Immunodeficiency: primary or acquired
Background: The CARD11–BCL10–MALT1 (CBM) complex is a critical signalling adaptor that regulates lymphocyte activation, proliferation, and survival. Primary immunodeficiencies (PIDs) affecting each component result in broad clinical manifestations ranging from combined immunodeficiency (CID) to lymphoproliferation. We present the laboratory and clinical findings of two Canadian First Nations patients found to be homozygous for the same novel CARD11 mutation (c.2509C>T; p.R837*).
Results: We have identified an 8-month-old boy who presented with a severe case of entero/rhinovirus bronchiolitis with interstitial lung disease and a 17-year-old boy with a history of severe pulmonary infections, chronic sinusitis, candidiasis, invasive bacteremia, and severe ileo-colitis and oral ulceration requiring total colectomy. Both patients lacked Tregs and memory B cells, and possessed hypogammaglobulinemia. Sequencing both patients revealed homozygosity for the same novel variant of CARD11 (c.2509C>T; p.R837*), which rendered CARD11 protein undetectable by immunoblot. To confirm CARD11 deficiency, we stimulated patient B cells with phorbol 12-myristate 13 acetate (PMA) and ionomycin across a time-course and immunoblotted for various signalling proteins in both the NF-κB and MAPK pathways and cleavage substrates of the MALT1 paracaspase. NF-κB and JNK activation were completely absent, MALT paracapase activity was lost, and the CBM complex could not be assembled.
Conclusions: These two cases highlight the crucial role of CARD11 in regulating lymphocyte development, function, and humoral responses. In addition, we have identified the oldest known living individual with CARD11 deficiency and he presented uniquely with inflammatory gastrointestinal disease in addition to CID, thus further broadening the spectrum of phenotypes associated with CARD11-related PIDs.