RESUMO
BACKGROUND: Irradiated syngeneic wild-type mice developed the same neutrophilic dermatosis-like disease (NDLD) after adoptive transfer of bone marrow cells from Ptpn6(meb2/meb2) mutant mice. OBJECTIVE: To analyze differentially expressed genes in the bone marrow of mice with NDLD to gain insight into the role of Ptpn6 in myelopoietic bone marrow pathology, and the mechanisms by which Ptpn6 insufficiency in the hematopoietic cells can lead to the development of skin lesions. METHODS: As Ptpn6 is involved in a myriad of signaling pathways, we used a global approach with microarray technology for the first time to characterize changes in the bone marrow and skin of motheaten-type mice. RESULTS: A total number of 1,511 probe sets in the bone marrow showed at least two-fold changes with FDR <0.05, of which 256 probe sets had over four-fold changes. A group of 63 genes in the bone marrow of NDLD mice had more than a 4-fold change with FDR <0.0001. From 503 genes encoding proteins with ITIM motif that binds to Ptpn6, 109 were up-regulated and 83 were down-regulated. We found that genes encoding hematopoietic receptors, neutrophil chemoattractants, Toll-like receptors (Tlr1, Tlr2 and Tlr4) and C-type lectin innate immunity receptors (Clec4e, Clec4d, Clec4n, Clec4a2 and Clec4a3) were significantly up-regulated in both NDLD bone marrow and skin. The Il1b gene was also significantly overexpressed in skin samples, confirming the importance of the IL-1/TLR pathway in the development of early skin inflammation in NDLD mice. CONCLUSION: Our results suggest that innate immunity genes play a major role in development of neutrophilic dermatosis-like disease in mice.
Assuntos
Imunidade Inata/genética , Interleucina-1beta/metabolismo , Lectinas Tipo C/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 6/genética , Pioderma Gangrenoso/genética , Síndrome de Sweet/genética , Animais , Células da Medula Óssea/metabolismo , Diferenciação Celular , Perfilação da Expressão Gênica , Humanos , Camundongos , Mutação , Neutrófilos/imunologia , Pioderma Gangrenoso/imunologia , Transdução de Sinais , Pele/metabolismo , Síndrome de Sweet/imunologia , Receptores Toll-Like/metabolismo , Regulação para CimaAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Hiperpigmentação/induzido quimicamente , Prurido/induzido quimicamente , Bleomicina/efeitos adversos , Dacarbazina/efeitos adversos , Doxorrubicina/efeitos adversos , Doença de Hodgkin/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Vimblastina/efeitos adversosRESUMO
Tinea versicolor is a commonly encountered superficial fungal infection often presenting on the chest and back with hyperpigmented or hypopigmented scaly macules and patches. We report an unusual and rare presentation of tinea versicolor affecting only the eyelids.
Assuntos
Doenças Palpebrais/diagnóstico , Malassezia/isolamento & purificação , Tinha Versicolor/diagnóstico , Adolescente , Biópsia , Doenças Palpebrais/microbiologia , Doenças Palpebrais/patologia , Feminino , Humanos , Tinha Versicolor/patologiaAssuntos
Dermatite Esfoliativa/tratamento farmacológico , Dermatite Esfoliativa/patologia , Eritema/patologia , Administração Tópica , Biópsia por Agulha , Dermatite Esfoliativa/diagnóstico , Diagnóstico Diferencial , Eritema/diagnóstico , Seguimentos , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Neoplasias , Índice de Gravidade de Doença , Resultado do Tratamento , Triancinolona/uso terapêuticoRESUMO
We found a spontaneous autosomal mutation in a mouse leading to neutrophil infiltration with ulceration in the upper dermis of homozygous offspring. These animals had increased neutrophil numbers, associated with normal lymphocyte count, in peripheral blood and bone marrow, suggesting a myeloproliferative disorder; however, granulocyte precursor proliferation in bone marrow was actually reduced (because circulating neutrophils were less susceptible to apoptosis). Neutrophil infiltration of the skin and other organs and high serum levels of immunoglobulins and autoantibodies, cytokines, and acute-phase proteins were additional abnormalities, all of which could be reduced by high-dose corticosteroid treatment or neutrophil depletion by antibodies. Use of genome-wide screening localized the mutation within an 0.4-Mbp region on mouse chromosome 6. We identified insertion of a B2 element in exon 6 of the Ptpn6 gene (protein tyrosine phosphatase, non-receptor type 6; also known as Shp-1). This insertion involves amino acid substitutions that significantly reduced the enzyme activity in mice homozygous for the mutation. Disease onset was delayed, and the clinical phenotype was milder than the phenotypes of other Ptpn6-mutants described in motheaten (me, mev) mice; we designated this new genotype as Ptpn6(meB2/meB2) and the phenotype as meB2. This new phenotype encompasses an autoinflammatory disease showing similarities to many aspects of the so-called neutrophilic dermatoses, a heterogeneous group of skin diseases with unknown etiology in humans.
