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1.
J Med Case Rep ; 13(1): 381, 2019 Dec 24.
Artículo en Inglés | MEDLINE | ID: mdl-31870441

RESUMEN

BACKGROUND: Autosomal dominant polycystic kidney disease is defined as an inherited disorder characterized by renal cyst formation due to mutations in the PKD1 or PKD2 gene, whereas tuberous sclerosis complex is an autosomal dominant neurocutaneous syndrome caused by mutation or deletion of the TSC2 gene. A TSC2/PKD1 contiguous gene syndrome, which is caused by a chromosomal mutation that disrupts both the TSC2 and PKD1 genes, has been identified in patients with tuberous sclerosis complex and severe early-onset autosomal dominant polycystic kidney disease. The tumor tissue of patients with breast cancer with contiguous gene syndrome has a high mutation burden and produces several neoantigens. A diffuse positive immunohistochemistry staining for cluster of differentiation 8+ in the T cells of breast cancer tissue is consistent with neoantigen production due to high mutation burden. CASE PRESENTATION: A 61-year-old Japanese woman who had been undergoing dialysis for 23 years because of end-stage renal failure secondary to autosomal dominant polycystic kidney disease was diagnosed as having triple-negative breast cancer and underwent mastectomy in 2015. She had a history of epilepsy and skin hamartoma. Her grandmother, mother, two aunts, four cousins, and one brother were also on dialysis for autosomal dominant polycystic kidney disease. Her brother had epilepsy and a brain nodule. Another brother had a syndrome of kidney failure, intellectual disability, and diabetes mellitus, which seemed to be caused by mutation in the CREBBP gene. Immunohistochemistry of our patient's breast tissue showed cluster of differentiation 8 and programmed cell death ligand 1 positivity. CONCLUSIONS: Programmed cell death ligand 1 checkpoint therapy may be effective for recurrence of triple-negative breast cancer in a patient with autosomal dominant polycystic kidney disease and tuberous sclerosis complex.


Asunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Recurrencia Local de Neoplasia/patología , Riñón Poliquístico Autosómico Dominante/fisiopatología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Neoplasias de la Mama Triple Negativas/patología , Esclerosis Tuberosa/fisiopatología , Antígeno B7-H1 , Linfocitos T CD8-positivos , Diferenciación Celular/inmunología , Femenino , Humanos , Inmunoterapia/métodos , Mastectomía , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Linaje , Riñón Poliquístico Autosómico Dominante/inmunología , Riñón Poliquístico Autosómico Dominante/terapia , Receptor de Muerte Celular Programada 1/inmunología , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/inmunología , Neoplasias de la Mama Triple Negativas/terapia , Esclerosis Tuberosa/inmunología , Esclerosis Tuberosa/terapia
2.
Brain Dev ; 41(10): 829-838, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31495513

RESUMEN

BACKGROUNDS: Focal cortical dysplasia type IIb (FCD IIb) and tuberous sclerosis complex (TSC) are very frequently associated with epilepsy in pediatric patients. Human leukocyte immunoglobulin-like receptor B2 (LILRB2) participates in the process of neurite growth, synaptic plasticity, and inflammatory reaction, suggesting a potential role of LILRB2 in epilepsy. However, little is known about the distribution and expression of LILRB2 in cortical lesions of FCD IIb and cortical tubers of TSC. METHODS: In this study, we have described the distribution and expression of LILRB2 signaling pathway in cortical lesions of pediatric patients with FCD IIb (n = 15) and TSC (n = 12) relative to age-matched autopsy control samples (CTX, n = 10), respectively. The protein levels of LILRB2 pathway molecules were assessed by western blotting and immunohistochemistry. The expression pattern was investigated by immunohistochemistry and double labeling experiment. Spearman correlation analysis to explore the correlation between LILRB2 protein level and seizure frequency. RESULTS: The protein levels of LILRB2 and its downstream molecules POSH, SHROOM3, ROCK1, ROCK2 were increased in cortices of patients compared to CTX. Protein levels of LILRB2 negatively correlated with the frequency of seizures in FCD IIb and TSC patients, respectively. Moreover, all LILRB2 pathway molecules were strongly expressed in dysmorphic neurons, balloon cells, and giant cells, LILRB2 co-localized with neuron marker and astrocyte marker. CONCLUSION: Taken together, the special expression patterns of LILRB2 signaling pathway in cortical lesions of FCD IIb and TSC implies that it may be involved in the process of epilepsy.


