RESUMO
BACKGROUND: Bullous pemphigoid (BP), the by far most frequent autoimmune blistering skin disease (AIBD), is immunopathologically characterized by autoantibodies against the two hemidesmosomal proteins BP180 (collagen type XVII) and BP230 (BPAG1 or dystonin). Several comorbidities and potentially disease-inducing medication have been described in BP, yet a systematic analysis of these clinically relevant findings and autoantibody reactivities has not been performed. OBJECTIVE: To determine associations of autoantibody reactivities with comorbidities and concomitant medication. METHODS: In this prospective multicenter study, 499 patients diagnosed with BP in 16 European referral centers were included. The relation between anti-BP180 NC16A and anti-BP230 IgG ELISA values at the time of diagnosis as well as comorbidities and concomitant medication collected by a standardized form were analysed. RESULTS: An association between higher serum anti-BP180 reactivity and neuropsychiatric but not atopic and metabolic disorders was observed as well as with the use of insulin or antipsychotics but not with dipeptidyl peptidase-4 (DPP4) inhibitors, inhibitors of platelet aggregation and L-thyroxine. The use of DPP4 inhibitors was associated with less anti-BP180 and anti-BP230 reactivity compared with BP patients without these drugs. This finding was even more pronounced when compared with diabetic BP patients without DPP4 inhibitors. Associations between anti-BP180 and anti-BP230 reactivities were also found in patients using insulin and antipsychotics, respectively, compared with patients without this medication, but not for the use of inhibitors of platelet aggregation, and L-thyroxine. CONCLUSION: Taken together, these data imply a relation between autoantibody reactivities at the time of diagnosis and both neuropsychiatric comorbidities as well as distinct concomitant medication suggesting a link between the pathological immune mechanisms and clinical conditions that precede the clinically overt AIBD.
Assuntos
Antipsicóticos , Inibidores da Dipeptidil Peptidase IV , Insulinas , Penfigoide Bolhoso , Doença do Soro , Antipsicóticos/efeitos adversos , Autoanticorpos , Autoantígenos , Vesícula , Dipeptidil Peptidase 4/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Distonina , Humanos , Hipoglicemiantes/uso terapêutico , Imunoglobulina G , Insulinas/uso terapêutico , Colágenos não Fibrilares , Estudos Prospectivos , Tiroxina/uso terapêuticoAssuntos
Penfigoide Bolhoso/diagnóstico , Pele/patologia , Idoso , Autoanticorpos/sangue , Autoanticorpos/imunologia , Autoantígenos/imunologia , Biópsia , Distonina/imunologia , Feminino , Humanos , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Masculino , Colágenos não Fibrilares/imunologia , Penfigoide Bolhoso/imunologia , Penfigoide Bolhoso/patologia , Colágeno Tipo XVIIAssuntos
Erupções Acneiformes/induzido quimicamente , Antineoplásicos/efeitos adversos , Toxidermias/etiologia , Inibidores de Proteínas Quinases/efeitos adversos , Sorafenibe/efeitos adversos , Idoso , Nádegas , Carcinoma Hepatocelular/tratamento farmacológico , Humanos , Neoplasias Hepáticas/tratamento farmacológico , MasculinoRESUMO
Monoallelic desmoglein 1 mutations have been known for many years to cause striate palmoplantar keratoderma, but only recently, biallelic loss-of-function mutations were associated with a new disorder, designated as SAM syndrome (comprising severe dermatitis, multiple allergies and metabolic wasting) in two consanguineous families. We report on a new case from a third independent family with the homozygous nonsense mutation, c.2659C>T, p.R887* in exon 15 of DSG1 (desmoglein 1 gene). This mutation led to mRNA decay and loss of expression of desmoglein 1. The clinical phenotype consisted of severe palmoplantar keratoderma, dermatitis and multiple allergies. In contrast to the previous cases, malabsorption, hypoalbuminaemia, developmental delay, hypotrichosis or severe recurrent infections were not observed.
