Mechanistic understanding of the combined immunodeficiency in complete human CARD11 deficiency

J Allergy Clin Immunol. 2021 Dec;148(6):1559-1574.e13. doi: 10.1016/j.jaci.2021.04.006. Epub 2021 Apr 17.

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 (cTFH) 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 cTFH cell development and abolishing activation of MALT1 paracaspase, NF-κB, and JNK activity. Hematopoietic stem cell transplantation functionally restores impaired signaling pathways.

Keywords: B-cell development; CARD11; CBM complex; Combined immunodeficiency; hematopoietic stem cell transplantation.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • B-Cell CLL-Lymphoma 10 Protein / metabolism
  • CARD Signaling Adaptor Proteins / genetics*
  • CARD Signaling Adaptor Proteins / metabolism
  • Child
  • Gene Expression Profiling
  • Germinal Center / immunology*
  • Guanylate Cyclase / genetics*
  • Guanylate Cyclase / metabolism
  • Hematopoietic Stem Cell Transplantation*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Immunophenotyping
  • Infant
  • Male
  • Mutation / genetics*
  • NF-kappa B / metabolism
  • Precursor Cells, B-Lymphoid / immunology*
  • Primary Immunodeficiency Diseases / immunology*
  • Primary Immunodeficiency Diseases / therapy
  • Signal Transduction
  • T-Lymphocytes, Helper-Inducer / immunology*

Substances

  • B-Cell CLL-Lymphoma 10 Protein
  • BCL10 protein, human
  • CARD Signaling Adaptor Proteins
  • NF-kappa B
  • CARD11 protein, human
  • Guanylate Cyclase