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

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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

• Document type: Journal article
• Source: JOURNAL OF NEUROINFLAMMATION; v. 19, n. 1, p. 15-pg., 2022-12-08.

Abstract

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)

• FAPESP's process: 17/08320-5 - Polymorphisms Identification related to HTLV-1 associated myelopathy / tropical spastic paraparesis (HAM / TSP)
• Grantee: Jorge Simao do Rosario Casseb
• Support Opportunities: Regular Research Grants
• FAPESP's process: 16/03025-2 - Identification of polymorphisms related to HTLV-1 associated myelopathy / tropical spastic paraparesis (HAM / TSP)
• Grantee: Tatiane Assone Casseb
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 18/07239-2 - Incidence, risk factors, and pathogenic mechanism of neurocognitive disorders (HAND) among HIV-1-infected subjects
• Grantee: Jorge Simao do Rosario Casseb
• Support Opportunities: Research Projects - Thematic Grants