Asunto(s)
Epilepsia/inmunología , Malformaciones del Desarrollo Cortical de Grupo I/inmunología , Glicoproteínas de Membrana/metabolismo , Receptores Inmunológicos/metabolismo , Esclerosis Tuberosa/inmunología , Astrocitos/patología , Encéfalo/patología , Encefalopatías/patología , Corteza Cerebral/patología , Niño , Preescolar , China , Epilepsia/genética , Epilepsia/metabolismo , Femenino , Humanos , Leucocitos/metabolismo , Masculino , Malformaciones del Desarrollo Cortical/patología , Malformaciones del Desarrollo Cortical de Grupo I/metabolismo , Neurogénesis , Neuronas/metabolismo , Transducción de Señal , Transcriptoma/genética , Esclerosis Tuberosa/metabolismo
4.
Front Immunol ; 10: 121, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30761153

RESUMEN

Brain-infiltrating lymphocytes (BILs) were isolated from resected brain tissue from 10 pediatric epilepsy patients who had undergone surgery for Hemimegalencephaly (HME) (n = 1), Tuberous sclerosis complex (TSC) (n = 2), Focal cortical dysplasia (FCD) (n = 4), and Rasmussen encephalitis (RE) (n = 3). Peripheral blood mononuclear cells (PBMCs) were also isolated from blood collected at the time of the surgery. Cells were immunostained with a panel of 20 antibody markers, and analyzed by mass cytometry. To identify and quantify the immune cell types in the samples, an unbiased clustering method was applied to the entire data set. More than 85 percent of the CD45+ cells isolated from resected RE brain tissue comprised T cells; by contrast NK cells and myeloid cells constituted 80-95 percent of the CD45+ cells isolated from the TSC and the FCD brain specimens. Three populations of myeloid cells made up >50 percent of all of the myeloid cells in all of the samples of which a population of HLA-DR+ CD11b+ CD4- cells comprised the vast majority of myeloid cells in the BIL fractions from the FCD and TSC cases. CD45RA+ HLA-DR- CD11b+ CD16+ NK cells constituted the major population of NK cells in the blood from all of the cases. This subset also comprised the majority of NK cells in BILs from the resected RE and HME brain tissue, whereas NK cells defined as CD45RA- HLA-DR+ CD11b- CD16- cells comprised 86-96 percent of the NK cells isolated from the FCD and TSC brain tissue. Thirteen different subsets of CD4 and CD8 αß T cells and γδ T cells accounted for over 80% of the CD3+ T cells in all of the BIL and PBMC samples. At least 90 percent of the T cells in the RE BILs, 80 percent of the T cells in the HME BILs and 40-66 percent in the TSC and FCD BILs comprised activated antigen-experienced (CD45RO+ HLA-DR+ CD69+) T cells. We conclude that even in cases where there is no evidence for an infection or an immune disorder, activated peripheral immune cells may be present in epileptogenic areas of the brain, possibly in response to seizure-driven brain inflammation.


Asunto(s)
Encéfalo/inmunología , Epilepsia/inmunología , Inmunidad Adaptativa , Adolescente , Niño , Preescolar , Encefalitis/inmunología , Encefalitis/cirugía , Epilepsia/cirugía , Femenino , Hemimegalencefalia/inmunología , Hemimegalencefalia/cirugía , Humanos , Inmunidad Innata , Lactante , Leucocitos Mononucleares/inmunología , Masculino , Esclerosis Tuberosa/inmunología , Esclerosis Tuberosa/cirugía
6.
Am J Respir Cell Mol Biol ; 59(6): 723-732, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30095976

RESUMEN

Pulmonary lymphangioleiomyomatosis (LAM) is a slow-progressing metastatic disease that is driven by mutations in the tumor suppressor tuberous sclerosis complex 1/2 (TSC1/2). Rapamycin inhibits LAM cell proliferation and is the only approved treatment, but it cannot cause the regression of existing lesions and can only stabilize the disease. However, in other cancers, immunotherapies such as checkpoint blockade against PD-1 and its ligand PD-L1 have shown promise in causing tumor regression and even curing some patients. Thus, we asked whether PD-L1 has a role in LAM progression. In vitro, PD-L1 expression in murine Tsc2-null cells is unaffected by mTOR inhibition with torin but can be upregulated by IFN-γ. Using immunohistochemistry and single-cell flow cytometry, we found increased PD-L1 expression both in human lung tissue from patients with LAM and in Tsc2-null lesions in a murine model of LAM. In this model, PD-L1 is highly expressed in the lung by antigen-presenting and stromal cells, and activated T cells expressing PD-1 infiltrate the affected lung. In vivo treatment with anti-PD-1 antibody significantly prolongs mouse survival in the model of LAM. Together, these data demonstrate that PD-1/PD-L1-mediated immunosuppression may occur in LAM, and suggest new opportunities for therapeutic targeting that may provide benefits beyond those of rapamycin.


