RESUMEN
Inflammasome complexes function as key innate immune effectors that trigger inflammation in response to pathogen- and danger-associated signals. Here, we report that germline mutations in the inflammasome sensor NLRP1 cause two overlapping skin disorders: multiple self-healing palmoplantar carcinoma (MSPC) and familial keratosis lichenoides chronica (FKLC). We find that NLRP1 is the most prominent inflammasome sensor in human skin, and all pathogenic NLRP1 mutations are gain-of-function alleles that predispose to inflammasome activation. Mechanistically, NLRP1 mutations lead to increased self-oligomerization by disrupting the PYD and LRR domains, which are essential in maintaining NLRP1 as an inactive monomer. Primary keratinocytes from patients experience spontaneous inflammasome activation and paracrine IL-1 signaling, which is sufficient to cause skin inflammation and epidermal hyperplasia. Our findings establish a group of non-fever inflammasome disorders, uncover an unexpected auto-inhibitory function for the pyrin domain, and provide the first genetic evidence linking NLRP1 to skin inflammatory syndromes and skin cancer predisposition.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Reguladoras de la Apoptosis/genética , Carcinoma/genética , Predisposición Genética a la Enfermedad , Inflamasomas/metabolismo , Queratosis/genética , Neoplasias Cutáneas/genética , Proteínas Adaptadoras Transductoras de Señales/química , Secuencia de Aminoácidos , Proteínas Reguladoras de la Apoptosis/química , Carcinoma/patología , Cromosomas Humanos Par 17/genética , Epidermis/patología , Mutación de Línea Germinal , Humanos , Hiperplasia/genética , Hiperplasia/patología , Inflamasomas/genética , Interleucina-1/metabolismo , Queratosis/patología , Proteínas NLR , Comunicación Paracrina , Linaje , Dominios Proteicos , Pirina/química , Transducción de Señal , Neoplasias Cutáneas/patología , SíndromeRESUMEN
PURPOSE: To date, only silicone oils and gases have the appropriate characteristics for use in vitreo-retinal surgery as vitreous substitutes with intraocular tamponading properties. This preliminary study evaluated the safety and efficacy of medium-chain triglycerides (MCTs) for use as a tamponading agent in minipigs. METHODS: In 15 minipigs, 15 right eyes underwent vitrectomies followed by injection of MCT tamponade (day 1). Two groups were defined. In Group A (ten eyes), the surgical procedure before MCT injection included induced rhegmatogenous retinal detachment (RRD), retina flattening, and retinopexy. In Group B (five eyes), MCT was injected without inducing RRD; in these eyes, MCT was removed on day 90. Pigs were sacrificed on day 45 (Group A) or 120 (Group B). Eyes were examined on days 1, 5, 15, and 45 in both groups and on days 90 and 120 in Group B. In Group B only, we performed bilateral electroretinography examinations on days 1 and 120, and histological examinations of MCTs and controlateral eyes were performed after sacrifice. RESULTS: In Group A eyes (n = 9; one eye was non-assessable), on day 45, the retina was flat in seven eyes and two RRD detachments were observed in insufficiently MCT-filled eyes. In Group B, electroretinography showed no significant differences between MCT eyes and controls on days 1 or 120. Histological analyses revealed no signs of retinal toxicity. CONCLUSIONS: This study showed that MCT tamponade seems to be effective and safe; however, additional studies are needed before it becomes commonly used as a tamponading agent in humans.
Asunto(s)
Endotaponamiento/métodos , Retina/cirugía , Desprendimiento de Retina/cirugía , Triglicéridos/administración & dosificación , Vitrectomía/métodos , Animales , Modelos Animales de Enfermedad , Electrorretinografía , Masculino , Microscopía Electrónica , Retina/fisiopatología , Retina/ultraestructura , Desprendimiento de Retina/diagnóstico , Desprendimiento de Retina/fisiopatología , Porcinos , Porcinos Enanos , Resultado del Tratamiento , Agudeza VisualRESUMEN
PURPOSE: To describe the surgical management of bilateral giant full-thickness macular hole with sudden onset two months after cataract surgery in a patient with Alport syndrome. METHODS: Observational, single-case report. RESULTS: A 54-year-old female with a history of Alport syndrome presented with severe bilateral visual loss two months after cataract surgery. The diagnosis of bilateral giant full-thickness macular hole was made. We found the absence of the internal limiting membrane and the inability to lift and peel a continuous posterior hyaloid sheet during surgical management with 25-gauge pars plana vitrectomy (left eye). Amniotic membrane grafting followed by gas tamponade were performed for hole closure. The hole remained closed but vision was poorly restored two months after. CONCLUSION: Cataract surgery in patients with Alport syndrome could promote early development of giant full-thickness macular hole. Collagen defects could underlie internal limiting membrane absence and the inability to properly peel the posterior hyaloid.