Mechanistic understanding of the combined immunodeficiency in complete human CARD11 deficiency.

Victor A Lewis, Stuart E Turvey, Sneha Suresh, Christopher M Overall, Eytan Wine, Consolato Sergi, Nicola A M Wright, Luis Murguia-Favela, Lyle McGonigle, Sunil Desai, Marta Rojas Vasquez, Henry Y Lu, Gregory M T Guilcher, Peter A Bell, Afshin Shameli, Poonam Dharmani-Khan, Joanne Luider, Ashley Szpurko, Atilano Lacson, Ashish A Sharma, Mehul Sharma

Journal: The Journal of allergy and clinical immunology 2021;148(6):1559-1574.e13

PMID: 33872653

Full Text on Elsevier Science View on PubMed

Abstract

BACKGROUND

Germline pathogenic variants impairing the caspase recruitment domain family member 11 (CARD11)-B cell chronic lymphocytic leukemia/lymphoma 10 (BCL10)-MALT1 paracaspase (MALT1) (CBM) complex are associated with diverse human diseases including combined immunodeficiency (CID), atopy, and lymphoproliferation. However, the impact of CARD11 deficiency on human B-cell development, signaling, and function is incompletely understood.

OBJECTIVES

This study sought to determine the cellular, immunological, and biochemical basis of disease for 2 unrelated patients who presented with profound CID associated with viral and fungal respiratory infections, interstitial lung disease, and severe colitis.

METHODS

Patients underwent next-generation sequencing, immunophenotyping by flow cytometry, signaling assays by immunoblot, and transcriptome profiling by RNA-sequencing.

RESULTS

Both patients carried identical novel pathogenic biallelic loss-of-function variants in CARD11 (c.2509C>T; p.Arg837∗) leading to undetectable protein expression. This variant prevented CBM complex formation, severely impairing the activation of nuclear factor-κB, c-Jun N-terminal kinase, and MALT1 paracaspase activity in B and T cells. This functional defect resulted in a developmental block in B cells at the naive and type 1 transitional B-cell stage and impaired circulating T follicular helper cell (cT) development, which was associated with impaired antibody responses and absent germinal center structures on lymph node histology. Transcriptomics indicated that CARD11-dependent signaling is essential for immune signaling pathways involved in the development of these cells. Both patients underwent hematopoietic stem cell transplantations, which led to functional normalization.

CONCLUSIONS

Complete human CARD11 deficiency causes profound CID by impairing naive/type 1 B-cell and cT cell development and abolishing activation of MALT1 paracaspase, NF-κB, and JNK activity. Hematopoietic stem cell transplantation functionally restores impaired signaling pathways.

Address: Department of Pediatrics, British Columbia Children's Hospital, The University of British Columbia, Vancouver, British Columbia, Canada; Experimental Medicine Program, Faculty of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada.; Department of Pathology, Case Western Reserve University, Cleveland, Ohio; Department of Pathology, Emory University, Atlanta, Ga.; Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.; Section of Oncology/Bone Marrow Therapy, Departments of Oncology and Pediatrics, Alberta Children's Hospital, University of Calgary, Calgary, Alberta, Canada.; Department of Pathology and Laboratory Medicine, University of Calgary, Alberta Precision Laboratories, Calgary, Alberta, Canada.; Centre for Blood Research, The University of British Columbia, Vancouver, British Columbia, Canada; Department of Oral Biological and Medical Sciences, Faculty of Dentistry, The University of British Columbia, Vancouver, British Columbia, Canada.; Department of Pediatrics, Division of Immunology, Hematology, Oncology and Palliative Care (iHOPE), University of Alberta, Edmonton, Alberta, Canada.; Department of Pediatrics, Division of General and Community Pediatrics, University of Alberta, Edmonton, Alberta, Canada.; Section of Pediatric Hematology-Immunology, Department of Pediatrics, Alberta Children's Hospital, University of Calgary, Calgary, Alberta, Canada.; Division of Pediatric Gastroenterology and Nutrition, Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada.; Department of Pediatrics, British Columbia Children's Hospital, The University of British Columbia, Vancouver, British Columbia, Canada; Experimental Medicine Program, Faculty of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada. Electronic address: [email protected].

DOI: 10.1016/j.jaci.2021.04.006