RESUMEN
The occurrence of a spontaneous nephropathy with intranuclear inclusions in laboratory mice has puzzled pathologists for over 4 decades, because its etiology remains elusive. The condition is more severe in immunodeficient animals, suggesting an infectious cause. Using metagenomics, we identify the causative agent as an atypical virus, termed "mouse kidney parvovirus" (MKPV), belonging to a divergent genus of Parvoviridae. MKPV was identified in animal facilities in Australia and North America, is transmitted via a fecal-oral or urinary-oral route, and is controlled by the adaptive immune system. Detailed analysis of the clinical course and histopathological features demonstrated a stepwise progression of pathology ranging from sporadic tubular inclusions to tubular degeneration and interstitial fibrosis and culminating in renal failure. In summary, we identify a widely distributed pathogen in laboratory mice and establish MKPV-induced nephropathy as a new tool for elucidating mechanisms of tubulointerstitial fibrosis that shares molecular features with chronic kidney disease in humans.
Asunto(s)
Nefritis Intersticial/virología , Parvovirus/aislamiento & purificación , Parvovirus/patogenicidad , Animales , Australia , Progresión de la Enfermedad , Femenino , Fibrosis/patología , Fibrosis/virología , Humanos , Riñón/metabolismo , Riñón/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Nefritis Intersticial/fisiopatología , América del Norte , Infecciones por Parvoviridae/metabolismoRESUMEN
Low birth weight is a risk factor for chronic kidney disease, whereas adult podocyte depletion is a key event in the pathogenesis of glomerulosclerosis. However, whether low birth weight due to poor maternal nutrition is associated with low podocyte endowment and glomerulosclerosis in later life is not known. Female Sprague-Dawley rats were fed a normal-protein diet (NPD; 20%) or low-protein diet (LPD; 8%), to induce low birth weight, from 3 wk before mating until postnatal day 21 (PN21), when kidneys from some male offspring were taken for quantitation of podocyte number and density in whole glomeruli using immunolabeling, tissue clearing, and confocal microscopy. The remaining offspring were fed a normal- or high-fat diet until 6 mo to induce catch-up growth and excessive weight gain, respectively. At PN21, podocyte number per glomerulus was 15% lower in low birth weight (LPD) than normal birth weight (NPD) offspring, with this deficit greater in outer glomeruli. Surprisingly, podocyte number in LPD offspring increased in outer glomeruli between PN21 and 6 mo, although an overall 9% podocyte deficit persisted. Postnatal fat feeding to LPD offspring did not alter podometric indexes or result in glomerular pathology at 6 mo, whereas fat feeding in NPD offspring was associated with far greater body and fat mass as well as podocyte loss, reduced podocyte density, albuminuria, and glomerulosclerosis. This is the first report that maternal diet can influence podocyte endowment. Our findings provide new insights into the impact of low birth weight, podocyte endowment, and postnatal weight on podometrics and kidney health in adulthood.NEW & NOTEWORTHY The present study shows, for the first time, that low birth weight as a result of maternal nutrition is associated with low podocyte endowment. However, a mild podocyte deficit at birth did not result in glomerular pathology in adulthood. In contrast, postnatal podocyte loss in combination with excessive body weight led to albuminuria and glomerulosclerosis. Taken together, these findings provide new insights into the associations between birth weight, podocyte indexes, postnatal weight, and glomerular pathology.
