RESUMO
To enhance the understanding of molecular mechanisms and mine previously unidentified biomarkers of pediatric atopic dermatitis, PBMC gene expression profiles were generated by RNA sequencing in infants with atopic dermatitis and age-matched controls. A total of 178 significantly differentially expressed genes (DEGs) (115 upregulations and 63 downregulations) were seen, compared with those in healthy controls. The DEGs identified included IL1ß, TNF, TREM1, IL18R1, and IL18RAP. DEGs were validated by real-time RT- qPCR in a larger number of samples from PBMCs of infants with atopic dermatitis aged <12 months. Using the DAVID (Database for Annotation, Visualization and Integrated Discovery) database, functional and pathway enrichment analyses of DEGs were performed. Gene ontology enrichment analysis showed that DEGs were associated with immune responses, inflammatory responses, regulation of immune responses, and platelet activation. Pathway analysis indicated that DEGs were enriched in cytokineâcytokine receptor interaction, immunoregulatory interactions between lymphoid and nonlymphoid cells, hematopoietic cell lineage, phosphoinositide 3-kinaseâprotein kinase B signaling pathway, NK cellâmediated cytotoxicity, and platelet activation. Furthermore, the proteinâprotein interaction network was predicted using the STRING (Search Tool for the Retrieval of Interacting Genes/Proteins) database and visualized with Cytoscape software. Finally, on the basis of the proteinâprotein interaction network, 18 hub genes were selected, and two significant modules were obtained. In conclusion, this study sheds light on the molecular mechanisms of pediatric atopic dermatitis and may provide diagnostic biomarkers and therapeutic targets.
RESUMO
Staphylococcus aureus colonizes the skin of the majority of patients with atopic dermatitis (AD), and its presence increases disease severity. Adhesion of S. aureus to corneocytes in the stratum corneum is a key initial event in colonization, but the bacterial and host factors contributing to this process have not been defined. Here, we show that S. aureus interacts with the host protein corneodesmosin. Corneodesmosin is aberrantly displayed on the tips of villus-like projections that occur on the surface of AD corneocytes as a result of low levels of skin humectants known as natural moisturizing factor (NMF). An S. aureus mutant deficient in fibronectin binding protein B (FnBPB) and clumping factor B (ClfB) did not bind to corneodesmosin in vitro. Using surface plasmon resonance, we found that FnBPB and ClfB proteins bound with similar affinities. The S. aureus binding site was localized to the N-terminal glycine-serine-rich region of corneodesmosin. Atomic force microscopy showed that the N-terminal region was present on corneocytes containing low levels of NMF and that blocking it with an antibody inhibited binding of individual S. aureus cells to corneocytes. Finally, we found that S. aureus mutants deficient in FnBPB or ClfB have a reduced ability to adhere to low-NMF corneocytes from patients. In summary, we show that FnBPB and ClfB interact with the accessible N-terminal region of corneodesmosin on AD corneocytes, allowing S. aureus to take advantage of the aberrant display of corneodesmosin that accompanies low NMF in AD. This interaction facilitates the characteristic strong binding of S. aureus to AD corneocytes.
Assuntos
Dermatite Atópica/microbiologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Staphylococcus aureus/metabolismo , Adesinas Bacterianas/metabolismo , Aderência Bacteriana/fisiologia , Coagulase/metabolismo , Dermatite Atópica/metabolismo , Epiderme , Células Epiteliais/metabolismo , Humanos , Microscopia de Força Atômica , Pele/metabolismo , Pele/microbiologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/patogenicidadeRESUMO
Staphylococcus aureus skin infection is a frequent and recurrent problem in children with the common inflammatory skin disease atopic dermatitis (AD). S. aureus colonizes the skin of the majority of children with AD and exacerbates the disease. The first step during colonization and infection is bacterial adhesion to the cornified envelope of corneocytes in the outer layer, the stratum corneum. Corneocytes from AD skin are structurally different from corneocytes from normal healthy skin. The objective of this study was to identify bacterial proteins that promote the adherence of S. aureus to AD corneocytes. S. aureus strains from clonal complexes 1 and 8 were more frequently isolated from infected AD skin than from the nasal cavity of healthy children. AD strains had increased ClfB ligand binding activity compared to normal nasal carriage strains. Adherence of single S. aureus bacteria to corneocytes from AD patients ex vivo was studied using atomic force microscopy. Bacteria expressing ClfB recognized ligands distributed over the entire corneocyte surface. The ability of an isogenic ClfB-deficient mutant to adhere to AD corneocytes compared to that of its parent clonal complex 1 clinical strain was greatly reduced. ClfB from clonal complex 1 strains had a slightly higher binding affinity for its ligand than ClfB from strains from other clonal complexes. Our results provide new insights into the first step in the establishment of S. aureus colonization in AD patients. ClfB is a key adhesion molecule for the interaction of S. aureus with AD corneocytes and represents a target for intervention.
