RESUMEN
Accepted by the WHO and EORTC as a variant of classic mycosis fungoides, folliculotropic (syn.: follicular or pilotropic) mycosis fungoides (FMF) is characterized by a broad clinical and histological spectrum with numerous differential diagnoses. Recent studies have shown that FMF can be divided into two prognostically different subgroups, both marked by histological as well as clinical differences. Treatment should therefore be tailored to the various subtypes and clinical courses. The present review highlights the clinical and histological manifestations of FMF as well as the new subclassification. Moreover, important differential diagnoses and therapeutic options are discussed.
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Micosis Fungoide , Diagnóstico Diferencial , Humanos , Micosis Fungoide/diagnóstico , Micosis Fungoide/patología , PronósticoAsunto(s)
Alergia e Inmunología/organización & administración , Biopsia/historia , Dermatología/historia , Técnicas Histológicas/historia , Histología/historia , Enfermedades de la Piel/historia , Enfermedades de la Piel/patología , Sociedades Médicas/historia , Alemania , Historia del Siglo XX , Historia del Siglo XXI , HumanosRESUMEN
BRAF exon 15 mutations have been identified in a large proportion of malignant melanomas, melanoma metastases and melanocytic nevi. Mutated BRAF is one of the potential activators of the mitogen-activated protein kinase (MAPK) signaling pathway by phosphorylating ERK (extracellular signal-regulated kinase). We therefore analyzed the correlation of BRAF V600E and ERK-activation in 20 malignant melanomas and 21 subsequently evolved, paired metastases of the same donor by BRAF exon 15 DNA sequencing and phospho-specific immunohistochemistry for ERK. Phospho-ERK expression was present in 84% of primary melanomas and in all 19 metastases analyzed. In contrast, BRAF mutational status was concordant in only 12/20 pairs (60%) of the primary melanoma and metastasis of the same patient. Surprisingly, the BRAF mutation did not correlate with pERK expression. As even single tumors showed heterogeneous staining for pERK, we used laser-capture microdissection to study BRAF V600E status in pERK positive and pERK negative cells separately. Even on the single cell level ERK activation did not correlate with the BRAF mutation. Our results demonstrate that, in melanomas, activation of the MAPK pathway can occur through signaling pathways operating independently of BRAF T1799A.
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Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Melanoma/genética , Melanoma/metabolismo , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/metabolismo , Línea Celular Tumoral , Humanos , Melanoma/secundario , Microdisección , Adhesión en Parafina , Fosforilación , Neoplasias Cutáneas/patologíaRESUMEN
Several groups confirmed Merkel cell polyomavirus (MCPyV) as the likely causative agent of Merkel cell carcinoma. Hematolymphoid disorders are known to be a substantial risk factor for Merkel cell carcinoma, and vice versa. The association between MCPyV and hematologic neoplasms is poorly analyzed, as well as the speculation that lymphocytes may serve as reservoir for MCPyV. Therefore, we investigated the prevalence of MCPyV DNA in primary cutaneous T- and B-cell lymphomas, pseudolymphomas (PLs), and inflammatory skin diseases with dominant lymphocytic infiltrate. We performed a molecular pathology study in 22 tissue samples and 1 blood sample of different cutaneous lymphomas from 19 patients (17 mature T-cell neoplasms, 5 mature B-cell neoplasms, and 1 immature hematopoietic malignancy), 13 PLs from 12 patients, and 25 various inflammatory skin diseases from 23 patients. All tumors were analyzed for the presence of MCPyV DNA by polymerase chain reaction, confirmed by Southern blot hybridization of polymerase chain reaction products. We detected MCPyV DNA in 4 of 23 (17.4%) cutaneous lymphoma tissue samples (3 of 17 mature T-cell neoplasms and 1 of 5 mature B-cell neoplasms), in 2 of 13 (15.4%) PL tissue samples, and 2 of 25 (8%) inflammatory skin conditions (1 drug reaction and 1 erythema multiforme). We conclude that MCPyV DNA is infrequently, but consistently present in lesional tissue from patients with primary cutaneous lymphomas, PLs, and inflammatory skin diseases; prevalence is in the range of 8%-17%. Our results suggest that MCPyV does not play a significant role in the pathogenesis of cutaneous lymphoproliferative disorders.
