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Thursday, November 5, 2015

Genetic errors of the human caspase recruitment domain-B-cell lymphoma 10–mucosa-associated lymphoid tissue lymphoma-translocation gene 1 (CBM) complex: Molecular, immunologic, and clinical heterogeneity

The CBM complex consists of three components: a capase recruitment domain (CARD) protein, B-cell lymphoma 10 (BCL10), and mucosa-associated lymphoid tissue lymphoma-translocation gene 1 (MALT1). For the first component, the complex uses one of three CARD family adaptors: CARD9, CARD10, or CARD11. These three proteins activate nuclear factor κB (NF- κB) in both innate and adaptive human immunity, and NF- κB plays a critical role in immune regulation, cell memory, cell survival/apoptosis, and cell-cycle progression. Much remains to be learned about the CBM complex, and inherited defects have been recently reported. Pérez de Diego et al discuss (J Allergy Clin Immunol 2015; 136: 1139-1149).

The authors summarize the reports on four patients with MALT1 deficiency, one patient with BCL10 deficiency, and two patients with autosomal recessive (AR) CARD11 deficiency. Most of these patients carried homozygous mutations with low levels of protein expression, and the broad range of clinical presentations included serious conditions of the skin and of the respiratory and gastrointestinal tracts, infection, and growth retardation. Thirty-eight patients were reported with AR CARD9 deficiency following its initial description in 2009, making it the most common genetic disorder of the CBM complex. All of these 38 patients were highly susceptible to various fungal diseases. Finally, mutations in MALT1, BCL10, and CARD11 have been found in patients with MALT lymphoma and other lymphoproliferative disorders.

It is clear that defects of CARD 11, BCL10, and MALT 1 generate severe forms of combined immunodeficiency. Three of the patients mentioned above have died, and two others have undergone bone marrow transplantation, which appears to be the best treatment currently available. In contrast, patients with CARD9 deficiency have abnormalities in innate immunity leading to increased susceptibility to invasive disease. Adjuvant GM-CSF treatment has shown benefit for one patient with C albicans meningoencephalititis; and terbinafine and posaconazole have been used to treat patients with extensive dermatophytosis. The CBM complex makes substantial contributions to human immunity. Further studies should improve our understanding of the specific role of each of its components.

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