RESUMEN
AIMS: As immunomodulatory therapy is being integrated into treatment regimens for non-small-cell lung carcinoma, we aimed to prospectively collect data on the immunohistochemical profile of tumours assessed in our institution and to correlate this with morphological tumour features. METHODS AND RESULTS: Immunohistochemistry for programmed death-ligand 1 (PD-L1) was considered to be adequate when >100 tumour cells were seen microscopically. When adequate, PD-L1 staining was scored as <1%, ≥1-49% or ≥50% positive membrane staining within tumour cells only. There were 197 assessable cases, of which 87% of those with pleomorphic features (n = 39) showed ≥50% positivity for PD-L1 expression, as compared with only 33% of cases without pleomorphic features (P < 0.05) (90% versus 25% in resected cases). Further correlation of PD-L1 expression with architectural patterns within the tumours was performed in 74 adenocarcinoma resections. All invasive mucinous adenocarcinomas scored <1%. All lepidic components in non-mucinous adenocarcinoma resections scored <1%. Thirty-five per cent of the acinar/papillary components and 53% of the solid/micropapillary components were positive for PD-L1 expression. CONCLUSIONS: There are significant differences in PD-L1 expression in relation to histological patterns, with particularly high levels in those with pleomorphic features and low/undetectable levels in invasive mucinous adenocarcinomas and the lepidic components of non-mucinous adenocarcinomas. Assessment of PD-L1 expression in a resected adenocarcinoma with a lepidic component may therefore not be reliable when immumodulatory therapy for recurrent disease is being considered, and either re-biopsy or limiting assessment to the invasive component may be more appropriate.
Asunto(s)
Antígeno B7-H1/biosíntesis , Biomarcadores de Tumor/análisis , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , Antígeno B7-H1/análisis , HumanosRESUMEN
Psoriasis is a common T cell-mediated autoimmune inflammatory disease. We show that blocking the interaction of alpha1beta1 integrin (VLA-1) with collagen prevented accumulation of epidermal T cells and immunopathology of psoriasis. Alpha1beta1 integrin, a major collagen-binding surface receptor, was exclusively expressed by epidermal but not dermal T cells. Alpha1beta1-positive T cells showed characteristic surface markers of effector memory cells and contained high levels of interferon-gamma but not interleukin-4. Blockade of alpha1beta1 inhibited migration of T cells into the epidermis in a clinically relevant xenotransplantation model. This was paralleled by a complete inhibition of psoriasis development, comparable to that caused by tumor necrosis factor-alpha blockers. These results define a crucial role for alpha1beta1 in controlling the accumulation of epidermal type 1 polarized effector memory T cells in a common human immunopathology and provide the basis for new strategies in psoriasis treatment focusing on T cell-extracellular matrix interactions.
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Células Epidérmicas , Integrina alfa1beta1/metabolismo , Psoriasis/metabolismo , Linfocitos T/metabolismo , Animales , Anticuerpos Monoclonales , Eliminación de Gen , Regulación de la Expresión Génica , Humanos , Integrina alfa1beta1/antagonistas & inhibidores , Ratones , Trasplante HeterólogoAsunto(s)
Neoplasias Pulmonares/patología , Lupus Eritematoso Sistémico/complicaciones , Linfoma de Células B de la Zona Marginal/patología , Seudolinfoma/patología , Amiloidosis/complicaciones , Amiloidosis/patología , Transformación Celular Neoplásica/patología , Femenino , Humanos , Neoplasias Pulmonares/complicaciones , Linfoma de Células B de la Zona Marginal/complicaciones , Persona de Mediana Edad , Seudolinfoma/complicacionesRESUMEN
γδ T cells mediate rapid tissue responses in murine skin and participate in cutaneous immune regulation including protection against cancer. The role of human γδ cells in cutaneous homeostasis and pathology is characterized poorly. In this study, we show in vivo evidence that human blood contains a distinct subset of proinflammatory cutaneous lymphocyte Ag and CCR6-positive Vγ9Vδ2 T cells, which is rapidly recruited into perturbed human skin. Vγ9Vδ2 T cells produced an array of proinflammatory mediators including IL-17A and activated keratinocytes in a TNF-α- and IFN-γ-dependent manner. Examination of the common inflammatory skin disease psoriasis revealed a striking reduction of circulating Vγ9Vδ2 T cells in psoriasis patients compared with healthy controls and atopic dermatitis patients. Decreased numbers of circulating Vγ9Vδ2 T cells normalized after successful treatment with psoriasis-targeted therapy. Taken together with the increased presence of Vγ9Vδ2 T cells in psoriatic skin, these data indicate redistribution of Vγ9Vδ2 T cells from the blood to the skin compartment in psoriasis. In summary, we report a novel human proinflammatory γδ T cell involved in skin immune surveillance with immediate response characteristics and with potential clinical relevance in inflammatory skin disease.
