Mechanisms of Immunodeficiency Due To NFkappaB Signaling Defects

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Mechanisms of Immunodeficiency Due To NFkappaB Signaling Defects

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dc.contributor.advisor Geha, Raif Salim
dc.contributor.author Mooster, Jana
dc.date.accessioned 2012-11-07T20:42:47Z
dash.embargo.terms 2014-06-21 en_US
dc.date.issued 2012-11-07
dc.date.submitted 2012
dc.identifier.other http://dissertations.umi.com/gsas.harvard:10389 en
dc.identifier.uri http://nrs.harvard.edu/urn-3:HUL.InstRepos:9882531
dc.description.abstract 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 \(NF\kappa B\) signaling. The most common form of ED-ID is X-linked. It is caused by hypomorphic mutations in the \(NF\kappa B\) essential modifier gene NEMO, which is an important regulatory component in the \(NF\kappa B\) 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 \(I \kappa B \alpha\). This mutation prevents IκBα phosphorylation and inhibits its degradation. The mutant sequesters \(NF\kappa B\) 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 \(I \kappa B \alpha\) and results in functional haploinsufficiency. We have constructed a knock-in mouse model of ED-ID caused by a heterozygous S32I mutation in \(I \kappa B \alpha\). 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 \(I \kappa B \alpha\) 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 \(I \kappa B \alpha\). 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 \(NF\kappa B\) signaling and have important implications for the treatment of patients who carry these mutations. en_US
dc.language.iso en_US en_US
dash.license LAA
dc.subject ectodermal dysplasia en_US
dc.subject NFkappaB en_US
dc.subject primary immunodeficiency en_US
dc.subject immunology en_US
dc.subject molecular biology en_US
dc.subject medicine en_US
dc.subject ectodermal dysplasia en_US
dc.title Mechanisms of Immunodeficiency Due To NFkappaB Signaling Defects en_US
dc.type Thesis or Dissertation en_US
dc.date.available 2014-06-21T07:30:42Z
thesis.degree.date 2012 en_US
thesis.degree.discipline Immunology en_US
thesis.degree.grantor Harvard University en_US
thesis.degree.level doctoral en_US
thesis.degree.name Ph.D. en_US

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