Asunto(s)
Antígeno B7-H1/metabolismo , Neoplasias Pulmonares/metabolismo , Pulmón/metabolismo , Linfangioleiomiomatosis/metabolismo , Esclerosis Tuberosa/metabolismo , Animales , Anticuerpos Monoclonales/farmacología , Antígeno B7-H1/inmunología , Estudios de Casos y Controles , Proliferación Celular , Modelos Animales de Enfermedad , Humanos , Pulmón/efectos de los fármacos , Pulmón/inmunología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Linfangioleiomiomatosis/tratamiento farmacológico , Linfangioleiomiomatosis/inmunología , Linfangioleiomiomatosis/patología , Ratones , Ratones Endogámicos C57BL , Esclerosis Tuberosa/tratamiento farmacológico , Esclerosis Tuberosa/inmunología , Esclerosis Tuberosa/patología , Regulación hacia Arriba
7.
JCI Insight ; 3(8)2018 04 19.
Artículo en Inglés | MEDLINE | ID: mdl-29669930

RESUMEN

Tuberous sclerosis complex (TSC) is an incurable multisystem disease characterized by mTORC1-hyperactive tumors. TSC1/2 mutations also occur in other neoplastic disorders, including lymphangioleiomyomatosis (LAM) and bladder cancer. Whether TSC-associated tumors will respond to immunotherapy is unknown. We report here that the programmed death 1 coinhibitory receptor (PD-1) is upregulated on T cells in renal angiomyolipomas (AML) and pulmonary lymphangioleiomyomatosis (LAM). In C57BL/6J mice injected with syngeneic TSC2-deficient cells, anti-PD-1 alone decreased 105K tumor growth by 67% (P < 0.0001); the combination of PD-1 and CTLA-4 blockade was even more effective in suppressing tumor growth. Anti-PD-1 induced complete rejection of TSC2-deficient 105K tumors in 37% of mice (P < 0.05). Double blockade of PD-1 and CTLA-4 induced rejection in 62% of mice (P < 0.01). TSC2 reexpression in TSC2-deficient TMKOC cells enhanced antitumor immunity by increasing T cell infiltration and production of IFN-γ/TNF-α by T cells, suggesting that TSC2 and mTORC1 play specific roles in the induction of antitumor immunity. Finally, 1 month of anti-PD-1 blockade reduced renal tumor burden by 53% (P < 0.01) in genetically engineered Tsc2+/- mice. Taken together, these data demonstrate for the first time to our knowledge that checkpoint blockade may have clinical efficacy for TSC and LAM, and possibly other benign tumor syndromes, potentially yielding complete and durable clinical responses.


Asunto(s)
Antígeno CTLA-4/antagonistas & inhibidores , Inmunoterapia/métodos , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Proteína 2 del Complejo de la Esclerosis Tuberosa/deficiencia , Esclerosis Tuberosa/genética , Angiomiolipoma/complicaciones , Angiomiolipoma/genética , Angiomiolipoma/inmunología , Animales , Antígeno CTLA-4/metabolismo , Quimioterapia Combinada , Linfangioleiomiomatosis/complicaciones , Linfangioleiomiomatosis/genética , Linfangioleiomiomatosis/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Mutación , Receptor de Muerte Celular Programada 1/metabolismo , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo , Esclerosis Tuberosa/tratamiento farmacológico , Esclerosis Tuberosa/etiología , Esclerosis Tuberosa/inmunología , Proteína 1 del Complejo de la Esclerosis Tuberosa , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Neoplasias de la Vejiga Urinaria/complicaciones , Neoplasias de la Vejiga Urinaria/patología
8.
Semin Pediatr Neurol ; 24(3): 152-160, 2017 08.
Artículo en Inglés | MEDLINE | ID: mdl-29103422

RESUMEN

Though the term "inflammation" is traditionally defined as proliferation or infiltration of lymphatic cells of the lymphatic immune system and macrophages or as immunoreactive proteins including cytokines, interleukins and major histocompatibility complexes, recently recognized reactions to tissue injury also are inflammation, often occurring in the central nervous system in conditions where they previously were not anticipated and where they may play a role in both pathogenesis and repair. We highlight 4 such novel inflammatory conditions revealed by neuropathologic studies: (1) inflammatory markers and cells in the brain of human fetuses with tuberous sclerosis complex and perhaps other disorders of the mechanistic target of rapamycin genetic or metabolic pathway, (2) inflammatory markers in the brain related to febrile seizures of infancy and early childhood, (3) heat-shock protein upregulation in glial cells and neurons at sites of chronic epileptic foci, and (4) the emerging role of astrocytes in the presence of and participation in inflammation. Novel evidence shows that cerebral inflammation plays a role in some genetic diseases as early as midgestation and thus is not always acquired postnatally or in adult life.


Asunto(s)
Astrocitos/fisiología , Encéfalo , Esclerosis Tuberosa , Cadena B de alfa-Cristalina/metabolismo , Animales , Astrocitos/patología , Encéfalo/inmunología , Encéfalo/metabolismo , Encéfalo/patología , Humanos , Convulsiones Febriles/inmunología , Convulsiones Febriles/metabolismo , Convulsiones Febriles/patología , Esclerosis Tuberosa/inmunología , Esclerosis Tuberosa/metabolismo , Esclerosis Tuberosa/patología
9.
Neuropediatrics ; 46(5): 335-43, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26356487