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Psoriasis/inmunología , Psoriasis/patología , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Piel/inmunología , Piel/patología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/patología , Adulto , Antígenos de Diferenciación de Linfocitos T/biosíntesis , Antígenos de Diferenciación de Linfocitos T/inmunología , Separación Celular , Quimiocinas/análisis , Quimiocinas/biosíntesis , Quimiotaxis de Leucocito/inmunología , Femenino , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Humanos , Inmunohistoquímica , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/patología , Masculino , Persona de Mediana Edad , Psoriasis/metabolismo , Receptores CCR6/biosíntesis , Receptores CCR6/inmunología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Subgrupos de Linfocitos T/metabolismoRESUMEN
Interleukin-23 is a key cytokine involved in the generation of Th17 effector cells. Clinical efficacy of an anti-p40 mAb blocking both IL-12 and IL-23 and disease association with single nucleotide polymorphisms in the IL23R gene raise the question of a functional role of IL-23 in psoriasis. In this study, we provide a comprehensive analysis of IL-23 and its receptor in psoriasis and demonstrate its functional importance in a disease-relevant model system. The expression of IL-23 and its receptor was increased in the tissues of patients with psoriasis. Injection of a mAb specifically neutralizing human IL-23 showed IL-23-dependent inhibition of psoriasis development comparable to the use of anti-TNF blockers in a clinically relevant xenotransplant mouse model of psoriasis. Together, our results identify a critical functional role for IL-23 in psoriasis and provide the rationale for new treatment strategies in chronic epithelial inflammatory disorders.
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Interleucina-23/antagonistas & inhibidores , Interleucina-23/inmunología , Psoriasis/inmunología , Animales , Anticuerpos Monoclonales/uso terapéutico , Separación Celular , Modelos Animales de Enfermedad , Citometría de Flujo , Humanos , Inmunohistoquímica , Ratones , Psoriasis/tratamiento farmacológico , Psoriasis/metabolismo , Receptores de Interleucina/inmunología , Receptores de Interleucina/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Immunohistochemical lack of nuclear INI1 protein expression has been recently described as characteristic finding in atypical teratoid/rhabdoid tumors (AT/RTs), and has been suggested as useful marker to distinguish AT/RTs from other malignant pediatric central nervous system (CNS) tumors. In this study, we examined a large series of malignant pediatric CNS tumors to determine the immunohistochemical expression of INI1 protein in different malignant pediatric tumor entities. Archival paraffin-embedded biopsy specimens of 289 malignant pediatric CNS tumors including medulloblastomas, supratentorial primitive neuroectodermal tumors, glioblastomas, anaplastic astrocytomas, anaplastic ependymomas, choroid plexus carcinomas, germ cell tumors, and AT/RTs were analyzed immunohistochemically for expression of nuclear INI1 protein. Positive INI1 staining was observed in 263 tumors. Lack of INI1 protein was detectable in 26 tumors. Seventeen of the 26 tumors showed morphologically characteristic features of AT/RTs, whereas 9 embryonal tumors did not display rhabdoid features. Tumors without rhabdoid phenotype but lack of INI1 showed an aggressive clinical course and poor response to conventional treatment regimens. In summary, immunohistochemical expression of INI1 protein is lacking in tumors displaying characteristic morphologic features of AT/RT. Furthermore, a certain number of embryonal tumors without rhabdoid features but lack of INI1 protein and aggressive biologic behavior can be detected. We conclude that INI1 protein analysis should be routinely performed in all malignant pediatric embryonal CNS tumors to detect cases with lack of INI1 protein, because patients with these tumors are likely to benefit from intensified treatment.
