Brief CommunicationTransplantation from a symptomatic carrier sister restores host defenses but does not prevent colitis in NEMO deficiency

•Behcet's disease-like symptoms can be a manifestation of NEMO mutations in females.•As little as 10% wild-type NEMO activity can suffice to protect from severe infections.•Epithelial NEMO deficiency can play an important role in the development of NEMO associated inflammatory bowel disease.•NEMO-associated intestinal inflammation can be abrogated by high doses of anti-TNF-therapy.

NF-κB essential modulator (NEMO) deficiency causes ectodermal dysplasia with immunodeficiency in males, while manifesting as incontinentia pigmenti in heterozygous females. We report a family with NEMO deficiency, in which a female carrier displayed skewed X-inactivation favoring the mutant NEMO allele associated with symptoms of Behçet's disease. Hematopoietic stem cell transplantation of an affected boy from this donor reconstituted an immune system with retained skewed X-inactivation. After transplantation no more severe infections occurred, indicating that an active wild-type NEMO allele in only 10% of immune cells restores host defense. Yet he developed inflammatory bowel disease (IBD). While gut infiltrating immune cells stained strongly for nuclear p65 indicating restored NEMO function, this was not the case in intestinal epithelial cells - in contrast to cells from conventional IBD patients. These results extend murine observations that epithelial NEMO-deficiency suffices to cause IBD. High anti-TNF doses controlled the intestinal inflammation and symptoms of Behçet's disease.