Assuntos
Doenças Hereditárias Autoinflamatórias/genética , Neutrófilos/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 6/genética , Proteína Tirosina Fosfatase não Receptora Tipo 6/fisiologia , Dermatopatias/metabolismo , Corticosteroides/farmacologia , Animais , Autoanticorpos/química , Mapeamento Cromossômico , Homozigoto , Humanos , Imunoglobulinas/química , Inflamação , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , MutaçãoRESUMO
We have found a B2 repeat insertion in the gene encoding protein tyrosine phosphatase nonreceptor type 6 (PTPN6) in a mouse that developed a skin disorder with clinical and histopathological features resembling those seen in human neutrophilic dermatoses. Neutrophilic dermatoses are a group of complex heterogeneous autoinflammatory diseases that all demonstrate excessive neutrophil infiltration of the skin. Therefore, we tested the cDNA and genomic DNA sequences of PTPN6 from patients with Sweet's syndrome (SW) and pyoderma gangrenosum and found numerous novel splice variants in different combinations. Isoforms resulting from deletions of exons 2, 5, 11, and 15 and retention of intron 1 or 5 were the most common in a patients with a familial case of SW, who had a neonatal onset of an inflammatory disorder with skin lesions and a biopsy specimen consistent with SW. These isoforms were associated with a heterozygous E441G mutation and a heterozygous 1.7-kbp deletion in the promoter region of the PTPN6 gene. Although full-length PTPN6 was detected in all other patients with either pyoderma gangrenosum or SW, it was always associated with splice variants: a partial deletion of exon 4 with the complete deletion of exon 5, alterations that were not detected in healthy controls. The defect in transcriptional regulation of the hematopoietic PTPN6 appears to be involved in the pathogenesis of certain subsets of the heterogeneous group of neutrophilic dermatoses.
Assuntos
Mutação , Neutrófilos/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 6/genética , Dermatopatias/genética , Adulto , Idoso , Processamento Alternativo , Sequência de Bases , Citocinas/metabolismo , Éxons , Feminino , Deleção de Genes , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Monoéster Fosfórico Hidrolases/química , Proteína Tirosina Fosfatase não Receptora Tipo 6/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase ReversaAssuntos
Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/virologia , Verrugas/virologia , Adulto , Agamaglobulinemia/complicações , Humanos , Infecções/complicações , Masculino , Papillomaviridae/genética , Infecções por Papillomavirus/diagnóstico , Receptores CXCR4/genética , Síndrome , Verrugas/complicações , Verrugas/diagnósticoAssuntos
Aminas/uso terapêutico , Analgésicos/uso terapêutico , Ácidos Cicloexanocarboxílicos/uso terapêutico , Leiomiomatose/tratamento farmacológico , Dor/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Ácido gama-Aminobutírico/uso terapêutico , Gabapentina , Humanos , Leiomiomatose/complicações , Leiomiomatose/patologia , Masculino , Pessoa de Meia-Idade , Dor/etiologia , Recidiva , Neoplasias Cutâneas/complicações , Neoplasias Cutâneas/patologiaRESUMO
Mastocytosis refers to a group of disorders characterized by the pathologic proliferation of mast cells. We present a 70-year-old white man with a rare presentation of nodular mastocytosis, characterized by disseminated nodular lesions, myelodysplastic syndrome, and a c-kit V560G receptor mutation. The patient presented to the clinic after initial presentation 6 months earlier, with ear pruritus, associated hearing loss, and widespread rash.