Assuntos
Adesinas Bacterianas/metabolismo , Dermatite Atópica/microbiologia , Células Epiteliais/microbiologia , Infecções Cutâneas Estafilocócicas/microbiologia , Staphylococcus aureus/metabolismo , Adesinas Bacterianas/genética , Aderência Bacteriana , Pré-Escolar , Feminino , Proteínas Filagrinas , Humanos , Masculino , Cavidade Nasal/microbiologia , Deleção de Sequência , Pele/citologia , Pele/microbiologia , Staphylococcus aureus/genéticaRESUMO
Blue rubber bleb nevus syndrome (Bean syndrome) is a rare, severe disorder of unknown cause, characterized by numerous cutaneous and internal venous malformations; gastrointestinal lesions are pathognomonic. We discovered somatic mutations in TEK, the gene encoding TIE2, in 15 of 17 individuals with blue rubber bleb nevus syndrome. Somatic mutations were also identified in five of six individuals with sporadically occurring multifocal venous malformations. In contrast to common unifocal venous malformation, which is most often caused by the somatic L914F TIE2 mutation, multifocal forms are predominantly caused by double (cis) mutations, that is, two somatic mutations on the same allele of the gene. Mutations are identical in all lesions from a given individual. T1105N-T1106P is recurrent in blue rubber bleb nevus, whereas Y897C-R915C is recurrent in sporadically occurring multifocal venous malformation: both cause ligand-independent activation of TIE2, and increase survival, invasion, and colony formation when expressed in human umbilical vein endothelial cells.
Assuntos
Neoplasias Gastrointestinais/genética , Predisposição Genética para Doença/epidemiologia , Mutação , Nevo Azul/genética , Receptor TIE-2/genética , Neoplasias Cutâneas/genética , Malformações Vasculares/genética , Bélgica , Estudos de Coortes , Feminino , Neoplasias Gastrointestinais/diagnóstico , Humanos , Incidência , Masculino , Nevo Azul/diagnóstico , Doenças Raras , Neoplasias Cutâneas/diagnóstico , Malformações Vasculares/diagnósticoRESUMO
BACKGROUND: Hereditary Fibrosing Poikiloderma (HFP) with tendon contractures, myopathy and pulmonary fibrosis (POIKTMP [MIM 615704]) is a very recently described entity of syndromic inherited poikiloderma. Previously by using whole exome sequencing in five families, we identified the causative gene, FAM111B (NM_198947.3), the function of which is still unknown. Our objective in this study was to better define the specific features of POIKTMP through a larger series of patients. METHODS: Clinical and molecular data of two families and eight independent sporadic cases, including six new cases, were collected. RESULTS: Key features consist of: (i) early-onset poikiloderma, hypotrichosis and hypohidrosis; (ii) multiple contractures, in particular triceps surae muscle contractures; (iii) diffuse progressive muscular weakness; (iv) pulmonary fibrosis in adulthood and (v) other features including exocrine pancreatic insufficiency, liver impairment and growth retardation. Muscle magnetic resonance imaging was informative and showed muscle atrophy and fatty infiltration. Histological examination of skeletal muscle revealed extensive fibroadipose tissue infiltration. Microscopy of the skin showed a scleroderma-like aspect with fibrosis and alterations of the elastic network. FAM111B gene analysis identified five different missense variants (two recurrent mutations were found respectively in three and four independent families). All the mutations were predicted to localize in the trypsin-like cysteine/serine peptidase domain of the protein. We suggest gain-of-function or dominant-negative mutations resulting in FAM111B enzymatic activity changes. CONCLUSIONS: HFP with tendon contractures, myopathy and pulmonary fibrosis, is a multisystemic disorder due to autosomal dominant FAM111B mutations. Future functional studies will help in understanding the specific pathological process of this fibrosing disorder.