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Tamaño Corporal/fisiología , Enfermedades Renales/patología , Podocitos/patología , Efectos Tardíos de la Exposición Prenatal/patología , Animales , Peso al Nacer/fisiología , Femenino , Riñón/patología , Glomérulos Renales/patología , Embarazo , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Acute kidney injury due to glomerular bleeding has been described with IgA nephropathy and supratherapeutic warfarin anticoagulation. There is usually demonstrable tubular obstruction by erythrocyte casts associated with acute tubular injury. Although severe thrombocytopaenia increases the risk of bleeding, most cases of haematuria have been ascribed to non-glomerular or urological bleeding without a direct link to acute kidney injury. We describe a patient with acute kidney injury due to glomerular bleeding and tubular injury related to severe thrombocytopaenia, who was subsequently found to have thin basement membrane disease. CASE PRESENTATION: A 56 year old man presented with macroscopic haematuria, acute kidney injury and a platelet count of 35 × 10(9)/L, in the absence of anticoagulation. Urinalysis demonstrated an active urinary sediment. His kidney biopsy demonstrated extensive intraluminal erythrocyte casts associated with acute tubular injury, along with haemosiderin deposition suggestive of recurrent glomerular bleeding. There was no histological evidence of glomerular pathology but electron microscopy analysis demonstrated thin basement membrane disease and effacement of podocyte foot processes. During long term follow-up, thrombocytopaenia and intermittent haematuria persisted. At 9 months, the patient progressed to Stage 5 chronic kidney disease with the development of gross renal atrophy. CONCLUSION: Recurrent macroscopic haematuria may be a risk factor for progressive renal injury in patients with thin basement membrane. The mechanism may be due to recurrent acute kidney injury from glomerular bleeding leading to repeated tubular damage. In the absence of anticoagulation, severe thrombocytopaenia may be a risk factor for heavy glomerular bleeding and acute kidney injury in these patients.
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Lesión Renal Aguda/diagnóstico , Lesión Renal Aguda/etiología , Hematuria/complicaciones , Hematuria/diagnóstico , Trombocitopenia/complicaciones , Trombocitopenia/diagnóstico , Lesión Renal Aguda/terapia , Diagnóstico Diferencial , Agregación Eritrocitaria , Hematuria/terapia , Humanos , Masculino , Persona de Mediana Edad , Trombocitopenia/terapiaRESUMEN
Immune checkpoint inhibitors that overcome T cell suppressive mechanisms in tumors have revolutionized the treatment of cancer but are only efficacious in a small subset of patients. Targeting suppressive mechanisms acting on innate immune cells could significantly improve the incidence of clinical response by facilitating a multi-lineage response against the tumor involving both adaptive and innate immune systems. Here, we show that intra-tumoral interleukin (IL)-38 expression is a feature of a large frequency of head and neck, lung and cervical squamous cancers and correlates with reduced immune cell numbers. We generated IMM20324, an antibody that binds human and mouse IL-38 proteins and inhibits the binding of IL-38 to its putative receptors, interleukin 1 receptor accessory protein-like 1 (IL1RAPL) and IL-36R. In vivo, IMM20324 demonstrated a good safety profile, delayed tumor growth in a subset of mice in an EMT6 syngeneic model of breast cancer, and significantly inhibited tumor expansion in a B16.F10 melanoma model. Notably, IMM20324 treatment resulted in the prevention of tumor growth following re-implantation of tumor cells, indicating the induction of immunological memory. Furthermore, exposure of IMM20324 correlated with decreased tumor volume and increased levels of intra-tumoral chemokines. Together, our data suggest that IL-38 is expressed in a high frequency of cancer patients and allows tumor cells to suppress anti-tumor immunity. Blockade of IL-38 activity using IMM20324 can re-activate immunostimulatory mechanisms in the tumor microenvironment leading to immune infiltration, the generation of tumor-specific memory and abrogation of tumor growth.
