Severe disease and greater impairment of NF-κB activation in IκBa point mutants versus truncation mutants in autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency

Publication date: Available online 17 June 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Daniel Petersheim, Michel J. Massaad, Saetbyul Lee, Alessia Scarselli, Caterina Cancrini, Kunihiko Moriya, Yoji Sasahara, Arjan C. Lankester, Morna Dorsey, Daniela Di Giovanni, Liliana Bezrodnik, Hidenori Ohnishi, Ryuta Nishikomori, Kay Tanita, Hirokazu Kanegane, Tomohiro Morio, Erwin W. Gelfand, Ashish Jain, Elizabeth Secord, Capucine Picard, Jean-Laurent Casanova, Michael H. Albert, Troy R. Torgerson, Raif S. Geha
BackgroundAutosomal dominant anhidrotic ectodermal dysplasia with immune deficiency (AD EDA-ID) is caused by heterozygous point mutations at or close to S32 and S36 or N-terminal truncations in IκBα that impair its phosphorylation and degradation, and thus activation of the canonical NF-κB pathway. The outcome of hematopoietic stem cell transplantation is poor in AD EDA-ID despite achievement of chimerism. Mice heterozygous for the S32I mutation in IκBα have impaired non-canonical NF-κB activity and defective lymphorganogenesis.ObjectiveTo establish genotype-phenotype correlation in AD EDA-ID.MethodsA disease severity scoring system was devised. Stability of IκBα mutants was examined in transfected cells. Immunological, biochemical, and gene expression analyses were performed to evaluate canonical and non-canonical NF-κB signaling in skin-derived fibroblasts.ResultsDisease severity was greater in patients with IκBα point mutations than in patients with truncation mutations. IκBα point mutants were expressed at significantly higher levels in transfectants compared to truncation mutants. Canonical NF-κB-dependent IL-6 secretion and upregulation of the NF-κB2/p100 and RelB components of the non-canonical NF-κB pathway were diminished significantly more in patients with point mutations compared to those with truncations. Non-canonical NF-κB-driven generation of the transcriptionally active p100 cleavage product p52, and upregulation of CCL20, ICAM1 and VCAM1, important for lymphorganogenesis, were diminished significantly more in LPS+α-LTβR-stimulated fibroblasts from patients with point mutations compared to those with truncations.ConclusionsIκBα point mutants accumulate at higher levels compared to truncation mutants and are associated with more severe disease and greater impairment of canonical and non-canonical NF-κB activity in AD EDA-ID.

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Capsule Summary: Higher levels of mutant protein may explain the more severe disease and the impaired development of secondary lymphoid organs in patients with IκBα point mutations, and thereby the poor response of these patients to hematopoietic stem cell transplantation.


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