Asunto(s)
Infecciones por Coronavirus/virología , Síndrome de Liberación de Citoquinas/virología , Interleucina-6/inmunología , Neumonía Viral/virología , COVID-19 , Infecciones por Coronavirus/inmunología , Humanos , Síndrome de Activación Macrofágica/inmunología , Pandemias , Neumonía Viral/inmunologíaAsunto(s)
Humanos , Neumonía Viral/virología , Interleucina-6/inmunología , Infecciones por Coronavirus/virología , Síndrome de Liberación de Citoquinas/virología , Neumonía Viral/inmunología , Infecciones por Coronavirus/inmunología , Síndrome de Activación Macrofágica/inmunología , Pandemias , COVID-19RESUMEN
Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening hyperferritinemic systemic inflammatory disorders. Although profound cytotoxic impairment causes familial HLH (fHLH), the mechanisms driving non-fHLH and MAS are largely unknown. MAS occurs in patients with suspected rheumatic disease, but the mechanistic basis for its distinction is unclear. Recently, a syndrome of recurrent MAS with infantile enterocolitis caused by NLRC4 inflammasome hyperactivity highlighted the potential importance of interleukin-18 (IL-18). We tested this association in hyperferritinemic and autoinflammatory patients and found a dramatic correlation of MAS risk with chronic (sometimes lifelong) elevation of mature IL-18, particularly with IL-18 unbound by IL-18 binding protein, or free IL-18. In a mouse engineered to carry a disease-causing germ line NLRC4T337S mutation, we observed inflammasome-dependent, chronic IL-18 elevation. Surprisingly, this NLRC4T337S-induced systemic IL-18 elevation derived entirely from intestinal epithelia. NLRC4T337S intestines were histologically normal but showed increased epithelial turnover and upregulation of interferon-γ-induced genes. Assessing cellular and tissue expression, classical inflammasome components such as Il1b, Nlrp3, and Mefv predominated in neutrophils, whereas Nlrc4 and Il18 were distinctly epithelial. Demonstrating the importance of free IL-18, Il18 transgenic mice exhibited free IL-18 elevation and more severe experimental MAS. NLRC4T337S mice, whose free IL-18 levels were normal, did not. Thus, we describe a unique connection between MAS risk and chronic IL-18, identify epithelial inflammasome hyperactivity as a potential source, and demonstrate the pathogenicity of free IL-18. These data suggest an IL-18-driven pathway, complementary to the cytotoxic impairment of fHLH, with potential as a distinguishing biomarker and therapeutic target in MAS.
Asunto(s)
Interleucina-18/inmunología , Síndrome de Activación Macrofágica/inmunología , Transducción de Señal/inmunología , Sustitución de Aminoácidos , Animales , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/inmunología , Proteínas Adaptadoras de Señalización CARD/genética , Proteínas Adaptadoras de Señalización CARD/inmunología , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/inmunología , Humanos , Inflamasomas/genética , Inflamasomas/inmunología , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/inmunología , Interleucina-18/genética , Interleucina-1beta/genética , Interleucina-1beta/inmunología , Mucosa Intestinal/inmunología , Mucosa Intestinal/patología , Linfohistiocitosis Hemofagocítica/genética , Linfohistiocitosis Hemofagocítica/inmunología , Linfohistiocitosis Hemofagocítica/patología , Síndrome de Activación Macrofágica/genética , Síndrome de Activación Macrofágica/patología , Ratones , Ratones Noqueados , Mutación Missense , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/inmunología , Pirina/genética , Pirina/inmunología , Transducción de Señal/genéticaRESUMEN
OBJECTIVES: To identify measures distinguishing macrophage activation syndrome (MAS) in systemic juvenile idiopathic arthritis (sJIA) from familial hemophagocytic lymphohistiocytosis (FHL) and virus-associated hemophagocytic lymphohistiocytosis (VA-HLH) and to define appropriate cutoff values. To evaluate suggested dynamic measures differentiating MAS in patients with sJIA from sJIA flares. STUDY DESIGN: In a cohort of patients referred for evaluation of hemophagocytic lymphohistiocytosis, we identified 27 patients with sJIA and MAS (MAS/sJIA) fulfilling the criteria of the proposed preliminary diagnostic guideline for the diagnosis of MAS in sJIA. Ten measures at diagnosis were compared between the MAS/sJIA group and 90 patients with FHL and 42 patients with VA-HLH, and cutoff values were determined. In addition, 5 measures were analyzed for significant change from before MAS until MAS diagnosis. RESULTS: Neutrophil count and C-reactive protein were significantly higher in patients with MAS/sJIA compared with patients with FHL and patients with VA-HLH, with 1.8×10(9)/L neutrophils (sensitivity 85%, specificity 83%) and 90 mg/L C-reactive protein (74%, 89%) as cutoff values. Soluble CD25<7900 U/L (79%, 76%) indicated MAS/sJIA rather than FHL/VA-HLH. Platelet (-59%) and white blood cell count (-46%) displayed a significant decrease, and neutrophil count (-35%) and fibrinogen (-28%) showed a trend during the development of MAS. However, a substantial portion of patients had values at diagnosis of MAS within or above the normal range for white blood cells (84%), neutrophils (77%), platelets (26%), and fibrinogen (71%). CONCLUSION: Readily available measures can rapidly differentiate between MAS/sJIA and FHL/VA-HLH. The findings substantiate that a decline of measures may facilitate the distinction of MAS from flares of sJIA.