Systemic cytokines and GlycA discriminate inflammaging, disease progression and corticosteroid response in HTLV-1-associated neuroinflammation

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. Objective: To investigate systemic cytokines and GlycA as possible biomarkers of immunopathogenesis and therapeutic response to corticosteroid pulse therapy in HAM/TSP. Methods: We prospectively followed 110 People living with HTLV-1 (PLwHTLV-1, 67 asymptomatic individuals and 43 HAM/TSP patients), for a total of 906 person-years. Plasma cytokine levels (IL-2/4/6/10/17A, IFN-γ, TNF) and GlycA were quantified by Cytometric Bead Array and 1NMR, respectively. Cytokine signaling and prednisolone response were validated in an independent cohort by nCounter digital transcriptomics. We applied logistic regression and machine learning algorithms to predict disease progression and glucocorticoid response. Results: IL-6 was positively correlated with age and GlycA in asymptomatics but not HAM/TSP patients. Systemic IFN-γ and IL-17A levels were increased in HAM/TSP patients, as compared to asymptomatics. All patients significantly decreased IL-17A levels post-treatment but only prednisolone-responders decreased IFN-γ levels post-treatment. Higher pre-treatment GlycA and TNF levels significantly predicted a negative therapeutic outcome, which was associated with higher post-treatment IFN-γ levels. Low IL-4 and IL-10 levels in incident HAM/TSP can be reverted to increased IL-10 and IL-4/IL-13 signaling by prednisolone in vitro. Conclusions: 1) An age-related increase in systemic IL-6/GlycA levels reveals inflammaging in PLwHTLV-1. 2) IFN-γ and IL-17A are biomarkers of untreated, active HAM/TSP disease, while pre-treatment GlycA and TNF predict therapeutic response to prednisolone pulse therapy. 3) Low IL-4/IL-10 and high IFN-γ signaling in incident HAM/TSP can be normalized by prednisolone.