Publications

Abstract

Severe combined immunodeficiency (SCID) due to mutations in IL2RG or JAK3 is characterized by lack of T and NK cells; B cells are present in normal number but antibody responses are defective. Hematopoietic cell transplantation (HCT) is curative for SCID. However, B-cell dysfunction persists in a substantial proportion of patients. We hypothesized that impaired B-cell responses post-HCT in IL2RG/JAK3-deficiency results from poor donor B-cell engraftment and defective gammac-dependent cytokine signaling in host B cells. To test this, and to identify which gammac cytokine(s) are critical for humoral immunity, we studied 28 transplanted patients with IL2RG/JAK3-deficiency. Lack of donor B cell engraftment associated with persistent humoral dysfunction and significantly reduced memory B cells. B cell proliferation induced by CD40L alone or together with CpG, anti-Ig, IL-4, IL-10 or IL-13 was comparable in healthy controls and in post-HCT SCID patients, irrespective of their chimerism status. However, in vitro stimulation with CD40L/IL-21 induced B cell proliferation, plasmablast differentiation and antibody secretion in patients with donor B cells, but not those with autologous B cells. These data imply that IL-21-mediated signalling is critical for long-lived humoral immunity and to restore antibody responses in IL2RG/JAK3-deficient patients post-HCT. Furthermore, in vitro stimulation with CD40L/IL-21 can predict in vivo B cell immunity in IL2RG/JAK3 SCID post transplant.