RESUMEN
The linear ubiquitin assembly complex (LUBAC) consists of HOIP, HOIL-1 and SHARPIN and is essential for proper immune responses. Individuals with HOIP and HOIL-1 deficiencies present with severe immunodeficiency, autoinflammation and glycogen storage disease. In mice, the loss of Sharpin leads to severe dermatitis due to excessive keratinocyte cell death. Here, we report two individuals with SHARPIN deficiency who manifest autoinflammatory symptoms but unexpectedly no dermatological problems. Fibroblasts and B cells from these individuals showed attenuated canonical NF-κB responses and a propensity for cell death mediated by TNF superfamily members. Both SHARPIN-deficient and HOIP-deficient individuals showed a substantial reduction of secondary lymphoid germinal center B cell development. Treatment of one SHARPIN-deficient individual with anti-TNF therapies led to complete clinical and transcriptomic resolution of autoinflammation. These findings underscore the critical function of the LUBAC as a gatekeeper for cell death-mediated immune dysregulation in humans.
Asunto(s)
Síndromes de Inmunodeficiencia , Proteínas del Tejido Nervioso , Ubiquitinas , Humanos , Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/inmunología , Femenino , Masculino , FN-kappa B/metabolismo , Ubiquitina-Proteína Ligasas/genética , Inflamación/inmunología , Inflamación/genética , Linfocitos B/inmunología , Mutación con Pérdida de Función , Fibroblastos/metabolismo , Fibroblastos/inmunología , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Animales , Ratones , AlelosRESUMEN
A 5-year-old girl with symmetrical expansion of mandible and both maxillae, lack of eruption of several teeth an hypertrophied palate was presented to our clinic. upon detailed laboratory, imaging and histopathological evaluation, the diagnosis of "Cherubism" a rare autoinflammatory bone disease was confirmed.