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Melanoma Experimental , Linfocitos T , Humanos , Ratones , Animales , Melanoma Experimental/tratamiento farmacológico , Memoria Inmunológica , Microambiente Tumoral , Línea Celular Tumoral , InterleucinasRESUMEN
Australia's Indigenous people have high rates of chronic kidney disease and kidney failure. To define renal disease among these people, we reviewed 643 renal biopsies on Indigenous people across Australia, and compared them with 249 biopsies of non-Indigenous patients. The intent was to reach a consensus on pathological findings and terminology, quantify glomerular size, and establish and compare regional biopsy profiles. The relative population-adjusted biopsy frequencies were 16.9, 6.6, and 1, respectively, for Aboriginal people living remotely/very remotely, for Torres Strait Islander people, and for non-remote-living Aboriginal people. Indigenous people more often had heavy proteinuria and renal failure at biopsy. No single condition defined the Indigenous biopsies and, where biopsy rates were high, all common conditions were in absolute excess. Indigenous people were more often diabetic than non-Indigenous people, but diabetic changes were still present in fewer than half their biopsies. Their biopsies also had higher rates of segmental sclerosis, post-infectious glomerulonephritis, and mixed morphologies. Among the great excess of biopsies in remote/very remote Aborigines, females predominated, with younger age at biopsy and larger mean glomerular volumes. Glomerulomegaly characterized biopsies with mesangiopathic changes only, with IgA deposition, or with diabetic change, and with focal segmental glomerulosclerosis (FSGS). This review reveals great variations in biopsy rates and findings among Indigenous Australians, and findings refute the prevailing dogma that most indigenous renal disease is due to diabetes. Glomerulomegaly in remote/very remote Aboriginal people is probably due to nephron deficiency, in part related to low birth weight, and probably contributes to the increased susceptibility to kidney disease and the predisposition to FSGS.
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Enfermedades Renales/etnología , Riñón/patología , Nativos de Hawái y Otras Islas del Pacífico , Adulto , Australia/epidemiología , Biopsia , Estudios de Casos y Controles , Distribución de Chi-Cuadrado , Comorbilidad , Susceptibilidad a Enfermedades , Femenino , Glomerulonefritis/etnología , Glomerulonefritis/patología , Humanos , Incidencia , Enfermedades Renales/patología , Fallo Renal Crónico/etnología , Fallo Renal Crónico/patología , Glomérulos Renales/patología , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Características de la Residencia , Factores de Riesgo , Terminología como Asunto , Factores de TiempoRESUMEN
Monoclonal antibodies are an efficacious therapy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, rapid viral mutagenesis led to escape from most of these therapies, outlining the need for an antibody cocktail with a broad neutralizing potency. Using an unbiased interrogation of the memory B cell repertoire of patients with convalescent COVID-19, we identified human antibodies with broad antiviral activity in vitro and efficacy in vivo against all tested SARS-CoV-2 variants of concern, including Delta and Omicron BA.1 and BA.2. Here, we describe an antibody cocktail, IMM-BCP-01, that consists of three patient-derived broadly neutralizing antibodies directed at nonoverlapping surfaces on the SARS-CoV-2 Spike protein. Two antibodies, IMM20184 and IMM20190, directly blocked Spike binding to the ACE2 receptor. Binding of the third antibody, IMM20253, to its cryptic epitope on the outer surface of RBD altered the conformation of the Spike Trimer, promoting the release of Spike monomers. These antibodies decreased Omicron SARS-CoV-2 infection in the lungs of Syrian golden hamsters in vivo and potently induced antiviral effector response in vitro, including phagocytosis, ADCC, and complement pathway activation. Our preclinical data demonstrated that the three-antibody cocktail IMM-BCP-01 could be a promising means for preventing or treating infection of SARS-CoV-2 variants of concern, including Omicron BA.1 and BA.2, in susceptible individuals.
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COVID-19 , SARS-CoV-2 , Animales , Anticuerpos Antivirales , Cricetinae , Humanos , Glicoproteína de la Espiga del Coronavirus/genéticaRESUMEN
Action myoclonus-renal failure syndrome (AMRF) is an autosomal-recessive disorder with the remarkable combination of focal glomerulosclerosis, frequently with glomerular collapse, and progressive myoclonus epilepsy associated with storage material in the brain. Here, we employed a novel combination of molecular strategies to find the responsible gene and show its effects in an animal model. Utilizing only three unrelated affected individuals and their relatives, we used homozygosity mapping with single-nucleotide polymorphism chips to localize AMRF. We then used microarray-expression analysis to prioritize candidates prior to sequencing. The disorder was mapped to 4q13-21, and microarray-expression analysis identified SCARB2/Limp2, which encodes a lysosomal-membrane protein, as the likely candidate. Mutations in SCARB2/Limp2 were found in all three families used for mapping and subsequently confirmed in two other unrelated AMRF families. The mutations were associated with lack of SCARB2 protein. Reanalysis of an existing Limp2 knockout mouse showed intracellular inclusions in cerebral and cerebellar cortex, and the kidneys showed subtle glomerular changes. This study highlights that recessive genes can be identified with a very small number of subjects. The ancestral lysosomal-membrane protein SCARB2/LIMP-2 is responsible for AMRF. The heterogeneous pathology in the kidney and brain suggests that SCARB2/Limp2 has pleiotropic effects that may be relevant to understanding the pathogenesis of other forms of glomerulosclerosis or collapse and myoclonic epilepsies.