RESUMEN

OBJECTIVE: Therapeutic options for the tuberous sclerosis complex (TSC) syndrome showed varying outcomes. Malfunctional tsc1/tsc2 genes leave mTOR uninhibited, a positive downstream modulator of the innate proinflammatory immune system, which has not yet been described in pediatric patients with TSC. METHODS: Using polymerase chain reaction (PCR) gene expression levels of monocytes after cultivation with lipopolysaccharide (LPS) or with LPS + mTOR inhibitor rapamycin, patients with TSC (n = 16) were compared with healthy subjects (n = 20). RESULTS: Compared with monocytes from healthy controls, LPS showed a more prominent gene expression pattern in patients with TSC (CCL24, CXCL10, IL-6, IL-10, and IL-1B). Proinflammatory reactions against LPS were modulated by rapamycin. With LPS + rapamycin monocytes from patients with TSC showed gene expression patterns different from healthy subjects. Furthermore, developmental differences were discernible in patients with TSC, compared with gene expression levels for patients 0 to 5 years to those 6 to 11 years of age, the latter with marked expression of IL-6 IL-1A, IL-1B, RIPK2, but also IL-10. CONCLUSION: The effects of LPS, even more of LPS with rapamycin on monocytes from patients with TSC suggested that inflammatory processes are distinct from those in healthy subjects. Furthermore, reaction to rapamycin indicates age-related gene expression levels. Our findings offer a model to decipher the unknown and varying gene expression pattern induced by rapamycin.


Asunto(s)
Mediadores de Inflamación/metabolismo , Inflamación/metabolismo , Monocitos/metabolismo , Esclerosis Tuberosa/inmunología , Esclerosis Tuberosa/metabolismo , Niño , Preescolar , Estudios Transversales , Citocinas/metabolismo , Expresión Génica , Humanos , Inmunosupresores/farmacología , Lactante , Recién Nacido , Inflamación/genética , Lipopolisacáridos/farmacología , Monocitos/efectos de los fármacos , Sirolimus/farmacología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/metabolismo , Esclerosis Tuberosa/genética
10.
J Trop Pediatr ; 61(1): 74-7, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25344617

RESUMEN

UNLABELLED: Cardiac rhabdomyoma is the most common primary cardiac tumor, is considered to be a hamartoma of developing cardiac myocytes. Cardiac rhabdomyoma is associated with tuberous sclerosis complex (TSC) in 50-86% of cases. Mutations in TSC-1/TSC-2 genes result in increased mammalian target of rapamycin (mTOR) pathway activation responsible for the hamartomatous lesions of tuberous sclerosis complex. Therapy with mTOR inhibitors is currently under investigation as a treatment option for tumors associated with TSC. In this report we present a case with multiple symptomatic rhabdomyomas associated with tuberous sclerosis complex, deemed to be ineligible for surgical removal, treated with everolimus (mTOR inhibitor). CONCLUSION: As we observed in our patient, in cases with inoperable symptomatic rhabdomyomas associated with TSC, everolimus, an mTOR inhibitor, may be the treatment of choice, which should be confirmed with additional studies.


Asunto(s)
Neoplasias Cardíacas/tratamiento farmacológico , Inmunosupresores/administración & dosificación , Rabdomioma/tratamiento farmacológico , Sirolimus/análogos & derivados , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Esclerosis Tuberosa/tratamiento farmacológico , Esquema de Medicación , Ecocardiografía , Everolimus , Neoplasias Cardíacas/diagnóstico , Humanos , Inmunosupresores/uso terapéutico , Recién Nacido , Masculino , Rabdomioma/diagnóstico , Sirolimus/administración & dosificación , Sirolimus/uso terapéutico , Resultado del Tratamiento , Esclerosis Tuberosa/inmunología
11.
Nat Commun ; 5: 4696, 2014 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-25175012

RESUMEN

Macrophages acquire distinct phenotypes during tissue stress and inflammatory responses, but the mechanisms that regulate the macrophage polarization are poorly defined. Here we show that tuberous sclerosis complex 1 (TSC1) is a critical regulator of M1 and M2 phenotypes of macrophages. Mice with myeloid-specific deletion of TSC1 exhibit enhanced M1 response and spontaneously develop M1-related inflammatory disorders. However, TSC1-deficient mice are highly resistant to M2-polarized allergic asthma. Inhibition of the mammalian target of rapamycin (mTOR) fails to reverse the hypersensitive M1 response of TSC1-deficient macrophages, but efficiently rescues the defective M2 polarization. Deletion of mTOR also fails to reverse the enhanced inflammatory response of TSC1-deficient macrophages. Molecular studies indicate that TSC1 inhibits M1 polarization by suppressing the Ras GTPase-Raf1-MEK-ERK pathway in mTOR-independent manner, whereas TSC1 promotes M2 properties by mTOR-dependent CCAAT/enhancer-binding protein-ß pathways. Overall, these findings define a key role for TSC1 in orchestrating macrophage polarization via mTOR-dependent and independent pathways.


