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1.
Immunity ; 53(3): 672-684.e11, 2020 09 15.
Artículo en Inglés | MEDLINE | ID: covidwho-797268

RESUMEN

Autoinflammatory disease can result from monogenic errors of immunity. We describe a patient with early-onset multi-organ immune dysregulation resulting from a mosaic, gain-of-function mutation (S703I) in JAK1, encoding a kinase essential for signaling downstream of >25 cytokines. By custom single-cell RNA sequencing, we examine mosaicism with single-cell resolution. We find that JAK1 transcription was predominantly restricted to a single allele across different cells, introducing the concept of a mutational "transcriptotype" that differs from the genotype. Functionally, the mutation increases JAK1 activity and transactivates partnering JAKs, independent of its catalytic domain. S703I JAK1 is not only hypermorphic for cytokine signaling but also neomorphic, as it enables signaling cascades not canonically mediated by JAK1. Given these results, the patient was treated with tofacitinib, a JAK inhibitor, leading to the rapid resolution of clinical disease. These findings offer a platform for personalized medicine with the concurrent discovery of fundamental biological principles.


Asunto(s)
Enfermedades Autoinflamatorias Hereditarias/genética , Enfermedades Autoinflamatorias Hereditarias/patología , Janus Quinasa 1/genética , Síndrome de Respuesta Inflamatoria Sistémica/genética , Síndrome de Respuesta Inflamatoria Sistémica/patología , Adolescente , COVID-19/mortalidad , Dominio Catalítico/genética , Línea Celular , Citocinas/metabolismo , Femenino , Mutación con Ganancia de Función/genética , Genotipo , Células HEK293 , Enfermedades Autoinflamatorias Hereditarias/tratamiento farmacológico , Humanos , Janus Quinasa 1/antagonistas & inhibidores , Mosaicismo , Piperidinas/uso terapéutico , Medicina de Precisión/métodos , Pirimidinas/uso terapéutico , Transducción de Señal/inmunología , Síndrome de Respuesta Inflamatoria Sistémica/tratamiento farmacológico
2.
J Pediatr Gastroenterol Nutr ; 71(2): 153-155, 2020 08.
Artículo en Inglés | MEDLINE | ID: covidwho-729245

RESUMEN

Coronavirus disease 2019 (COVID-19) may lead to a severe inflammatory response referred to as a cytokine storm. We describe a case of severe COVID-19 infection in a recently diagnosed pediatric Crohn disease patient successfully treated with tumor necrosis factor-alpha (TNF-α) blockade. The patient presented with 5 days of fever, an erythematous maculopapular facial rash, and abdominal pain without respiratory symptoms. SARS-CoV-2 polymerase chain reaction was positive. Despite inpatient treatment for COVID-19 and a perianal abscess, the patient acutely decompensated, with worsening fever, tachycardia, fluid-refractory hypotension, elevation of liver enzymes, and transformation of the rash into purpura extending from the face to the trunk, upper and lower extremities, including the palmar and plantar surfaces of the hands and feet. Cytokine profile revealed rising levels of interleukin (IL)-6, IL-8, and TNF-α, higher than those described in either inflammatory bowel disease or severe COVID-19 alone. The patient was treated with infliximab for TNF-α blockade to address both moderately to severely active Crohn disease and multisystem inflammatory syndrome in children temporally related to COVID-19. Within hours of infliximab treatment, fever, tachycardia, and hypotension resolved. Cytokine profile improved with normalization of TNF-α, a decrease in IL-6, and IL-8 concentrations. This case supports a role for blockade of TNF-α in the treatment of COVID-19 inflammatory cascade. The role of anti-TNF agents in patients with multisystem inflammatory syndrome in children temporally related to COVID-19 requires further investigation.


Asunto(s)
Infecciones por Coronavirus/tratamiento farmacológico , Enfermedad de Crohn/complicaciones , Enfermedades Genéticas Ligadas al Cromosoma X/complicaciones , Eritrodermia Ictiosiforme Congénita/complicaciones , Infliximab/uso terapéutico , Interleucina-6/sangre , Interleucina-8/sangre , Deformidades Congénitas de las Extremidades/complicaciones , Neumonía Viral/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Anomalías Múltiples , Adolescente , Antirreumáticos/uso terapéutico , Betacoronavirus , COVID-19 , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/virología , Humanos , Masculino , Pandemias , Neumonía Viral/complicaciones , Neumonía Viral/virología , SARS-CoV-2 , Factor de Necrosis Tumoral alfa/sangre
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