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Linfoma/patología , Infecciones por Polyomavirus/patología , Seudolinfoma/patología , Neoplasias Cutáneas/patología , Infecciones Tumorales por Virus/patología , Adulto , Anciano , Anciano de 80 o más Años , ADN Viral/análisis , Femenino , Humanos , Linfoma/virología , Masculino , Persona de Mediana Edad , Poliomavirus/aislamiento & purificación , Infecciones por Polyomavirus/complicaciones , Seudolinfoma/virología , Neoplasias Cutáneas/virología , Infecciones Tumorales por Virus/complicaciones , Adulto JovenRESUMEN
This review focuses on the evolution and conceptual aspects of classifications for cutaneous lymphomas. The World Health Organization/European Organization for Research and Treatment of Cancer (WHO/EORTC) classification and the WHO classification (4th edn, 2008) represent the first widely accepted classifications for lymphomas, in which the complete spectrum of primary cutaneous lymphomas is included. These classifications for primary cutaneous lymphomas define disease entities with distinct clinical, histological, immunophenotypic and genetic features. Final diagnosis is based on a synoptic integration of these features and implies clinicopathological correlation as a pivotal element of the diagnostic approach for primary cutaneous lymphomas. The entities, their definitions and diagnostic criteria of cutaneous lymphomas listed in the WHO/EORTC and WHO classifications are presented. Recent changes in the terminology and staging, practical implications and future perspectives are discussed.
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Linfoma/clasificación , Neoplasias Cutáneas/clasificación , Humanos , Linfoma/patología , Neoplasias Cutáneas/patología , Organización Mundial de la SaludRESUMEN
BACKGROUND: Merkel cell polyomavirus (MCPyV) is the likely causative agent of Merkel cell carcinoma (MCC). However, the prevalence of MCPyV in non-MCC population and its possible role in the pathogenesis of other skin cancers are not known yet. METHODS: A molecular pathology study was performed in 33 MCC samples and 33 age- and sex-matched samples of sun exposed non-MCC tumors [12 seborrheic keratoses (SK), 11 basal cell carcinomas (BCC) and 10 lentigo maligna melanomas (LMM)]. All tumors were analyzed for presence of MCPyV-DNA by polymerase chain reaction (PCR) and Southern-Blot hybridization of PCR products. RESULTS: MCPyV sequences were detected in 21 MCC samples (64%) and in 2 non-MCC tumors of sun exposed skin (6%; both SK-patients). Neither the tissue samples from BCC nor LMM proved positive for MCPyV sequences. CONCLUSION: We were able to confirm prior data on prevalence of MCPyV-DNA in MCC. Furthermore, a female predominance of MCPyV-positive MCC-patients was detected. There was no relevant association of MCPyV with SK, BCC and LMM. Speculative, prevalence of MCPyV in an age- and sex-matched non-MCC population could average up to 6%.
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Carcinoma de Células de Merkel/virología , Peca Melanótica de Hutchinson/virología , Neoplasias Basocelulares/virología , Infecciones por Polyomavirus/complicaciones , Poliomavirus/aislamiento & purificación , Neoplasias Cutáneas/virología , Adulto , Anciano , Anciano de 80 o más Años , Antígenos Virales de Tumores/análisis , Carcinoma de Células de Merkel/epidemiología , Carcinoma de Células de Merkel/patología , Comorbilidad , ADN de Neoplasias/análisis , ADN Viral/análisis , Femenino , Alemania/epidemiología , Humanos , Peca Melanótica de Hutchinson/patología , Queratosis Seborreica/patología , Queratosis Seborreica/virología , Masculino , Persona de Mediana Edad , Neoplasias Basocelulares/patología , Poliomavirus/genética , Poliomavirus/inmunología , Infecciones por Polyomavirus/epidemiología , Infecciones por Polyomavirus/patología , Factores Sexuales , Piel/patología , Piel/virología , Envejecimiento de la Piel , Neoplasias Cutáneas/epidemiología , Neoplasias Cutáneas/patologíaRESUMEN
BACKGROUND: With an incidence of 1.5-1.8/1 million inhabitants per year, toxic epidermal necrolysis is a rare but life threatening disease. It is almost always drug-induced and its lethality is pronounced with up to 50 %. Several therapeutic options are described in literature; however, there is still lack of a universally accepted and specific therapy of toxic epidermal necrolysis. METHODS: This survey considers 8 cases of toxic epidermal necrolysis diagnosed and treated in our clinic from 2003 to 2007. The epidermal sloughing was > 30 % of the body surface in each case. RESULTS: After immediately discontinuing the drug suspected of being responsible for toxic epidermal necrolysis, we treated with systemic corticosteroids in an initial dose of up to 1.5 mg/kg. Moreover, special emphasis was put on basic measures such as control of vital parameters. With this treatment we reached good results; none of the patients died. conclusions: Immediate beginning of therapy is essential for a successful treatment of toxic epidermal necrolysis. Besides systemic therapy with corticosteroids, certain basic measures such as isolation of patients at adequate room temperature to prevent hypothermia, strict control of circulation, temperature and laboratory parameters, daily smears of skin and mucous membranes and a diet rich in calories due to the catabolic metabolic status are very important for successful outcome.