Asunto(s)
Asma/genética , Macrófagos/inmunología , Serina-Treonina Quinasas TOR/genética , Esclerosis Tuberosa/genética , Proteínas Supresoras de Tumor/genética , Animales , Asma/inmunología , Asma/patología , Proteína beta Potenciadora de Unión a CCAAT/genética , Proteína beta Potenciadora de Unión a CCAAT/inmunología , Diferenciación Celular , Linaje de la Célula/inmunología , Femenino , Regulación de la Expresión Génica , Sistema de Señalización de MAP Quinasas , Macrófagos/patología , Masculino , Ratones , Ratones Noqueados , Proteínas Proto-Oncogénicas c-raf/genética , Proteínas Proto-Oncogénicas c-raf/inmunología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/inmunología , Esclerosis Tuberosa/inmunología , Esclerosis Tuberosa/patología , Proteína 1 del Complejo de la Esclerosis Tuberosa , Proteínas Supresoras de Tumor/deficiencia , Proteínas Supresoras de Tumor/inmunología , Proteínas Activadoras de ras GTPasa/genética , Proteínas Activadoras de ras GTPasa/inmunología
12.
PLoS One ; 9(3): e91952, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24633152

RESUMEN

Germline and somatic biallelic mutations of the Tuberous sclerosis complex (TSC) 1 and TSC2 gene products cause TSC, an autosomal dominant multifocal hamartomatosis with variable neurological manifestations. The consequences of TSC1 or TSC2 loss in cells of hematopoietic origin have recently started to be unveiled in mice and showed to hinder the development of proper T cell immunity. To date, the consequences of germline TSC1 mutations and/or its loss in mature human T cells remain to be determined. To address these issues, we analyzed subset representation, phenotype and responsiveness to mitogens in T cells from patients with inherited monoallelic TSC1 mutations, and induced shRNA-mediated TSC1 down-regulation in primary and transformed human T cells. We report that, the distribution of peripheral CD4 and CD8 T cell subsets, their cytokine-secretion profile, and responsiveness to in vitro stimulation were largely preserved in TSC subjects with monoallelic TSC1 germline mutations when compared to healthy controls. Sufficient levels of hamartin and tuberin and proper control of mTOR-dependent signaling in primary T cells from TSC subjects best explained this. In contrast, shRNA-induced down-regulation of TSC1, likely mimicking biallelic inactivation of TSC1, compromised hamartin and tuberin expression and mTORC2/AKT/FoxO1/3 signaling causing both primary and transformed T cells to die by apoptosis. Thus, our results indicate that, while one functional TSC1 allele preserves human T lymphocytes development and homeostasis, TSC1 acute down-regulation is detrimental to the survival of both primary and transformed T cells.


Asunto(s)
Alelos , Mutación de Línea Germinal , Homeostasis , Subgrupos de Linfocitos T/citología , Esclerosis Tuberosa/genética , Esclerosis Tuberosa/inmunología , Proteínas Supresoras de Tumor/genética , Adulto , Animales , Apoptosis/genética , Proliferación Celular , Supervivencia Celular/genética , Regulación hacia Abajo/genética , Proteína Forkhead Box O1 , Factores de Transcripción Forkhead/metabolismo , Silenciador del Gen , Humanos , Ratones , Persona de Mediana Edad , Mitocondrias/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Interferente Pequeño/genética , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Proteína 1 del Complejo de la Esclerosis Tuberosa , Proteínas Supresoras de Tumor/deficiencia
13.
J Immunol ; 192(6): 2643-50, 2014 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-24532578

RESUMEN

Development of effective immune therapies for cancer patients requires better understanding of hurdles that prevent the generation of effective antitumor immune responses. Administration of α-galactosylceramide (α-GalCer) in animals enhances antitumor immunity via activation of the invariant NKT (iNKT) cells. However, repeated injections of α-GalCer result in long-term unresponsiveness or anergy of iNKT cells, severely limiting its efficacy in tumor eradication. The mechanisms leading to iNKT cell anergy remain poorly understood. We report in this study that the tuberous sclerosis 1 (TSC1), a negative regulator of mTOR signaling, plays a crucial role in iNKT cell anergy. Deficiency of TSC1 in iNKT cells results in resistance to α-GalCer-induced anergy, manifested by increased expansion of and cytokine production by iNKT cells in response to secondary Ag stimulation. It is correlated with impaired upregulation of programmed death-1, Egr2, and Grail. Moreover, TSC1-deficient iNKT cells display enhanced antitumor immunity in a melanoma lung metastasis model. Our data suggest targeting TSC1/2 as a strategy for boosting antitumor immune therapy.


