| First Author | Mooster JL | Year | 2015 |
| Journal | J Exp Med | Volume | 212 |
| Issue | 2 | Pages | 185-202 |
| PubMed ID | 25601653 | Mgi Jnum | J:301951 |
| Mgi Id | MGI:6207199 | Doi | 10.1084/jem.20140979 |
| Citation | Mooster JL, et al. (2015) Defective lymphoid organogenesis underlies the immune deficiency caused by a heterozygous S32I mutation in IkappaBalpha. J Exp Med 212(2):185-202 |
| abstractText | Patients with ectodermal dysplasia with immunodeficiency (ED-ID) caused by mutations in the inhibitor of NF-kappaB alpha (IkappaBalpha) are susceptible to severe recurrent infections, despite normal T and B cell numbers and intact in vitro lymphocyte function. Moreover, the outcome of hematopoietic stem cell transplantation (HSCT) in these patients is poor despite good engraftment. Mice heterozygous for the IkappaBalpha S32I mutation found in patients exhibited typical features of ED-ID. Strikingly, the mice lacked lymph nodes, Peyer's patches, splenic marginal zones, and follicular dendritic cells and failed to develop contact hypersensitivity (CHS) or form germinal centers (GCs), all features not previously recognized in patients and typical of defective noncanonical NF-kappaB signaling. Lymphotoxin beta receptor (LTbetaR)-driven induction of chemokines and adhesion molecules mediated by both canonical and noncanonical NF-kappaB pathways was impaired, and levels of p100 were markedly diminished in the mutant. IkappaBalpha mutant --> Rag2(-/-), but not WT-->IkappaBalpha mutant, bone marrow chimeras formed proper lymphoid organs and developed CHS and GCs. Defective architectural cell function explains the immunodeficiency and poor outcome of HSCT in patients with IkappaBalpha deficiency and suggests that correction of this niche is critical for reconstituting their immune function. |
