Human CARD11 deficiency causes profound combined immunodeficiency (P3325)

Patients with primary immunodeficiency present an excellent opportunity to understand the role of specific molecules in the human immune system. Recently we had the chance to investigate a young girl with a complete CARD11 deficiency due to a homozygous deletion of exon 21. Clinically the child presented with increased susceptibility to respiratory tract infections at 6 months, before she was diagnosed at 13 months with Pneumocystis jirovecii revealing her combined immunodeficiency. The immunological characterization showed severe hypogammaglobulinemia, but normal T-, B- and NK-cell numbers. While there were only subtle changes in the T cell compartment, B-cell differentiation was blocked at the transitional stage. In the absence of CARD11 protein expression activation of the canonical NF-κB pathway after antigen receptor or PMA stimulation was abrogated, while CD40 signaling in B cells was preserved. CARD11 deficient T cells were severely impaired in the up-regulation of ICOS, OX40, cytokine production and proliferation after TCR stimulation. On B cells BAFF receptor expression was reduced and after activation ICAM1 and CD25 were not induced while CD86 induction was comparable to control cells. Immunoglobulin production was intact after anti-IL-21/CD40L stimulation, demonstrating that plasma cell differentiation was not dependent on intact CARD11. Thus CARD11 plays a crucial, non-redundant role in the antigen specific immune response in humans.