, SRC homology 3 (SH3); GUK, guanylate kinase domain; S/T, serine/threonine; DD, death domain; Ig, immunoglobulin-like domain.

Figure 2

The central role of the CBM complex in BCR- and TCR- signaling. Schematic representation of proximal antigen receptor signaling events in the BCR and TCR, activation and assembly of the CBM complex, and downstream targets and effects of CBM activation. Gray circles represent ubiquitin chains.

Figure 3

The expanding clinical spectrum of CBM-opathies. Shown is a gradient of CBM activity caused by germline mutations. Activity ranges from absent to hyperactive CBM activity. Red indicates loss-of-function (LOF) mutations (CARD11, BCL10, and MALT1 deficiencies), yellow indicates hypomorphic mutations that do not completely abrogate signaling leading to combined immunodeficiency and atopy as well as novel emerging phenotypes (DN LOF CARD11), purple indicates gain-of-function (GOF) mutations that can lead to BENTA (GOF CARD11) or malignancy (somatic GOF in CBM). Biologics refer to antibodies, which target cells, cytokines or cell surface receptors. SCID, severe combined immunodeficiency; CID, combined immunodeficiency; AA, amino acid; HSCT, hematopoietic stem cell transplantation.