Background: Boys with X-linked ectodermal dysplasia and immunodeficiency caused by mutations of nuclear factor-kappaB essential modulator have defects in innate and adaptive immunity, and some have colitis.
Objective: We sought to determine whether curing the immune defect in such patients by means of allogeneic hematopoietic stem cell transplantation abolishes the susceptibility to colitis.
Methods: A boy with X-linked hypohydrotic ectodermal dysplasia with immunodeficiency underwent allogeneic transplantation from a matched unaffected sibling identified by means of preimplantation genetic diagnosis. Toll-like receptor (TLR) function was assessed by measuring TLR agonist-induced cytokine production in whole blood tested in vitro. B-cell proliferation was measured by means of tritiated thymidine incorporation. Natural killer cell function was examined in PBMCs by means of K562 target cell lysis. Colitis severity was assessed clinically based on corticosteroid requirement and histology of large intestinal biopsy specimens.
Results: Defects in cytokine production in response to TLR agonists, CD40-mediated proliferation, and natural killer cell cytotoxicity were all corrected after hematopoietic stem cell transplantation. Despite successful hematopoietic and immune reconstitution, the patient continued to have flares of colitis, often associated with bacterial infection.
Conclusions: Our findings strongly suggest that nuclear factor-kappaB essential modulator deficiency intrinsic to the intestinal epithelium is sufficient to predispose to colitis, despite robust correction of immune defects.