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Prednisona/uso terapéutico , Síndrome de Stevens-Johnson/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Alopurinol/uso terapéutico , Alopurinol/toxicidad , Antibacterianos/uso terapéutico , Antibacterianos/toxicidad , Antiinflamatorios/uso terapéutico , Anticonvulsivantes/uso terapéutico , Anticonvulsivantes/toxicidad , Infecciones Bacterianas/diagnóstico , Infecciones Bacterianas/tratamiento farmacológico , Infecciones Bacterianas/mortalidad , Ciprofloxacina/uso terapéutico , Ciprofloxacina/toxicidad , Combinación de Medicamentos , Femenino , Ácido Fólico/uso terapéutico , Ácido Fólico/toxicidad , Supresores de la Gota/uso terapéutico , Supresores de la Gota/toxicidad , Humanos , Hidroxocobalamina/uso terapéutico , Hidroxocobalamina/toxicidad , Lidocaína/uso terapéutico , Lidocaína/toxicidad , Masculino , Persona de Mediana Edad , Fenitoína/uso terapéutico , Fenitoína/toxicidad , Piridoxina/uso terapéutico , Piridoxina/toxicidad , Síndrome de Stevens-Johnson/diagnóstico , Síndrome de Stevens-Johnson/mortalidad , Sobreinfección/diagnóstico , Sobreinfección/tratamiento farmacológico , Sobreinfección/mortalidad , Tasa de Supervivencia , Combinación Trimetoprim y Sulfametoxazol/uso terapéutico , Combinación Trimetoprim y Sulfametoxazol/toxicidadAsunto(s)
Carcinoma de Células de Merkel/virología , Infecciones por Polyomavirus/complicaciones , Poliomavirus/aislamiento & purificación , Neoplasias Cutáneas/virología , Infecciones Tumorales por Virus/complicaciones , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células de Merkel/secundario , ADN Viral/aislamiento & purificación , Femenino , Alemania , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Poliomavirus/genética , Factores de Riesgo , Neoplasias Cutáneas/patologíaRESUMEN
Only 40 cases of primary cutaneous gamma/delta T-cell lymphoma (GD-TCL) have been described. GD-TCL was included as a provisional entity in the WHO-EORTC classification of cutaneous lymphomas in 2005. GD-TCL often failed to respond to polychemotherapy and radiation therapy and have a poor prognosis with a mean survival of only 15 months. We present a patient treated with surgery, immunomodulatory therapy, and polychemotherapy. He then received hematopoietic stem cell transplantation and has been in complete remission since. Allogeneic stem cell transplantation appears to be a promising therapeutic option for aggressive and generally fatal lymphomas like GD-TCL.