Asunto(s)
Cromosomas Humanos Par 4/genética , Genes Recesivos , Glomerulonefritis/genética , Proteínas de Membrana de los Lisosomas/genética , Epilepsias Mioclónicas Progresivas/genética , Receptores Depuradores/genética , Animales , Corteza Cerebelosa/patología , Mapeo Cromosómico , Expresión Génica , Ligamiento Genético , Genotipo , Glomerulonefritis/patología , Humanos , Ratones , Ratones Noqueados , Epilepsias Mioclónicas Progresivas/patología , Análisis de Secuencia por Matrices de OligonucleótidosRESUMEN
A 28-year-old Costa Rican woman presented with a 6-year history of an asymptomatic progressive localized livedo racemosa on her limbs. Histological examination revealed a lymphocytic vasculitis targeting the arterioles in the deep dermis. In addition, a distinct hyalinised fibrin ring was noted at the periphery of the vessel lumen. These findings were consistent with the recently described entity known as lymphocytic thrombophilic arteritis. An extensive array of investigations did not show any underlying systemic disease, and the patient has remained in good health without treatment.
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Arteritis/complicaciones , Arteritis/patología , Enfermedades Cutáneas Vasculares/complicaciones , Enfermedades Cutáneas Vasculares/patología , Adulto , Femenino , HumanosRESUMEN
Patients who recover from SARS-CoV-2 infections produce antibodies and antigen-specific T cells against multiple viral proteins. Here, an unbiased interrogation of the anti-viral memory B cell repertoire of convalescent patients has been performed by generating large, stable hybridoma libraries and screening thousands of monoclonal antibodies to identify specific, high-affinity immunoglobulins (Igs) directed at distinct viral components. As expected, a significant number of antibodies were directed at the Spike (S) protein, a majority of which recognized the full-length protein. These full-length Spike specific antibodies included a group of somatically hypermutated IgMs. Further, all but one of the six COVID-19 convalescent patients produced class-switched antibodies to a soluble form of the receptor-binding domain (RBD) of S protein. Functional properties of anti-Spike antibodies were confirmed in a pseudovirus neutralization assay. Importantly, more than half of all of the antibodies generated were directed at non-S viral proteins, including structural nucleocapsid (N) and membrane (M) proteins, as well as auxiliary open reading frame-encoded (ORF) proteins. The antibodies were generally characterized as having variable levels of somatic hypermutations (SHM) in all Ig classes and sub-types, and a diversity of VL and VH gene usage. These findings demonstrated that an unbiased, function-based approach towards interrogating the COVID-19 patient memory B cell response may have distinct advantages relative to genomics-based approaches when identifying highly effective anti-viral antibodies directed at SARS-CoV-2.
RESUMEN
BACKGROUND: Ischaemia/reperfusion (I/R) is an important factor in delayed graft function in renal transplantation and is a determinant of long-term graft outcome. This study examined the role of c-Jun N-terminal kinase (JNK) signalling in human and experimental renal I/R injury. METHODS: Biopsies obtained 15-20 min after reperfusion of human renal allografts were examined for JNK signalling by immunostaining for phospho-c-Jun. To examine the pathologic role of JNK signalling, a selective JNK inhibitor (CC-401) was administered to rats before or after the induction of a 30-min period of bilateral renal ischaemia followed by reperfusion. Renal function and tubular damage were analysed. RESULTS: Substantial JNK activation was evident in tubular epithelial cells in kidneys from deceased donors (n = 30) which was less prominent in kidneys from live donors (n = 7) (44.6 +/- 24.8% vs 29.1 +/- 20% p-c-Jun+, respectively; P < 0.05), whereas biopsies of thin basement membrane disease exhibited little, or no, p-c-Jun staining. The degree of p-c-Jun staining correlated with ischaemic time in deceased donor allografts, but not with graft function. Administration of CC-401 to rats prior to bilateral renal I/R prevented acute renal failure and largely prevented tubular damage, leucocyte infiltration and upregulation of pro-inflammatory molecules. However, delaying CC-401 treatment until 1 h after reperfusion (after the peak of JNK activation) had no protective effect. CONCLUSIONS: We have identified acute activation of the JNK signalling pathway following I/R in human kidney allografts. Experimental studies indicate that blockade of JNK signalling, commenced prior to this activation, can prevent acute tubular necrosis and renal dysfunction secondary to I/R injury.