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Biomarcadores de Tumor/análisis , Neoplasias Encefálicas/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , Proteínas de Unión al ADN/metabolismo , Tumores Neuroectodérmicos Primitivos/metabolismo , Tumor Rabdoide/metabolismo , Teratoma/metabolismo , Factores de Transcripción/metabolismo , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Niño , Preescolar , Femenino , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Lactante , Recién Nacido , Masculino , Tumores Neuroectodérmicos Primitivos/mortalidad , Tumores Neuroectodérmicos Primitivos/patología , Tumor Rabdoide/mortalidad , Tumor Rabdoide/patología , Proteína SMARCB1 , Análisis de Supervivencia , Teratoma/mortalidad , Teratoma/patologíaRESUMEN
Psoriasis is an inflammatory skin disorder that is inherited as a complex trait. Genetic studies have repeatedly highlighted HLA-C as the major determinant for psoriasis susceptibility, with the Cw*0602 allele conferring significant disease risk in a wide range of populations. Despite the potential importance of HLA-C variation in psoriasis, either via an effect on peptide presentation or immuno-inhibitory activity, allele-specific expression patterns have not been investigated. Here, we used reporter assays to characterize two regulatory variants, which virtually abolished the response to tumor necrosis factor (TNF)-α (rs2524094) and IFN-γ (rs10657191) in HLA-Cw*0602 and a cluster of related alleles. We validated these findings through the analysis of HLA-Cw*0602 expression in primary keratinocytes treated with TNF-α and IFN-γ. Finally, we showed that HLA-Cw*0602 transcripts are not increased in psoriatic skin lesions, despite highly elevated TNF-α levels. Thus, our findings demonstrate the presence of allele-specific differences in HLA-C expression and indicate that HLA-Cw*0602 is unresponsive to upregulation by key proinflammatory cytokines in psoriasis. These data pave the way for functional studies into the pathogenic role of the major psoriasis susceptibility allele.
Asunto(s)
Citocinas/inmunología , Sitios Genéticos , Antígenos HLA-C/inmunología , Interferón gamma/inmunología , Psoriasis/inmunología , Factor de Necrosis Tumoral alfa/inmunología , Adulto , Anciano , Células Cultivadas , Femenino , Predisposición Genética a la Enfermedad , Antígenos HLA-C/genética , Humanos , Queratinocitos/inmunología , Masculino , Persona de Mediana Edad , Psoriasis/genéticaRESUMEN
IL-23 and Th17 cells are key players in tissue immunosurveillance and are implicated in human immune-mediated diseases. Genome-wide association studies have shown that the IL23R R381Q gene variant protects against psoriasis, Crohn's disease and ankylosing spondylitis. We investigated the immunological consequences of the protective IL23R R381Q gene variant in healthy donors. The IL23R R381Q gene variant had no major effect on Th17 cell differentiation as the frequency of circulating Th17 cells was similar in carriers of the IL23R protective (A) and common (G) allele. Accordingly, Th17 cells generated from A and G donors produced similar amounts of Th17 cytokines. However, IL-23-mediated Th17 cell effector function was impaired, as Th17 cells from A allele carriers had significantly reduced IL-23-induced IL-17A production and STAT3 phosphorylation compared to G allele carriers. Our functional analysis of a human disease-associated gene variant demonstrates that IL23R R381Q exerts its protective effects through selective attenuation of IL-23-induced Th17 cell effector function without interfering with Th17 differentiation, and highlights its importance in the protection against IL-23-induced tissue pathologies.