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Linfoma Cutáneo de Células T/patología , Linfoma Cutáneo de Células T/cirugía , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/cirugía , Trasplante de Células Madre , Adulto , Humanos , Linfoma Cutáneo de Células T/genética , Masculino , Receptores de Antígenos de Linfocitos T gamma-delta/genética , Neoplasias Cutáneas/genética , Resultado del TratamientoRESUMEN
Signaling through tumor necrosis factor receptor 1 (TNFR1) controls bacterial infections and the induction of inflammatory Th1 cell-mediated autoimmune diseases. By dissecting Th1 cell-mediated delayed-type hypersensitivity responses (DTHRs) into single steps, we localized a central defect to the missing TNFR1 expression by endothelial cells (ECs). Adoptive transfer and mast cell knockin experiments into Kit(W)/Kit(W-v), TNF(-/-), and TNFR1(-/-) mice showed that the signaling defect exclusively affects mast cell-EC interactions but not T cells or antigen-presenting cells. As a consequence, TNFR1(-/-) mice had strongly reduced mRNA and protein expression of P-selectin, E-selectin, ICAM-1, and VCAM-1 during DTHR elicitation. In consequence, intravital fluorescence microscopy revealed up to 80% reduction of leukocyte rolling and firm adhesion in TNFR1(-/-) mice. As substitution of TNF(-/-) mice with TNF-producing mast cells fully restored DTHR in these mice, signaling of mast cell-derived TNF through TNFR1-expressing ECs is essential for the recruitment of leukocytes into sites of inflammation.
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Endotelio Vascular/patología , Inflamación/etiología , Mastocitos/fisiología , Receptor Cross-Talk/fisiología , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/metabolismo , Células Cultivadas , Endotelio Vascular/inmunología , Endotelio Vascular/metabolismo , Haptenos/efectos adversos , Hipersensibilidad Tardía/inducido químicamente , Hipersensibilidad Tardía/genética , Hipersensibilidad Tardía/inmunología , Inflamación/genética , Inflamación/metabolismo , Mastocitos/inmunología , Mastocitos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Cloruro de Picrilo/efectos adversos , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Receptores Tipo I de Factores de Necrosis Tumoral/fisiología , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/fisiologíaRESUMEN
Subcorneal pustulosis (Sneddon-Wilkinson disease) is a rare inflammatory neutrophilic dermatosis. While subcorneal pustulosis is often associated with an IgA gammopathy, the combined lack of IgG/IgM seen in our case is rare. An 83-year-old man with combined lack of IgG/IgM and monoclonal gammopathy type IgA/Kappa presented with subcorneal pustules. Intravenous immunoglobulin therapy led to complete regression and might be another therapeutic option.
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Deficiencia de IgG/complicaciones , Deficiencia de IgG/tratamiento farmacológico , Inmunoglobulinas Intravenosas/administración & dosificación , Paraproteinemias/complicaciones , Paraproteinemias/tratamiento farmacológico , Enfermedades Cutáneas Vesiculoampollosas/complicaciones , Enfermedades Cutáneas Vesiculoampollosas/tratamiento farmacológico , Anciano de 80 o más Años , Humanos , Factores Inmunológicos/administración & dosificación , Masculino , Resultado del TratamientoRESUMEN
Chronic graft-versus-host disease (GVHD) is almost always associated with skin diseases appearing either as lichenoid GVHD, sclerodermatous GVHD (sGVHD) or as eosinophilic fasciitis-like disease. The two latter frequently result in severe and deep sclerosis. Immunosuppressive therapy is of little help in sclerodermatous or eosinophilic fasciitis-like types of GVHD. Based on data showing that PUVA-bath photochemotherapy is effective in the treatment of severe localized sclerosis of the skin, we investigated the efficacy of PUVA-bath photochemotherapy and isotretinoin in sGVHD. In a retrospective study we analyzed fourteen consecutive patients with sGVHD who received PUVA-bath photochemotherapy, five in combination with oral isotretinoin. Seven patients improved and four showed complete remission. Surprisingly, the therapy was complicated by the development of ulcers within the sclerotic plaques during the early periods of treatment. These ulcers cleared in most patients when PUVA-bath photochemotherapy was continued. Thus, PUVA-bath photochemotherapy alone or in combination with isotretinoin may resolve or improve GVHD associated sclerosis in selected patients.
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Fármacos Dermatológicos/uso terapéutico , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Isotretinoína/uso terapéutico , Terapia PUVA , Adulto , Baños , Enfermedad Crónica , Enfermedad Injerto contra Huésped/patología , Humanos , Metoxaleno/administración & dosificación , Persona de Mediana Edad , Fármacos Fotosensibilizantes/administración & dosificación , Esclerosis , Piel/patologíaRESUMEN
Immune responses may arrest tumor growth by inducing tumor dormancy. The mechanisms leading to either tumor dormancy or promotion of multistage carcinogenesis by adaptive immunity are poorly characterized. Analyzing T antigen (Tag)-induced multistage carcinogenesis in pancreatic islets, we show that Tag-specific CD4+ T cells home selectively into the tumor microenvironment around the islets, where they either arrest or promote transition of dysplastic islets into islet carcinomas. Through combined TNFR1 signaling and IFN-gamma signaling, Tag-specific CD4+ T cells induce antiangiogenic chemokines and prevent alpha(v)beta(3) integrin expression, tumor angiogenesis, tumor cell proliferation, and multistage carcinogenesis, without destroying Tag-expressing islet cells. In the absence of either TNFR1 signaling or IFN-gamma signaling, the same T cells paradoxically promote angiogenesis and multistage carcinogenesis. Thus, tumor-specific T cells can directly survey multistage carcinogenesis through cytokine signaling.