Asunto(s)
Anergia Clonal/inmunología , Melanoma Experimental/inmunología , Células T Asesinas Naturales/inmunología , Esclerosis Tuberosa/inmunología , Animales , Línea Celular Tumoral , Citocinas/inmunología , Citocinas/metabolismo , Proteína 2 de la Respuesta de Crecimiento Precoz/genética , Proteína 2 de la Respuesta de Crecimiento Precoz/inmunología , Proteína 2 de la Respuesta de Crecimiento Precoz/metabolismo , Citometría de Flujo , Expresión Génica/inmunología , Homeostasis/genética , Homeostasis/inmunología , Immunoblotting , Inmunoterapia Adoptiva , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/secundario , Melanoma Experimental/patología , Melanoma Experimental/terapia , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células T Asesinas Naturales/metabolismo , Células T Asesinas Naturales/trasplante , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Esclerosis Tuberosa/genética , Esclerosis Tuberosa/metabolismo , Proteína 2 del Complejo de la Esclerosis Tuberosa , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/inmunología , Proteínas Supresoras de Tumor/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/inmunología , Ubiquitina-Proteína Ligasas/metabolismo
14.
J Neuroimmunol ; 262(1-2): 85-91, 2013 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-23906968

RESUMEN

The role of interleukin 17 (IL-17) to epilepsy-associated cortical tubers of tuberous sclerosis complex (TSC) is unknown. We investigated the expression patterns of the IL-17 and IL-17 receptor (IL-17R) in cortical tubers of TSC compared with normal control cortex (CTX). We found that IL-17 and IL-17R were clearly upregulated in cortical tubers at the protein levels. Immunostaining indicated that IL-17 was specifically distributed in the innate immunity cells (DNs, GCs, astrocytes, and microglia) and adaptive immunity cells (T-lymphocytes) as well as the endothelial cells of blood vessels. The overexpression and distribution patterns of IL-17 may be involved in the epileptogenicity of cortical tubers in TSC.


Asunto(s)
Corteza Cerebral/inmunología , Interleucina-17/genética , Esclerosis Tuberosa/inmunología , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Niño , Preescolar , Epilepsia/etiología , Epilepsia/inmunología , Epilepsia/patología , Femenino , Humanos , Lactante , Interleucina-17/biosíntesis , Masculino , Receptores de Interleucina-17/biosíntesis , Receptores de Interleucina-17/genética , Esclerosis Tuberosa/complicaciones , Esclerosis Tuberosa/patología
15.
Ann N Y Acad Sci ; 1291: 14-32, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23659703

RESUMEN

Everolimus is a potent, oral inhibitor of the mammalian target of rapamycin (mTOR) that has been investigated in multiple clinical development programs since 1996. A unique collaboration between academic and pharmaceutical experts fostered research that progressed rapidly, with simultaneous indication findings across numerous tumor types. Initially developed for the prophylaxis of organ transplant rejection, everolimus has demonstrated efficacy and safety for the treatment of patients with various types of cancer (renal cell carcinoma, neuroendocrine tumors of pancreatic origin, and breast cancer) and for adult and pediatric patients with tuberous sclerosis complex. The FDA approval of everolimus for these diseases has addressed several unmet medical needs and is widely accepted by the medical community where treatment options may be limited. An extensive clinical development program is ongoing to establish the role of everolimus as monotherapy, or in combination with other agents, in the treatment of a broad spectrum of malignancies.


Asunto(s)
Antineoplásicos/administración & dosificación , Inmunosupresores/administración & dosificación , Neoplasias/tratamiento farmacológico , Sirolimus/análogos & derivados , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Administración Oral , Animales , Antineoplásicos/inmunología , Ensayos Clínicos como Asunto/métodos , Everolimus , Humanos , Inmunosupresores/química , Neoplasias/inmunología , Sirolimus/administración & dosificación , Sirolimus/inmunología , Serina-Treonina Quinasas TOR/inmunología , Esclerosis Tuberosa/tratamiento farmacológico , Esclerosis Tuberosa/inmunología
16.
J Neuroinflammation ; 10: 12, 2013 Jan 24.
Artículo en Inglés | MEDLINE | ID: mdl-23347564

RESUMEN

PURPOSE: The expression of the major histocompatibility complex class I (MHC-I) in the brain has received considerable interest not only because of its fundamental role in the immune system, but also for its non-immune functions in the context of activity-dependent brain development and plasticity. METHODS: In the present study we evaluated the expression and cellular pattern of MHC-I in focal glioneuronal lesions associated with intractable epilepsy. MHC-I expression was studied in epilepsy surgery cases with focal cortical dysplasia (FCD I, n = 6; FCD IIa, n = 6 and FCD IIb, n = 15), tuberous sclerosis complex (TSC, cortical tubers; n = 6) or ganglioglioma (GG; n = 15) using immunocytochemistry. Evaluation of T lymphocytes with granzyme-B+ granules and albumin immunoreactivity was also performed. RESULTS: All lesions were characterized by MHC-I expression in blood vessels. Expression in both endothelial and microglial cells as well as in neurons (dysmorphic/dysplastic neurons) was observed in FCD II, TSC and GG cases. We observed perivascular and parenchymal T lymphocytes (CD8+, T-cytotoxic) with granzyme-B+ granules in FCD IIb and TSC specimens. Albumin extravasation, with uptake in astrocytes, was observed in FCD IIb and GG cases. CONCLUSIONS: Our findings indicate a prominent upregulation of MHC-I as part of the immune response occurring in epileptogenic glioneuronal lesions. In particular, the induction of MHC-I in neuronal cells appears to be a feature of type II FCD, TSC and GG and may represent an important accompanying event of the immune response, associated with blood-brain barrier dysfunction, in these developmental lesions.


