Systemic cytokines and GlycA discriminate disease status and predict corticosteroid response in HTLV-1-associated neuroinflammation

Autor(es):Mostrar menos -

Assone, Tatiane ; Menezes, Soraya Maria ; Goncalves, Fernanda de Toledo ; Folgosi, Victor Angelo ; Prates, Gabriela da Silva ; Dierckx, Tim ; Braz, Marcos ; Smid, Jerusa ; Haziot, Michel E. ; Marcusso, Rosa M. N. ; Dahy, Flavia E. ; Vanderlinden, Evelien ; Claes, Sandra ; Schols, Dominique ; Bruhn, Roberta ; Murphy, Edward L. ; Penalva de Oliveira, Augusto Cesar ; Daelemans, Dirk ; Vercauteren, Jurgen ; Casseb, Jorge ; Van Weyenbergh, Johan

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF NEUROINFLAMMATION; v. 19, n. 1, p. 15-pg., 2022-12-08.

Resumo

Background: HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) is an incapacitating neuroinflammatory disorder for which no disease-modifying therapy is available, but corticosteroids provide some clinical benefit. Although HAM/TSP pathogenesis is not fully elucidated, older age, female sex and higher proviral load are established risk factors. We investigated systemic cytokines and a novel chronic inflammatory marker, GlycA, as possible biomarkers of immunopathogenesis and therapeutic response in HAM/TSP, and examined their interaction with established risk factors. Patients and methods: We recruited 110 People living with HTLV-1 (PLHTLV-1, 67 asymptomatic individuals and 43 HAM/TSP patients) with a total of 946 person-years of clinical follow-up. Plasma cytokine levels (IL-2, IL-4, IL-6, IL-10, IL-17A, IFN-gamma, TNF) and GlycA were quantified by Cytometric Bead Array and (NMR)-N-1, respectively. Cytokine signaling and prednisolone response were validated in an independent cohort by nCounter digital transcriptomics. We used multivariable regression, machine learning algorithms and Bayesian network learning for biomarker identification. Results: We found that systemic IL-6 was positively correlated with both age (r = 0.50, p < 0.001) and GlycA (r = 0.45, p = 0.00049) in asymptomatics, revealing an 'inflammaging " signature which was absent in HAM/TSP. GlycA levels were higher in women (p = 0.0069), but cytokine levels did not differ between the sexes. IFN-gamma (p = 0.007) and IL-17A (p = 0.0001) levels were increased in untreated HAM/TSP Multivariable logistic regression identified IL-17A and proviral load as independent determinants of clinical status, resulting in modest accuracy of predicting HAM/TSP status (64.1%), while a machine learning-derived decision tree classified HAM/TSP patients with 90.7% accuracy. Pre-treatment GlycA and TNF levels significantly predicted clinical worsening (measured by Osame Motor Disability Scale), independent of proviral load. In addition, a poor prednisolone response was significantly correlated with higher post-treatment IFN-gamma levels. Likewise, a transcriptomic IFN signaling score, significantly correlated with previously proposed HAM/TSP biomarkers (CASP5/CXCL10/FCGR1A/STAT1), was efficiently blunted by in vitro prednisolone treatment of PBMC from PLHTLV-1 and incident HAM/TSP. Conclusions: An age-related increase in systemic IL-6/GlycA levels reveals inflammaging in PLHTLV-1, in the absence of neurological disease. IFN-gamma and IL-17A are biomarkers of untreated HAM/TSP, while pre-treatment GlycA and TNF predict therapeutic response to prednisolone pulse therapy, paving the way for a precision medicine approach in HAM/TSP. (AU)

• Processo FAPESP: 17/08320-5 - Identificação de polimorfismos relacionados à mielopatia associada ao HTLV-1/paraparesia espástica tropical (HAM/TSP)
• Beneficiário: Jorge Simao do Rosario Casseb
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 16/03025-2 - Identificação de polimorfismos relacionados à mielopatia associada ao HTLV-1/paraparesia espástica tropical (HAM/TSP)
• Beneficiário: Tatiane Assone Casseb
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 18/07239-2 - Incidência, fatores de risco, mecanismos patogênicos e prevenção de distúrbios neurocognitivos (HAND) entre indivíduos infectados com HIV-1
• Beneficiário: Jorge Simao do Rosario Casseb
• Modalidade de apoio: Auxílio à Pesquisa - Temático