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Linfocitos T CD4-Positivos/inmunología , Proliferación Celular , Transformación Celular Neoplásica/inmunología , Insulinoma/inmunología , Interferón gamma/metabolismo , Neoplasias Pancreáticas/inmunología , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Transducción de Señal , Animales , Antígenos Virales de Tumores/genética , Antígenos Virales de Tumores/metabolismo , Glucemia/metabolismo , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/patología , Linfocitos T CD4-Positivos/trasplante , Movimiento Celular , Supervivencia Celular , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Células Cultivadas , Proteínas Activadoras de GTPasa/genética , Proteínas Activadoras de GTPasa/metabolismo , Inmunoterapia/métodos , Insulinoma/irrigación sanguínea , Insulinoma/genética , Insulinoma/metabolismo , Insulinoma/patología , Insulinoma/terapia , Integrina alfaVbeta3/metabolismo , Ratones , Ratones Endogámicos C3H , Ratones Noqueados , Ratones Transgénicos , Neovascularización Patológica/inmunología , Neovascularización Patológica/patología , Neoplasias Pancreáticas/irrigación sanguínea , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/terapia , Receptores Tipo I de Factores de Necrosis Tumoral/deficiencia , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Células TH1/inmunología , Células TH1/patología , Factores de Tiempo , Irradiación Corporal TotalRESUMEN
Lichen aureus is a rare disease of unknown origin that is classified under the group of pigmented purpuric dermatoses. Its most important differential diagnosis is both clinically and histologically mycosis fungoides, into which the disease can proceed in very rare cases. We describe an unusual multilocular lichen aureus possibly induced by the almost daily consumption of an energy drink. An 11-year-old boy presented with a history of asymptomatic ochre patches on his extremities and abdomen occurring after regular consumption of an energy drink. Histologic examination showed a band-like lymphocytic infiltrate, containing hemosiderin deposits and extravasal erythrocytes adjacent to dermal blood vessels, in the iron-stain detection of hemosiderin. Because of these findings, lichen aureus was diagnosed. After a 2-month abstention from the energy drink, no new lesions appeared and the present lesions grew pale and finally disappeared. The case shows a rare multilocular lichen aureus, which disappeared after the consumption of an energy drink was stopped. The ingredients of the energy drink are an example of a possible trigger of the disease.
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Bebidas/efectos adversos , Enfermedades de la Piel/etiología , Enfermedades de la Piel/inmunología , Enfermedades de la Piel/patología , Linfocitos T/inmunología , Niño , Células Clonales , Diagnóstico Diferencial , Reordenamiento Génico de la Cadena gamma de los Receptores de Antígenos de los Linfocitos T , Hemosiderina/metabolismo , Humanos , Masculino , Micosis Fungoide/patología , Reacción en Cadena de la PolimerasaAsunto(s)
Leucemia Mieloide/diagnóstico , Infiltración Leucémica/diagnóstico , Neoplasias Cutáneas/diagnóstico , Anciano , Carcinoma Basocelular/diagnóstico , Diagnóstico Diferencial , Humanos , Leucemia Mieloide/patología , Infiltración Leucémica/patología , Nariz , Neoplasias Nasales/diagnóstico , Neoplasias Cutáneas/patologíaRESUMEN
It is established that primary malignant melanomas (pMM) can be infiltrated by T-cell populations with predominantly one T-cell clone. As pMM generally express multiple tumor-associated antigens (TAA), here we used laser-capture microdissection (LCM) to isolate different tumor-infiltrating lymphocyte (TIL) clusters in order to determine whether pMM are infiltrated only by one single clone or whether the TAA may attract various T-cell populations. As T-cell receptor (TCR) clonality is a useful tool for the demonstration of specific T-cell clones, we analyzed 56 pMM, three cutaneous melanoma metastases, and 15 pairs of pMM with a sentinel lymph node (SLN) for clonal rearrangements of the (TCR) gamma chain gene. We detected the clonality of TCR gamma chain gene in 25 of 56 pMM, and in 10 of 17 SLN studied. In four of the 15 pairs of primary tumor and SLN, we found clonal TCR gamma in both the melanoma and the SLN, with two pairs harboring the identical clone. As we detected different clones in pMM and the corresponding SLN, we subsequently performed LCM in 21 malignant melanomas with multiple lymphocytic clusters for the presence of focal clonal T cells in different regions of the melanoma. In seven melanomas, both clusters of TILs showed the same rearranged TCR gamma chain gene and in five of the seven biopsies the clonal rearrangement occurred in different variable (V) regions of the TCR gamma chain gene. These tumors showed infiltration by more than one clone. In 10 biopsies TCR clonality was restricted to one cluster, while the second microdissected sample of the infiltrate was polyclonal. In conclusion, within one primary malignant melanoma several T-cell clones with different rearrangements may occur. The balance between these clones may decide on the progress of melanoma.