Asunto(s)
Regulación de la Expresión Génica/inmunología , Genes MHC Clase I/inmunología , Microglía/metabolismo , Neuronas/metabolismo , Esclerosis Tuberosa/metabolismo , Esclerosis Tuberosa/patología , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Humanos , Complejo Mayor de Histocompatibilidad/inmunología , Masculino , Microglía/inmunología , Microglía/patología , Neuronas/inmunología , Neuronas/patología , Esclerosis Tuberosa/inmunología , Adulto Joven
17.
Diagn Pathol ; 7: 117, 2012 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-22937790

RESUMEN

Perivascular epithelioid cell (PEC) tumors (PEComas) are a family of related mesenchymal tumors composed of PECs which co-express melanocytic and smooth muscle markers. Although their distinctive histologic, immunohistochemical, ultrastructural, and genetic features have been clearly demonstrated, their histogenesis and normal counterpart remain largely unknown. Precursor lesions of PEComas have rarely been reported. We herein describe a tuberous sclerosis patient with microscopic PEC nodules in the endometrium of adenomyosis, pelvic endometriosis, an ovarian endometriotic cyst, and the endometrium of the uterine cavity. The nodules showed a mixture of spindle-shaped and epithelioid cells concentrically arranged around small arteries. The cells exhibited uniform nuclei, light eosinophilic cytoplasm, and immunoreactivity with HMB-45 and CD10. Some nodules revealed continuity with a PEComa in the myometrium. These findings support microscopic endometrial PEC nodules possibly being precursor lesions of uterine PEComas. The wide distribution of the nodules in the pelvis may be related to the multicentricity of PEComas in tuberous sclerosis patients. Owing to the immunoreactivity with CD10, microscopic endometrial PEC nodules may be misinterpreted as endothelial stromal cells unless melanocytic markers are stained. To the best of our knowledge, this is a case with the earliest manifestation of PEC lesions occurring in the endometrium. Virtual slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/9658280017862643.


Asunto(s)
Endometrio/patología , Células Epitelioides/patología , Neoplasias de Células Epitelioides Perivasculares/patología , Lesiones Precancerosas/patología , Esclerosis Tuberosa/patología , Neoplasias Uterinas/patología , Adenomiosis/patología , Adulto , Biomarcadores de Tumor/análisis , Biopsia , Detección Precoz del Cáncer , Endometriosis/patología , Endometrio/química , Endometrio/inmunología , Endometrio/cirugía , Células Epitelioides/química , Células Epitelioides/inmunología , Femenino , Humanos , Inmunohistoquímica , Linfangioleiomiomatosis/patología , Antígenos Específicos del Melanoma/análisis , Neprilisina/análisis , Quistes Ováricos/patología , Neoplasias de Células Epitelioides Perivasculares/química , Neoplasias de Células Epitelioides Perivasculares/inmunología , Neoplasias de Células Epitelioides Perivasculares/cirugía , Lesiones Precancerosas/química , Lesiones Precancerosas/inmunología , Lesiones Precancerosas/cirugía , Valor Predictivo de las Pruebas , Resultado del Tratamiento , Esclerosis Tuberosa/inmunología , Esclerosis Tuberosa/cirugía , Neoplasias Uterinas/química , Neoplasias Uterinas/inmunología , Neoplasias Uterinas/cirugía , Antígeno gp100 del Melanoma
18.
Expert Rev Anticancer Ther ; 11(8): 1181-92, 2011 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21916571

RESUMEN

Tuberous sclerosis complex (TSC) is a devastating disease affecting virtually all organ systems of the body and is characterized by multiple hamartomas and neurodevelopmental disorders. The majority of patients with TSC have mutations in TSC1 or TSC2, resulting in constitutive activation of mTOR. Because the pathogenesis of the disease is mTOR hyperactivity, mTOR inhibitors have the potential to treat the underlying cause in TSC patients. Everolimus is the first mTOR inhibitor approved in the USA for the treatment of patients with subependymal giant-cell astrocytomas (SEGAs) associated with TSC. Evidence supports and ongoing studies are evaluating the role of mTOR inhibitors in the treatment of a wide spectrum of disease manifestations, including reduction in tumor volume (SEGAs, renal angiomyolipoma) and improvement in epilepsy, lung function and skin manifestations, including facial angiofibromas. In time, the use of mTOR inhibitors in patients with TSC will likely be very well established.