Asunto(s)
Lesión Renal Aguda/prevención & control , Modelos Animales de Enfermedad , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Daño por Reperfusión/metabolismo , Daño por Reperfusión/prevención & control , Lesión Renal Aguda/complicaciones , Lesión Renal Aguda/terapia , Animales , Western Blotting , Humanos , Técnicas para Inmunoenzimas , Mediadores de Inflamación/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos/antagonistas & inhibidores , Trasplante de Riñón , Masculino , Pirazolonas/farmacología , ARN Mensajero/genética , Ratas , Ratas Sprague-Dawley , Daño por Reperfusión/etiología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de SeñalRESUMEN
RIPK1 has emerged as a key effector in programmed necrosis or necroptosis. This function of RIPK1 is mediated by its protein serine/threonine kinase activity and through the downstream kinase RIPK3. Deletion of RIPK1 prevents embryonic lethality in mice lacking FADD, a signaling adaptor protein required for activation of Caspase 8 in extrinsic apoptotic pathways. This indicates that FADD-mediated apoptosis inhibits RIPK1-dependent necroptosis to ensure successful embryogenesis. However, the molecular mechanism for this critical regulation remains unclear. In the current study, a novel mouse model has been generated, by disrupting a potential caspase cleavage site at aspartic residue (D)324 in RIPK1. Interestingly, replacing D324 with alanine (A) in RIPK1 results in midgestation lethality, similar to the embryonic defect in FADD-/- mice but in stark contrast to the normal embryogenesis of RIPK1-/- null mutant mice. Surprisingly, disrupting the downstream RIPK3 alone is insufficient to rescue RIPK1D324A/D324A mice from embryonic lethality, unless FADD is deleted simultaneously. Further analyses reveal a paradoxical role for RIPK1 in promoting caspase activation and apoptosis in embryos, a novel mechanism previously unappreciated.
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Apoptosis/genética , Desarrollo Embrionario/genética , Necroptosis/genética , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Animales , Apoptosis/efectos de los fármacos , Caspasa 8/metabolismo , Proteína de Dominio de Muerte Asociada a Fas/genética , Fibroblastos , Genes Letales , Linfadenopatía/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mutación , Necroptosis/efectos de los fármacos , Proteína Serina-Treonina Quinasas de Interacción con Receptores/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Esplenomegalia/genética , Linfocitos T , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
TRADD is an adaptor for TNFR1-induced apoptosis and NFκB activation. However, TRADD-deficient mice undergo normal development and contain normal lymphoid populations, which contrasts with an embryonic defect in mice lacking FADD, the shared adaptor mediating apoptosis. Recent studies indicate FADD suppresses embryonic necroptosis mediated by RIPK1. TRADD was suggested to also mediate necroptosis. Here we report that targeting TRADD fails to rescue Fadd-/- embryos from necroptosis, and ablation of TRADD rescues Ripk1-/- mice from perinatal lethality when RIPK3-mediated necroptosis is disabled. The resulting Ripk1-/-Ripk3-/-Tradd-/- mice survive until early adulthood, but die thereafter. A single allele of Tradd is optimal for survival of Ripk1-/-Ripk3-/-Tradd+/- mice. We show that TRADD plays a more dominating role in NFκB-signaling than RIPK1. While RIPK1 protects thymocytes from TNFα-induced apoptosis, TRADD promotes this process. The data demonstrate that TRADD is critical in perinatal and adult mice lacking RIPK1 and RIPK3, which has not been appreciated in prior studies.