Asunto(s)
Enfermedades del Sistema Inmune/genética , Inmunidad Celular/genética , Interleucina-23/farmacología , Activación de Linfocitos/efectos de los fármacos , Receptores de Interleucina/genética , Células Th17/efectos de los fármacos , Adulto , Anciano , Sustitución de Aminoácidos/genética , Sustitución de Aminoácidos/fisiología , Arginina/genética , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Células Cultivadas , Citoprotección/efectos de los fármacos , Citoprotección/genética , Regulación hacia Abajo/genética , Regulación hacia Abajo/inmunología , Femenino , Ácido Glutámico/genética , Humanos , Inmunidad Celular/efectos de los fármacos , Interleucina-23/metabolismo , Activación de Linfocitos/genética , Masculino , Persona de Mediana Edad , Mutación Missense/fisiología , Polimorfismo de Nucleótido Simple/fisiología , Receptores de Interleucina/fisiología , Células Th17/inmunología , Células Th17/fisiología , Adulto JovenRESUMEN
In Central European tick-borne encephalitis (TBE) mechanisms of tissue destruction are poorly understood. To evaluate the contribution of immunological mechanisms to tissue injury, the authors immunohistochemically analyzed paraffin-embedded autoptic brain tissue of 26 human TBE cases. In the parenchymal compartment, there was a predominance of macrophages/microglia and cytotoxic T cells. In addition, it was found that granzyme B-expressing lymphocytes were in close contact with TBE-expressing neurons up-regulating caspase-3. These findings indicate that cellular and humoral pathways of the immune system, especially granzyme B-releasing cytotoxic T cells and macrophages/microglia, mainly contribute to tissue destruction in TBE.
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Encéfalo/inmunología , Encefalitis Transmitida por Garrapatas/inmunología , Adolescente , Adulto , Anciano , Animales , Apoptosis/fisiología , Encéfalo/patología , Encéfalo/virología , Encefalitis Transmitida por Garrapatas/patología , Encefalitis Transmitida por Garrapatas/virología , Flavivirus , Granzimas/biosíntesis , Granzimas/inmunología , Humanos , Inmunohistoquímica , Inflamación/inmunología , Ixodes/virología , Macrófagos/inmunología , Microglía/inmunología , Persona de Mediana Edad , Linfocitos T Citotóxicos/enzimología , Linfocitos T Citotóxicos/inmunologíaRESUMEN
Toll-like receptors (TLR) represent an ancient front-line defence system that enables the host organism to sense the presence of microbial components within minutes. As inducers of inflammation, TLR act as important triggers of distinct entities such as sepsis or autoimmune disease exacerbation. We report here that vitamin D3 [1alpha,25-dihydroxycholecalciferol, 1,25(OH)(2)D3] suppresses the expression of TLR2 and TLR4 protein and mRNA in human monocytes in a time- and dose-dependent fashion. Despite 1,25(OH)(2)D3-induced up-regulation of CD14, challenge of human monocytes with either LPS or lipoteichoic acid resulted in impaired TNF-alpha and procoagulatory tissue factor (CD142) production, emphasizing the critical role of TLR in the induction of inflammation. Moreover, reduced TLR levels in 1,25(OH)(2)D3-treated phagocytes were accompanied by impaired NF-kappaB/RelA translocation to the nucleus and by reduced p38 and p42/44 (extracellular signal-regulated kinase 1/2) phosphorylation upon TLR-ligand engagement. Both TLR down-regulation and CD14 up-regulation were substantially inhibited by the vitamin D receptor (VDR) antagonist ZK 159222, indicating that the immunomodulatory effect of 1,25(OH)(2)D3 on innate immunity receptors requires VDR transcription factor activation. Our data provide strong evidence that 1,25(OH)(2)D3 primes monocytes to respond less effectively to bacterial cell wall components in a VDR-dependent mechanism, most likely due to decreased levels of TLR2 and TLR4.