Cirillo, Luisa (2016) Characterization of an autoimmune condition associated with AEC syndrome. [Tesi di dottorato]

Cirillo Luisa PhD thesis PFM 2016.pdf

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Item Type: Tesi di dottorato
Lingua: English
Title: Characterization of an autoimmune condition associated with AEC syndrome
Date: 31 March 2016
Number of Pages: 82
Institution: Università degli Studi di Napoli Federico II
Department: Medicina Molecolare e Biotecnologie Mediche
Scuola di dottorato: Medicina molecolare
Dottorato: Patologia e fisiopatologia molecolare
Ciclo di dottorato: 28
Coordinatore del Corso di dottorato:
Avvedimento, Vittorio
Missero, CaterinaUNSPECIFIED
Date: 31 March 2016
Number of Pages: 82
Uncontrolled Keywords: Skin, inflammation, knock-in mouse
Settori scientifico-disciplinari del MIUR: Area 05 - Scienze biologiche > BIO/11 - Biologia molecolare
Area 06 - Scienze mediche > MED/04 - Patologia generale
Date Deposited: 13 Apr 2016 10:46
Last Modified: 05 May 2017 01:00


Ankyloblepharon- Ectodermal defects Cleft lip/palate (AEC) syndrome, also known as Hay-Wells syndrome, is a severe genetic disorder caused by mutation in p63 gene and characterized by congenital erythroderma and severe skin erosions in infants that resolve very slowly leaving scars. To identify molecular mechanisms underlying the severe skin defects, we generated a conditional knock-in mouse carrying an inducible p63 mutation (L514F). AEC conditional mutant mice showed a strong phenotype including focal skin erosions, crusting and complete hair loss. A high percentage of mutant mice died between 8 and 15 days after birth. Epidermis was hyperplastic and hyperkeratotic, and massive infiltration of macrophages and mast cells was observed in the dermis. At the molecular level, reduced mechanical stress resilience was accompanied with a progressive skin inflammation due to strongly elevated level of Thymic stromal lymphopoietin (Tslp), an IL-7 like cytokine. Epidermal-derived Tslp was circulating in the bloodstream, causing a dramatic expansion of immature B-cells (pre B-cells) in the bone marrow and spleen, leading to the insurgence of an autoimmune lymphoproliferative disorder. Genetic ablation of Tslp in the epidermis ameliorated the general health condition of mutant mice, significantly reducing skin inflammation, rescuing B-cell differentiation, and increasing survival in AEC mice. Mechanistically, massive Tslp release was accompanied by strong induction of kallikrein-6 (Klk6) and NFAT accumulation in mutant epidermis. Klk6 is repressed by wild-type p63 in epidermis and NFAT overexpression strongly induced Tslp in keratinocytes. Taken together these data indicate that in AEC mutant epidermis, Klk6 upregulation leads to massive Tslp induction by an NFAT-dependent mechanism. We propose that since extended skin erosions in AEC patients can also be associated with an autoimmune proliferative disorder, controlling Tslp in severely affected patients may be therapeutically beneficial.


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