Asunto(s)
Inmunosupresores/uso terapéutico , Sirolimus/análogos & derivados , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Esclerosis Tuberosa/tratamiento farmacológico , Esclerosis Tuberosa/inmunología , Animales , Everolimus , Humanos , Sirolimus/uso terapéutico , Serina-Treonina Quinasas TOR/metabolismo , Esclerosis Tuberosa/metabolismo
19.
Transpl Int ; 23(8): 777-85, 2010 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-20070623

RESUMEN

Tuberous sclerosis complex (TSC) is caused by constitutively activated mammalian target of rapamycin (mTOR) resulting in nonmalignant tumours of several organs and consequently renal failure. Recent reports suggest a possible beneficial role of the mTOR-inhibitor (mTOR-I) sirolimus for TSC; however, safety and efficiency of sirolimus in TSC patients after renal transplantation, both as primary immunosuppressant as well as anti-proliferative agent, are still undefined. Moreover, it is currently unknown whether the TSC mutation affects the primary immune response in these patients. In this article, we report on three TSC patients after renal transplantation who have been converted from a calcineurin-inhibitor (CNI)-based immunosuppression to sirolimus. During 2 years of follow-up, renal allograft function was stable or even improved, and no significant sirolimus-associated side-effects were noted. Beneficial effects of sirolimus against TSC were detected in the skin, along with improved spirometric measurements and an arrest of astrocytoma progression. We show that the inflammatory immune response was significantly altered in TSC patients as compared with controls and sirolimus potently affected both inflammatory cytokine production and vascular endothelial growth factor levels in these patients. Larger studies are warranted to further examine the relationship between clinical parameters and the molecular response to mTOR-inhibition in TSC patients after renal transplantation.


Asunto(s)
Rechazo de Injerto/complicaciones , Rechazo de Injerto/tratamiento farmacológico , Inmunosupresores/administración & dosificación , Trasplante de Riñón , Sirolimus/administración & dosificación , Esclerosis Tuberosa/complicaciones , Adulto , Inhibidores de la Calcineurina , Femenino , Rechazo de Injerto/inmunología , Humanos , Sistema Inmunológico/efectos de los fármacos , Sistema Inmunológico/inmunología , Inmunosupresores/efectos adversos , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Linfangioleiomiomatosis/complicaciones , Linfangioleiomiomatosis/inmunología , Masculino , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Sirolimus/efectos adversos , Serina-Treonina Quinasas TOR , Resultado del Tratamiento , Esclerosis Tuberosa/inmunología
20.
Epilepsia ; 50(12): 2619-28, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19583780

RESUMEN

PURPOSE: Doublecortin (DCX) is a microtubule-associated protein with regulatory roles in radial and tangential migration of neurons during cortical development. In normal adult cortex there is restricted expression, and DCX is widely used as a marker of neurogenesis. Imperfect corticogenesis is thought to underpin many focal cortical pathologies in epilepsy surgical series, including focal cortical dysplasia (FCD). The aim was to study DCX expression patterns in such lesions compared to normal developing and mature cortex. METHOD: Cases of FCD types Ia (13) and IIb (4), pediatric hippocampal sclerosis (HS) (5), temporal lobe sclerosis (5), glioneuronal tumors (5), gray matter heterotopia (3), and control tissues (16) from a wide age range [20 gestational weeks (GW) to 85 years] were studied using immunohistochemistry to DCX. RESULTS: In controls and all epilepsy cases, perinuclear labeling of small round cells (SRCs) and satellite perineuronal cells was observed in both postmortem and surgical tissues. In FCD Ia up to the age of 4 years, prominent DCX-positive (DCX(+)), immature cells were present along the junction of layers I and II, with processes extending into the molecular layer. These cell types were not a significant feature in other pathologies, which showed multipolar DCX(+) cells or labeling of dysmorphic cells throughout the cortex. DISCUSSION: Persistent cellular DCX expression is confirmed in normal adult cortex. Characteristic expression patterns in layer II of FCD Ia could indicate delayed or abnormal cortical maturation rather than ongoing cytogenesis. This could be indicative of enhanced local cortical plasticity as well as a potential diagnostic feature of this type of pathology.


Asunto(s)
Malformaciones del Desarrollo Cortical/genética , Neocórtex/patología , Esclerosis Tuberosa/genética , Adolescente , Adulto , Animales , Autopsia , Western Blotting , Ensayos de Migración Celular/estadística & datos numéricos , Niño , Preescolar , Proteínas de Dominio Doblecortina , Proteína Doblecortina , Epilepsia/genética , Epilepsia/inmunología , Epilepsia/cirugía , Femenino , Técnica del Anticuerpo Fluorescente , Regulación del Desarrollo de la Expresión Génica , Células Gigantes/inmunología , Células Gigantes/patología , Humanos , Inmunohistoquímica , Lactante , Masculino , Malformaciones del Desarrollo Cortical/inmunología , Malformaciones del Desarrollo Cortical/cirugía , Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Microtúbulos/inmunología , Proteínas Asociadas a Microtúbulos/metabolismo , Neocórtex/crecimiento & desarrollo , Neocórtex/cirugía , Neurogénesis/genética , Neuronas/inmunología , Neuronas/metabolismo , Neuropéptidos/genética , Neuropéptidos/inmunología , Esclerosis Tuberosa/inmunología , Esclerosis Tuberosa/cirugía
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