Mutaciones bialélicas en RIPK3 en un paciente con encefalitis herpética

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Medicina, leída el 17/12/2020Life-threatening herpes simplex virus encephalitis (HSE) is the most common form of sporadic viral encephalitis worldwide. A diverse collection of genetic etiologies can predispose to this condition: inborn errors of the TLR3 responsive pathway impair central nervous system (CNS) cortical neuron- and oligodendrocyte-intrinsic immunity to herpes simplex virus type 1 (HSV-1) and underlie forebrain HSE; heterozygous SNORA31 variants have also been associated with forebrain HSE; last, genetic defects of RNA lariat metabolism, due to mutations in DBR1, can trigger brainstem HSE. Still, the vast majority of HSE patients enrolled in our cohort lack a genetic diagnose. Here, we report autosomal recessive RIPK3 deficiency in a patient with recurrent forebrain HSE. The patient is compound heterozygous for one nonsense and one frameshift RIPK3 mutations that lead to impaired protein expression and function of RIPK3 via distinct mechanisms. We show that the patient’s fibroblasts do not phosphorylate MLKL upon stimulation via TNFR1 or TLR3, while the production of IFN-b or -l was normal upon TLR3 activation. We further demonstrate that the TLR3-induced RIPK3-dependent necroptosis signaling cascade is selectively impaired in fibroblasts from previously described patients with TLR3 pathway deficiencies. Taken together, our findings suggest that RIPK3 deficiency predisposes to HSE, due to disruption of the TLR3-RIPK3-mediated necroptosis pathway. This novel genetic etiology expands our understanding of the TLR3 circuit as a non-redundant mechanism of antiviral immunity of the CNS in humans.La encefalitis herpética (HSE) es la forma más común de encefalitis esporádica en todo el mundo. La predisposición a esta condición está causada por un grupo heterogéneo de etiologías genéticas: Mutaciones en la vía del TLR3 dañan a la inmunidad intrínseca de las neuronas y los oligodendrocitos del Sistema Nervioso Central (SNC) frente al virus del herpes simple tipo 1 (VHS-1) y son responsables de ciertos casos de encefalitis herpética en el lóbulo frontal. Del mismo modo, mutaciones heterocigóticas en SNORA31 también ha sido asociadas con la encefalitis herpética frontal; por último, defectos genéticos del metabolismo de los lazos de ARN, causados por mutaciones en DBR1, pueden causar encefalitis herpética en el tallo cerebral. Sin embargo, la mayor parte de los pacientes de nuestra cohorte de pacientes con encefalitis herpética no tiene una etiología genética identificada. Aquí describimos un paciente con encefalitis herpética con deficiencia en RIPK3 autosómica recesiva. El paciente es heterocigoto compuesto por una mutación nonsense y una mutación frameshift que conducen a la pérdida de expresión y función de la proteína mediante distintos mecanismos. Nuestros resultados muestran que los fibroblastos del paciente no fosforilan MLKL tras la estimulación de la vía del TLR3 y la del TNFR1. Sin embargo, la producción de interferones b y l es normal tras la activación del TLR3. También demostramos que la vía inducida por el TLR3 y mediada por RIPK3 está selectivamente dañada en fibroblastos de pacientes previamente descritos con mutaciones en la ruta del TLR3. Esto sugiere que deficiencia en RIPK3 predispone a la encefalitis herpética y que lo hace de forma dependiente del TLR3. Esta nueva etiología genética expande nuestro conocimiento sobre el papel del circuito gobernado por el TLR3 como un mecanismo no redundante en la inmunidad antiviral del SNC en humanos.Fac. de MedicinaTRUEunpu

Switching TNF antagonists in patients with chronic arthritis: An observational study of 488 patients over a four-year period

The objective of this work is to analyze the survival of infliximab, etanercept and adalimumab in patients who have switched among tumor necrosis factor (TNF) antagonists for the treatment of chronic arthritis. BIOBADASER is a national registry of patients with different forms of chronic arthritis who are treated with biologics. Using this registry, we have analyzed patient switching of TNF antagonists. The cumulative discontinuation rate was calculated using the actuarial method. The log-rank test was used to compare survival curves, and Cox regression models were used to assess independent factors associated with discontinuing medication. Between February 2000 and September 2004, 4,706 patients were registered in BIOBADASER, of whom 68% had rheumatoid arthritis, 11% ankylosing spondylitis, 10% psoriatic arthritis, and 11% other forms of chronic arthritis. One- and two-year drug survival rates of the TNF antagonist were 0.83 and 0.75, respectively. There were 488 patients treated with more than one TNF antagonist. In this situation, survival of the second TNF antagonist decreased to 0.68 and 0.60 at 1 and 2 years, respectively. Survival was better in patients replacing the first TNF antagonist because of adverse events (hazard ratio (HR) for discontinuation 0.55 (95% confidence interval (CI), 0.34-0.84)), and worse in patients older than 60 years (HR 1.10 (95% CI 0.97-2.49)) or who were treated with infliximab (HR 3.22 (95% CI 2.13-4.87)). In summary, in patients who require continuous therapy and have failed to respond to a TNF antagonist, replacement with a different TNF antagonist may be of use under certain situations. This issue will deserve continuous reassessment with the arrival of new medications. © 2006 Gomez-Reino and Loreto Carmona; licensee BioMed Central Ltd