Assuntos
Códon sem Sentido/genética , Dermatite/genética , Desmogleína 1/genética , Hipersensibilidade/genética , Ceratodermia Palmar e Plantar/genética , Adolescente , Feminino , Homozigoto , Humanos , Síndrome de Emaciação/genéticaAssuntos
Anodontia/genética , Mama/anormalidades , Dermatite Esfoliativa/genética , Displasia Ectodérmica/genética , Obstrução dos Ductos Lacrimais/genética , Deformidades Congênitas dos Membros/genética , Mutação/genética , Unhas Malformadas/genética , Transtornos da Pigmentação/genética , Fatores de Transcrição/genética , Transglutaminases/genética , Proteínas Supressoras de Tumor/genética , Anodontia/diagnóstico , Criança , Dermatite Esfoliativa/diagnóstico , Displasia Ectodérmica/diagnóstico , Feminino , Heterozigoto , Humanos , Obstrução dos Ductos Lacrimais/diagnóstico , Deformidades Congênitas dos Membros/diagnóstico , Masculino , Unhas Malformadas/diagnóstico , Transtornos da Pigmentação/diagnóstico , Dermatopatias/congênitoRESUMO
BACKGROUND: Integrin α6ß4 is a transmembrane receptor and a key component of the hemidesmosome anchoring complex. It is involved in cell-matrix adhesion and signalling in various tissues. Mutations in the ITGA6 and ITGB4 genes coding for α6ß4 integrin compromise dermal-epidermal adhesion and are associated with skin blistering and pyloric atresia (PA), a disorder known as epidermolysis bullosa with PA (EB-PA). OBJECTIVES: To elucidate the molecular pathology of skin fragility in eight cases, disclose the underlying ITGA6 and ITGB4 mutations and study genotype-phenotype correlations. METHODS: DNA was isolated from ethylenediaminetetraacetic acid-blood samples, and the coding exons and exon-intron boundaries of ITGA6 and ITGB4 were amplified by polymerase chain reaction (PCR), and directly sequenced. Skin samples were submitted to immunofluorescence mapping with antibodies to adhesion proteins of the dermal-epidermal junction. Primary keratinocytes were isolated, and used for RNA and protein extraction, reverse transcription PCR and immunoblotting. Ultrastructural analysis of the skin was performed in one patient. RESULTS: We disclose 10 novel mutations, one in ITGA6 and nine in ITGB4. Skin cleavage was either intraepidermal or junctional. Lethal outcome and PA correlated with loss-of-function mutations in two cases. Solely mild skin involvement was associated with deletion of the C-terminus of ß4 integrin. Combinations of missense, nonsense or frameshift mutations caused severe urinary tract involvement in addition to skin fragility in five cases. CONCLUSIONS: The present study reveals novel ITGA6 and ITGB4 gene mutations and supports previous reports showing that the phenotype may lack PA and be limited to skin and nail involvement. In four out of six cases of EB-PA, life expectancy was not impaired. A high frequency of urinary tract involvement was found in this study, and represented the main cause of morbidity. Low levels of ß4 integrin expression were compatible with hemidesmosomal integrity and a mild skin phenotype.
Assuntos
Epidermólise Bolhosa/genética , Integrina alfa6beta4/genética , Mutação/genética , Adolescente , Adulto , Criança , Pré-Escolar , DNA/análise , Epidermólise Bolhosa/patologia , Evolução Fatal , Feminino , Imunofluorescência , Genótipo , Humanos , Lactente , Integrina beta4/genética , Masculino , Microscopia Eletrônica , Fenótipo , Pele/ultraestruturaRESUMO
BACKGROUND: Dystrophic epidermolysis bullosa (DEB) is a severe genetic skin blistering disorder caused by mutations in the gene COL7A1, encoding collagen VII. Recently, the MMP1 promoter single nucleotide polymorphism (SNP) rs1799750, designated as 1G 2G, was shown to be involved in modulation of disease severity in patients with recessive DEB (RDEB), and was proposed as a genetic modifier. OBJECTIVES: To identify the molecular basis of DEB in 103 individuals and to replicate the results of the MMP1 promoter SNP analysis in an independent patient group, as verification is necessary in such a rare and heterogeneous disorder. METHODS: To determine the molecular basis of the disease, we performed COL7A1 mutation screening, reverse transcription-polymerase chain reaction (PCR) and real-time quantitative PCR. The status of the MMP1 SNP was analysed by PCR and restriction enzyme digestion and verified by sequencing. RESULTS: We disclosed 42 novel COL7A1 mutations, including the first large genomic deletion of 4 kb affecting only the COL7A1 gene, and three apparently silent mutations affecting splicing. Even though the frequency of the high-risk allele was increased in patients with RDEB, no statistically significant correlation between disease severity and genotype could be made. Also, no correlation was observed with development of squamous cell carcinoma, a severe complication of DEB. CONCLUSIONS: Taken together, the results suggest that the MMP1 SNP is not the sole disease modifier in different forms of DEB, and other genetic and environmental factors contribute to the clinical phenotype.