ABSTRACT
In a transgenic mouse line hK14mIL33tg, with the expression of interleukin-33 (IL-33) driven by a keratin 14 promoter, keratoconjunctivitis developed spontaneously between 18 and 22 weeks of age under specific-pathogen-free conditions. These mice showed blepharitis and corneal impairments, and the histology revealed epithelial thickening in the conjunctiva and the cornea with infiltration of eosinophils, mast cells and basophils. IL-5, IL-13 and CCL11 were abundant in lacrimal fluid in the mice, and the gene expressions of IL-4, IL-5, IL-13, IL-33, Prg2 and Mmcp8 were significantly increased in the cornea. Furthermore, group 2 innate lymphoid cells (ILC2) producing IL-5 and IL-13 were markedly increased in the cornea. These phenotypes closely resemble human atopic keratoconjunctivitis (AKC). The characteristic ocular phenotype in these mice strongly suggests that IL-33 is crucial for the development of AKC. The mouse line may be useful as a novel model for research and development of therapeutic strategies for AKC.
Subject(s)
Disease Models, Animal , Epithelium, Corneal/immunology , Founder Effect , Interleukin-33/immunology , Keratoconjunctivitis/genetics , Lymphocytes/immunology , Animals , Basophils/immunology , Basophils/pathology , Chemokine CCL11/genetics , Chemokine CCL11/immunology , Conjunctiva/immunology , Conjunctiva/pathology , Eosinophils/immunology , Eosinophils/pathology , Epithelium, Corneal/pathology , Gene Expression Regulation , Immunity, Innate , Interleukin-13/genetics , Interleukin-13/immunology , Interleukin-33/genetics , Interleukin-4/genetics , Interleukin-4/immunology , Interleukin-5/genetics , Interleukin-5/immunology , Keratin-14/genetics , Keratin-14/immunology , Keratoconjunctivitis/immunology , Keratoconjunctivitis/pathology , Lymphocytes/pathology , Mast Cells/immunology , Mast Cells/pathology , Membrane Proteins/genetics , Membrane Proteins/immunology , Mice , Mice, Transgenic , Promoter Regions, Genetic , Signal Transduction , Tryptases/genetics , Tryptases/immunologySubject(s)
Ichthyosiform Erythroderma, Congenital/genetics , Mutation , Receptors, Cell Surface/genetics , Adult , Biopsy , DNA Mutational Analysis , Female , Fluorescent Antibody Technique , Genetic Predisposition to Disease , Glucosylceramides/metabolism , Homozygote , Humans , Ichthyosiform Erythroderma, Congenital/diagnosis , Ichthyosiform Erythroderma, Congenital/drug therapy , Ichthyosiform Erythroderma, Congenital/metabolism , Japan , Lipid Droplets/metabolism , Phenotype , Skin/metabolism , Skin/ultrastructureABSTRACT
Mutations of the transglutaminase 1 gene (TGM1) are a major cause of autosomal recessive congenital ichthyoses (ARCIs) that are associated with defects in skin barrier structure and function. However, the molecular processes induced by the transglutaminase 1 deficiency are not fully understood. The aim of the present study was to uncover those processes by analysis of cutaneous molecular signatures. Gene expression profiles of wild-type and Tgm1-/-epidermis were assessed using microarrays. Gene ontology analysis of the data showed that genes for innate defense responses were up-regulated in Tgm1-/-epidermis. Based on that result, the induction of Il1b and antimicrobial peptide genes, S100a8, S100a9, Defb14, Camp, Slpi, Lcn2, Ccl20 and Wfdc12, was confirmed by quantitative real-time PCR. A protein array revealed that levels of IL-1ß, G-CSF, GM-CSF, CXCL1, CXCL2, CXCL9 and CCL2 were increased in Tgm1-/-skin. Epidermal growth factor receptor (EGFR) ligand genes, Hbegf, Areg and Ereg, were activated in Tgm1-/-epidermis. Furthermore, the antimicrobial activity of an epidermal extract from Tgm1-/-mice was significantly increased against both Escherichia coli and Staphylococcus aureus. In the epidermis of ichthyosiform skins from patients with TGM1 mutations, S100A8/9 was strongly positive. The expression of those antimicrobial and defense response genes was also increased in the lesional skin of an ARCI patient with TGM1 mutations. These results suggest that the up-regulation of molecular signatures for antimicrobial and innate defense responses is characteristic of skin with a transglutaminase 1 deficiency, and this autonomous process might be induced to reinforce the defective barrier function of the skin.
Subject(s)
Gene Expression Profiling , Immunity, Innate/genetics , Skin/enzymology , Skin/immunology , Transglutaminases/deficiency , Animals , Antimicrobial Cationic Peptides/genetics , Antimicrobial Cationic Peptides/metabolism , Chemokines/genetics , Chemokines/metabolism , Epidermis/metabolism , ErbB Receptors/genetics , ErbB Receptors/metabolism , Gene Expression Regulation , Humans , Ichthyosis/genetics , Immunohistochemistry , Ligands , Mice, Inbred C57BL , Mutation/genetics , S100 Proteins/genetics , S100 Proteins/metabolism , Skin/microbiology , Transglutaminases/geneticsABSTRACT
We report a case of a 12-year-old boy who was born as a collodion baby after which thick scales developed on his entire body surface. His younger brother showed a similar skin condition. Arcuate-shaped, large, brownish scales covered his face with ectropion. His lower legs were also covered with larger thick, brownish, plate-like scales, but other areas were covered with smaller scales. Next-generation sequencing for exons and splice sites detected a stop-gain TGM1 mutation leading to p.R71* in transglutaminase 1 (TG1). Another mutation identified was a cryptic mutation in intron 3 that activated a pseudoexon, which was detected by RNA-based analysis of hair bulbs. The deep intronic mutation caused another truncation mutation, p.N171Tfs(*) 45, in TG1. An in situ TG1 assay demonstrated that TG1 activity was totally lost in this case. Thus, we conclude that the severe phenotype of the patient developed due to those novel compound heterozygous null truncation mutations in TGM1.
