CBM opathies

Congenital immunodeficiency with atopic phenotype caused by mutations in the CARD11-BCL10-MALT complex.

Germline mutations in MALT1, CARD11 and BCL10 can be considered primary atopic diseases, as they are associated with early-onset severe atopic diseases, among others (Lyons JJ et al. 2018). Primary atopic diseases are often associated with primary immunodeficiency, usually caused by mutations in cytokine signaling or defects in TCR signaling or the TCR repertoire. Atopy is thought to be caused by the propensity of naïve CD4 T cells to evolve towards Th2 differentiation in the presence of relatively weak TCR signaling (Milner JD 2018). While CBM-associated mutations, as in the CBM-opathies, are directly associated with TCR signaling, other disorders also exist that can indirectly affect TCR signaling and cause atopic disease. These include genes involved in the remodeling of the actin cytoskeleton, such as

• the deficiency of DOCK8 (Dedicator of Cytokinesis 8) (Zhang Q et al. (2009),
• the deficiency of WIS protein (Wiskott-Aldrich syndrome, WAS) (Lanzi G et al. 2012).
• Mutations of the ARP2/3 complex (Kuijpers TW et al. 2017) and
• mutations in ZAP70 (Karaca E et al. 2013).

The clinical presentation of DOCK8 deficiency is somewhat similar to CBM mutation-associated atopy, but infectious and neoplastic manifestations are more severe.

The most prominent TCR repertoire defect associated with atopic diseases is Omenn syndrome. This does not correspond to a genetically uniform clinical picture. In a heterogeneous genotype, a similar phenotype is expressed. Mutations are found in RAG1/RAG2, IL7-Ralpha and the RMRP gene. The Omenn phenotype is associated with SCID. The oligoclonal expansion of CD4 T cells in turn leads to severe (atopic) dermatitis, increased IgE, eosinophilia and lymphoproliferation.

In adaptive immunity, the CBM complex functions in a highly synergistic manner. Accordingly, patients with CARD11, BCL10, and MALT1 deficiency share many common features, including CID/SCID with normal total B and T cell numbers, abnormal B and T cell subpopulations, few to no Tregs, impaired T cell proliferation, and recurrent bacterial/viral infections. As a group, patients with these CBM-opathies have shown that the CBM complex is a critical regulator of human Treg development and tolerance; however, the exact mechanisms by which this occurs are not yet fully understood (Lee AJ et al. 2010).

While CARD11 is largely restricted to hematopoietic cells, BCL10 and MALT1 exhibit much broader cellular expression. Each individual CBM-opathy has its own characteristic features. For example, patients with CARD11 deficiency exhibit panhypogammaglobulinemia, which does not occur in MALT1 or BCL10 deficiency.

Another clinical feature that varies between CBM-opathies is susceptibility to Pneumocystis jirovecii pneumonia (PJP). PJP is a very common infection in CARD11 deficiency (reported in 75% of identified patients), but not in MALT1 and BCL10 deficiency.

Furthermore, both MALT1- and BCL10-deficient patients show concomitant immunodeficiency and immune dysregulation, developing inflammatory gastrointestinal diseases in addition to recurrent infections.

In adaptive immunity, the CBM complex functions in a highly synergistic manner. Accordingly, patients with CARD11, BCL10, and MALT1 deficiency share many common features, including CID/SCID with normal total B and T cell numbers, abnormal B and T cell subpopulations, few to no Tregs, impaired T cell proliferation, and recurrent bacterial/viral infections. As a group, patients with these CBM-opathies have shown that the CBM complex is a critical regulator of human Treg development and tolerance; however, the exact mechanisms by which this occurs are not yet fully understood (Lee AJ et al. 2010).

While CARD11 is largely restricted to hematopoietic cells, BCL10 and MALT1 exhibit much broader cellular expression. Each individual CBM-opathy has its own characteristic features. For example, patients with CARD11 deficiency have panhypogammaglobulinemia, which does not occur in MALT1 or BCL10 deficiency.

Another clinical feature that varies between CBM-opathies is susceptibility to Pneumocystis jirovecii pneumonia (PJP). PJP is a very common infection in CARD11 deficiency (reported in 75% of identified patients), but not in MALT1 and BCL10 deficiency.

Furthermore, both MALT1- and BCL10-deficient patients show concomitant immunodeficiency and immune dysregulation, developing inflammatory gastrointestinal diseases in addition to recurrent infections.

Given the role of the CBM complex in a number of human pathologies, there is great interest in the development and research of therapeutics. MALT1 inhibitors may prove to be promising options for the treatment of cancers and diseases with a lymphoproliferative component, including BENTA.

Currently, treatment of complete CARD11, BCL10 and MALT1 deficiencies is based on hematopoietic stem cell transplantation to functionally normalize immune function (with immunoglobulin replacement and prophylactic antimicrobials as supportive therapy). Without transplantation, the survival rate is very low.

1. Karaca E et al. (2013) Identification of a novel mutation in ZAP70 and prenatal diagnosis in a Turkish family with severe combined immunodeficiency disorder. Genes 512:189-193.
2. Kuijpers TW et al. (2017) Combined immunodeficiency with severe inflammation and allergy caused by ARPC1B deficiency. J Allergy Clin Immunol 140:273-7 e10.
3. Lanzi G et al. (2012) A novel primary human immunodeficiency due to deficiency in the WASP-interacting protein WIP. J Exp Med 209:29-34.
4. Lee AJ et al. (2010) CARMA1 regulation of regulatory T cell development involves modulation of interleukin-2 receptor signaling. J Biol Chem 285:15696-15703.
5. Lyons JJ et al (2018) Primary atopic disorders. J Exp Med 215:1009-1022.
6. Milner JD (2018) TCR signaling abnormalities in human Th2-associated atopic disease. Front Immunol 9:719.
7. Molinero LL et al. (2012) T cell receptor/CARMA1/NF-kappaB signaling controls T-helper (Th) 17 differentiation. Proc Natl Acad Sci USA 109:18529-18534.
8. Ochs HD (2009) Mutations of the Wiskott-Aldrich Syndrome Protein affect protein expression and dictate the clinical phenotypes. Immunol Res 44:84-88.
9. Zhang Q et al. (2009) Combined immunodeficiency associated with DOCK8 mutations. N Engl J Med 361:2046-2055.