Asunto(s)
Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Proteína de Dominio de Muerte Asociada a Receptor de TNF/metabolismo , Animales , Apoptosis/efectos de los fármacos , Caspasa 8/genética , Caspasa 8/metabolismo , Muerte Celular , Proliferación Celular/efectos de los fármacos , Proteína de Dominio de Muerte Asociada a Fas/metabolismo , Fibroblastos , Eliminación de Gen , Regulación de la Expresión Génica , Intestinos/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , FN-kappa B , Necrosis , Proteína Serina-Treonina Quinasas de Interacción con Receptores/genética , Proteína Serina-Treonina Quinasas de Interacción con Receptores/farmacología , Transducción de Señal , Análisis de Supervivencia , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo , Proteína de Dominio de Muerte Asociada a Receptor de TNF/genética , Proteína de Dominio de Muerte Asociada a Receptor de TNF/farmacología , Timocitos/efectos de los fármacos , Transcriptoma , Factor de Necrosis Tumoral alfaRESUMEN
Daxx was originally isolated as a Fas-binding protein. However, the in vivo function of Daxx in Fas-induced apoptosis has remained enigmatic. Fas plays an important role in homeostasis in the immune system. Fas gene mutations lead to autoimmune-lymphoproliferation (lpr) diseases characterized by hyperplasia of secondary lymphoid organs. It is well established that the FADD adaptor binds to Fas, and recruits/activates caspase 8. However, additional proteins including Daxx have also been indicated to associate with Fas. It was proposed that Daxx mediates a parallel apoptotic pathway that is independent of FADD and caspase 8, but signals through ASK1-mediated apoptotic pathway. However, because the deletion of Daxx leads to embryonic lethality, the in vivo function of Daxx has not been properly analyzed. In the current study, analysis was performed using a conditional mutant mouse in which Daxx was deleted specifically in T cells. The data show that Daxx-/- T cells were able to undergo normal Fas-induced apoptosis. While containing normal thymocyte populations, the T cell-specific Daxx-/- mice have a reduced peripheral T cell pool. Importantly, Daxx-deficient T cells displayed increased death responses upon activation through TCR stimulation. These results unequivocally demonstrated that Daxx does not mediate Fas-induced apoptosis, but rather that it plays a critical role in survival responses in primary mature T cells.
Asunto(s)
Apoptosis/fisiología , Proteínas Portadoras/fisiología , Supervivencia Celular/fisiología , Péptidos y Proteínas de Señalización Intracelular/fisiología , Proteínas Nucleares/fisiología , Linfocitos T/citología , Receptor fas/metabolismo , Animales , Proteínas Portadoras/metabolismo , Proliferación Celular , Proteínas Co-Represoras , Citometría de Flujo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ratones , Ratones Transgénicos , Chaperonas Moleculares , Proteínas Nucleares/metabolismoRESUMEN
A 28-year-old woman underwent peripheral-blood stem cell transplantation from her HLA-identical sister for cytogenetic progression of Fanconi anemia. She had received a living-related renal allograft from her father 2 years previously. Nine days after peripheral-blood stem cell transplantation, she developed acute renal failure secondary to acute rejection. Severe microangiopathic hemolysis developed, and cyclosporine therapy was discontinued. Renal biopsy showed humoral rejection and thrombotic microangiopathy. Despite daily plasmapheresis and immunosuppression, she remained dialysis dependent. The renal graft was removed, with rapid resolution of microangiopathic hemolysis. At no stage was there evidence of acute graft-versus-host disease. We speculate that the engrafting third-party hematopoiesis produced acute renal allograft rejection with secondary microangiopathic hemolysis through a graft-versus-graft mechanism.