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Reordenamiento Génico de la Cadena gamma de los Receptores de Antígenos de los Linfocitos T , Linfocitos Infiltrantes de Tumor/inmunología , Melanoma/inmunología , Neoplasias Cutáneas/inmunología , Linfocitos T/inmunología , Células Clonales , ADN de Neoplasias/análisis , Humanos , Rayos Láser , Linfocitos Infiltrantes de Tumor/citología , Melanoma/genética , Microdisección , Estadificación de Neoplasias , Receptores de Antígenos de Linfocitos T gamma-delta/genética , Neoplasias Cutáneas/genética , Linfocitos T/citologíaRESUMEN
Circumscribed palmar or plantar hypokeratosis is a new entity recently described by Perez et al in 2002. It seems to be underdiagnosed or clinically it is often misdiagnosed as Bowen's disease or porokeratosis. Obviously the number of case reports of circumscribed palmar or plantar hypokeratosis has increased since the first publication by Perez et al.The histopathological hallmarks of this condition are a stair-like configuration with an abrupt thinning of the stratum corneum from uninvolved to involved skin with a central hypokeratotic area. There are no atypical keratinocytes or cornoid lamellation. We describe two new patients with circumscribed palmar hypokeratosis. In one case there were additional histopathological features including the loss of granular cell layer in the center of the lesion and an overlying compact thin parakeratotic layer.
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Dermatosis del Pie/patología , Dermatosis de la Mano/patología , Queratosis/patología , Enfermedad de Bowen/patología , Diagnóstico Diferencial , Femenino , Humanos , Persona de Mediana Edad , Poroqueratosis/patología , Psoriasis/patologíaRESUMEN
BACKGROUND: Bartonella species are the only known bacterial pathogens causing vasculoproliferative disorders in humans (bacillary angiomatosis [BA]). Cellular and bacterial pathogenetic mechanisms underlying the induction of BA are largely unknown. METHODS AND RESULTS: Activation of hypoxia-inducible factor-1 (HIF-1), the key transcription factor involved in angiogenesis, was detected in Bartonella henselae-infected host cells in vitro by immunofluorescence, Western blotting, electrophoretic mobility shift, and reporter gene assays and by immunohistochemistry in BA tissue lesions in vivo. Gene microarray analysis revealed that a B henselae infection resulted in the activation of genes typical for the cellular response to hypoxia. HIF-1 was essential for B henselae-induced expression of vascular endothelial growth factor as shown by inhibition with the use of HIF-1-specific short-interfering RNA. Moreover, infection with B henselae resulted in increased oxygen consumption, cellular hypoxia, and decreased ATP levels in host cells. Infection with a pilus-negative variant of B henselae did not lead to cellular hypoxia or activation of HIF-1 or vascular endothelial growth factor secretion, suggesting a crucial role of this bacterial surface protein in the angiogenic reprogramming of the host cells. CONCLUSIONS: B henselae induces a proangiogenic host cell response via HIF-1. Our data provide for the first time evidence that HIF-1 may play a role in bacterial infections.