Assuntos
Proteínas de Ciclo Celular/genética , Contratura/genética , Doenças Musculares/genética , Fibrose Pulmonar/genética , Esclerose/genética , Anormalidades da Pele/genética , Dermatopatias Genéticas/genética , Tendões/patologia , Adolescente , Adulto , Sequência de Aminoácidos , Criança , Pré-Escolar , Contratura/complicações , Contratura/diagnóstico , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Doenças Musculares/complicações , Doenças Musculares/diagnóstico , Mutação/genética , Fibrose Pulmonar/complicações , Fibrose Pulmonar/diagnóstico , Esclerose/complicações , Esclerose/diagnóstico , Anormalidades da Pele/complicações , Anormalidades da Pele/diagnóstico , Dermatopatias Genéticas/complicações , Dermatopatias Genéticas/diagnósticoRESUMO
BACKGROUND: Severe dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome is a recently recognized syndrome caused by mutations in the desmoglein 1 gene (DSG1). To date, only 3 families have been reported. OBJECTIVE: We studied a new case of SAM syndrome known to have no mutations in DSG1 to detail the clinical, histopathologic, immunofluorescent, and ultrastructural phenotype and to identify the underlying molecular mechanisms in this rare genodermatosis. METHODS: Histopathologic, electron microscopy, and immunofluorescent studies were performed. Whole-exome sequencing data were interrogated for mutations in desmosomal and other skin structural genes, followed by Sanger sequencing of candidate genes in the patient and his parents. RESULTS: No mutations were identified in DSG1; however, a novel de novo heterozygous missense c.1757A>C mutation in the desmoplakin gene (DSP) was identified in the patient, predicting the amino acid substitution p.His586Pro in the desmoplakin polypeptide. CONCLUSIONS: SAM syndrome can be caused by mutations in both DSG1 and DSP. Knowledge of this genetic heterogeneity is important for both analysis of patients and genetic counseling of families. This condition and these observations reinforce the importance of heritable skin barrier defects, in this case desmosomal proteins, in the pathogenesis of atopic disease.
Assuntos
Dermatite/genética , Desmoplaquinas/genética , Hipersensibilidade/genética , Mutação de Sentido Incorreto/genética , Síndrome de Emaciação/genética , Criança , Pré-Escolar , Análise Mutacional de DNA , Dermatite/diagnóstico , Desmogleína 1/genética , Progressão da Doença , Humanos , Hipersensibilidade/diagnóstico , Lactente , Recém-Nascido , Masculino , Linhagem , Estrutura Terciária de Proteína/genética , Pele/patologia , Síndrome de Emaciação/diagnósticoAssuntos
Exposição Ocupacional , Rosácea/etiologia , Raios Ultravioleta/efeitos adversos , Adulto , Feminino , HumanosAssuntos
Antipruriginosos/uso terapêutico , Prurido/tratamento farmacológico , Talidomida/uso terapêutico , Idoso , Antipruriginosos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/complicações , Evolução Fatal , Feminino , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Neoplasias Pulmonares/complicações , Cuidados Paliativos , Prurido/etiologia , Risco , Talidomida/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND: The prevalence and pathogenesis of rosacea is uncertain. Previously, studies used varying definitions of disease and have not explored the relationship of its prevalence to ultraviolet (UV) exposure or photodamage. OBJECTIVES: We investigated the prevalence of papulopustular rosacea (PPR) and its relationship to UV radiation exposure in 1000 randomly selected Irish individuals. METHODS: A total of 1000 individuals (500 with low UV exposure and 500 with high UV exposure) were examined. PPR was diagnosed using a standardized definition and photodamage was assessed using a photodamage scale. RESULTS: The prevalence of PPR was 2.7%. PPR prevalence was not significantly related to photodamage or UV exposure. LIMITATIONS: The power to compare UV exposure among those with and without PPR was limited. CONCLUSIONS: PPR prevalence in Ireland was 2.7%. UV radiation exposure does not appear to affect the prevalence of PPR.