Asunto(s)
Lesión Renal Aguda/etiología , Anemia de Fanconi/cirugía , Rechazo de Injerto/inmunología , Trasplante de Riñón/inmunología , Trasplante de Células Madre de Sangre Periférica , Lesión Renal Aguda/patología , Adulto , Anemia Hemolítica/etiología , Anemia Hemolítica/inmunología , Epítopos , Anemia de Fanconi/inmunología , Femenino , Rechazo de Injerto/patología , Hematopoyesis/inmunología , Prueba de Histocompatibilidad , Humanos , Linfocitos/inmunología , Reoperación , Trasplante HomólogoRESUMEN
OBJECTIVES: To investigate the spectrum of growth rates in melanomas and to identify clinical associations of rapidly growing melanomas. DESIGN: Clinical interview, skin examination, and pathology review. SETTING: Three tertiary melanoma referral centers and 2 private dermatology practices. PATIENTS: A total of 404 consecutive patients with invasive primary cutaneous melanomas. MAIN OUTCOME MEASURE: A surrogate for rate of growth in primary invasive melanoma was calculated as the ratio of Breslow thickness to time to melanoma development based on a previously reported assessment tool. RESULTS: One third of the melanomas grew 0.5 mm per month or more. The median monthly growth rate was 0.12 mm for superficial spreading melanomas, 0.13 mm for lentigo maligna melanomas, and 0.49 mm for nodular melanomas. Rapid tumor growth was associated with tumor thickness (
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Melanoma/patología , Neoplasias Cutáneas/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Factores Sexuales , Encuestas y CuestionariosRESUMEN
Indoleamine 2,3-dioxygenase (IDO) is a heme-containing oxidoreductase that catalyzes the initial and rate-limiting step in the breakdown of non-dietary tryptophan. The biology and immunomodulatory role for IDO is discussed in this review with a focus on its interaction with immune cells and its potential therapeutic target in the clinic. IDO has been revealed to be a central regulator of immune responses in a broad variety of physiological and pathological settings, mostly serving as a multifaceted negative feedback mechanism, to self-regulate immune responses. IDO is considered a therapeutic target in cancer and the use of IDO inhibitors as single agent or in combination with other treatment modalities are under active investigation.
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Tolerancia Inmunológica/inmunología , Inmunoterapia/métodos , Indolamina-Pirrol 2,3,-Dioxigenasa/inmunología , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Neoplasias/terapia , Inhibidores Enzimáticos/farmacología , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Terapia Molecular Dirigida , Neoplasias/inmunología , Células TH1/inmunología , Células Th2/inmunología , Microambiente Tumoral/inmunologíaRESUMEN
The death receptor, Fas, triggers apoptotic death and is essential for maintaining homeostasis in the peripheral lymphoid organs. RIP1 was originally cloned when searching for Fas-binding proteins and was later shown to associate also with the signaling complex of TNFR1. Although Fas exclusively induces apoptosis, TNFR1 primarily activates the pro-survival/pro-inflammatory NF-κB pathway. Mutations in Fas lead to lymphoproliferative (lpr) diseases, and deletion of TNFR1 results in defective innate immune responses. However, the function of RIP1 in the adult lymphoid system has not been well understood, primarily owing to perinatal lethality in mice lacking the entire RIP1 protein in germ cells. This current study investigated the requirement for RIP1 in the T lineage using viable RIP1 mutant mice containing a conditional and kinase-dead RIP1 allele. Disabling the kinase activity of RIP1 had no obvious impact on the T-cell compartment. However, T-cell-specific deletion of RIP1 led to a severe T-lymphopenic condition, owing to a dramatically reduced mature T-cell pool in the periphery. Interestingly, the immature T-cell compartment in the thymus appeared intact. Further analysis showed that mature RIP1-/- T cells were severely defective in antigen receptor-induced proliferative responses. Moreover, the RIP1-/- T cells displayed greatly increased death and contained elevated caspase activities, an indication of apoptosis. In total, these results revealed a novel, kinase-independent function of RIP1, which is essential for not only promoting TCR-induced proliferative responses but also in blocking apoptosis in mature T cells.
