| Ectodermal dysplasia with immunodeficiency (ED-ID) is a rare primary immunodeficiency syndrome characterized by defects in ectodermal tissues (skin, hair and sweat glands), recurrent infections, impaired response to Toll-like receptor ligands, hypogammaglobulinemia and deficient antibody production. It is caused by defective NFkappaB signaling.;The most common form of ED-ID is X-linked. It is caused by hypomorphic mutations in the NFkappaB essential modifier gene NEMO, which is an important regulatory component in the NFkappaB signaling pathway. We report the first case of ED-ID caused by insufficient expression of a NEMO protein of normal sequence, due to a mutation in the 5' untranslated region of the NEMO gene.;Autosomal dominant ED-ID, a rare form of ED-ID, has been reported to be caused by a heterozygous S32I mutation in the IkappaBalpha. This mutation prevents IkappaBalpha phosphorylation and inhibits its degradation. The mutant sequesters NFkappaB in the cytoplasm and acts as a dominant negative. We report the first ED-ID patient with a heterozygous mutation (W11X) that causes N-terminal truncation of IkappaBalpha and results in functional haploinsufficiency.;We have constructed a knock-in mouse model of ED-ID caused by a heterozygous S32I mutation in IkappaBalpha. The mutant mice had ED, increased mortality, complete lack of lymph nodes and Peyer's patches, and disorganized spleens that lacked follicles, marginal zone B cells and follicular dendritic cells. T cell proliferation and cytokine production was normal in vitro, but in vivo contact hypersensitivity was severely impaired, B cell function in vitro and specific antibody response to antigens were severely reduced. All immune defects, except those that affected B cell function, were absent in IIkappaBalpha S32I mutant Rag2-/- bone marrow chimeras, indicating that defects in non-lymphiod cells play a major role in the immunodeficiency of patients with ED-ID due to mutations in IkappaBalpha. This has important clinical implications, as bone marrow transplant may not be able to correct immune function in such patients.;The lessons learned in these chapters may be applicable to other mutations that impair NFkappaB signaling and have important implications for the treatment of patients who carry these mutations. |