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Proteínas Activadoras de GTPasa/metabolismo , Linfocitos T/citología , Linfocitos T/enzimología , Animales , Apoptosis/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Eliminación de Gen , Activación de Linfocitos/inmunología , Ratones , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores de Muerte Celular/metabolismo , Linfocitos T/efectos de los fármacos , Timo/citología , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
OBJECTIVE: To determine the incidence of new, changed, and regressed nevi and melanomas in a cohort of patients at high risk for melanoma using baseline total body photography and dermatoscopy. DESIGN: Cohort study of patients at high risk for melanoma who underwent baseline cutaneous photography between January 1, 1992, and December 31, 1997, and had at least 1 follow-up visit by December 31, 1998. SETTING: Private practice rooms of 1 dermatologist in conjunction with a public hospital-based, multidisciplinary melanoma clinic in Victoria, Australia. PATIENTS: A total of 309 patients who had at least 1 of the following risk factors for melanoma: personal history, family history, 100 or more nevi, or 4 or more dysplastic nevi. MAIN OUTCOME MEASURES: Number of new, changed, and regressed nevi and melanomas detected and excised during the study interval. RESULTS: The incidence of new, changed, and regressed nevi decreased with increasing age (P<.001), whereas the incidence of melanomas increased (P = .05). The number of dysplastic nevi at baseline was positively associated with the incidence of changed nevi (P<.001) and melanomas (P = .03). The use of baseline photography and dermatoscopy was associated with low biopsy rates and early detection of melanomas. The development of melanoma in association with a preexisting nevus was not directly correlated with a change in a preexisting lesion monitored by baseline photography. CONCLUSIONS: Nevi are dynamic, and only a small percentage of all new and changed melanocytic lesions are melanomas. Patients younger than 50 years had a lower incidence of melanomas and a higher rate of new, changed, and regressed nevi when compared with patients older than 50 years. A new or changed pigmented lesion is more likely to be a melanoma in patients older than 50 years.
Asunto(s)
Dermoscopía , Melanoma/patología , Nevo/patología , Fotograbar , Neoplasias Cutáneas/patología , Adolescente , Adulto , Estudios de Cohortes , Síndrome del Nevo Displásico/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nevo Pigmentado/patología , Remisión Espontánea , Factores de RiesgoRESUMEN
Action myoclonus-renal failure syndrome (AMRF) is a distinctive form of progressive myoclonus epilepsy associated with renal dysfunction. The syndrome was not recognized prior to the advent of dialysis and renal transplantation because of its rapidly fatal course if renal failure is untreated. The first and only description of AMRF was in four French Canadian patients in three families (Andermann et al., 1986). We now describe 15 individuals with AMRF from five countries, including a follow-up of the four French Canadian patients, allowing a more complete characterization of this disease. Our 15 patients with AMRF belong to nine different families. Segregation analyses were compatible with autosomal recessive inheritance. In addition, our findings show that AMRF can present with either renal or neurological features. Tremor (onset 17-26 years, mean 19.8 years, median 19 years) and progressively disabling action myoclonus (onset 14-29 years, mean 21.7 years, median 21 years), with infrequent generalized seizures (onset 20-28 years, mean 22.7 years, median 22 years) and cerebellar features are characteristic. Proteinuria, detected between ages 9 and 30 years in all cases, progressed to renal failure in 12 out of 15 patients within 0-8 years after proteinuria detection. Brain autopsy in two patients revealed extraneuronal pigment accumulation. Renal biopsies showed collapsing glomerulopathy, a severe variant of focal glomerulosclerosis. This study extends the AMRF phenotype, and demonstrates a more extensive ethnic and geographic distribution of a syndrome originally believed to be confined to individuals of French Canadian ancestry. The independent progression of neurological and renal disorders in AMRF suggests a unitary molecular lesion with pleiotropic effects. Our results demonstrate that the renal lesion in AMRF is a recessive form of collapsing glomerulopathy. Genes identified for focal segmental glomerulosclerosis and involved with the function of the glomerular basement membrane and related proteins are thus good candidates. Treatment can improve quality of life and extend the lifespan of these patients. Dialysis and renal transplantation are effective for the renal but not the neurological features, which continue to progress even in the presence of normalized renal function; the latter can be managed with anti-myoclonic and anti-epileptic drugs.