Following the Clues: Usefulness of Biomarkers of Neuroinflammation and Neurodegeneration in the Investigation of HTLV-1-Associated Myelopathy Progression.

Flávia Dos Santos Souza,Abelardo De Queiroz Campos Araújo,Nicole Lardini Freitas,Yago Côrtes Pinheiro Gomes,Otávio Melo Espíndola,Isaac Lima Da Silva-Filho,Juliana Echevarria-Lima,Ana Claudia Celestino Bezerra Leite,Marcus Tulius Teixeira Da Silva,Rafael Carvalho Torres,Marco Antonio Sales Dantas De Lima

doi:10.3389/fimmu.2021.737941

Abstract

Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neurodegenerative disease due to axonal damage of the corticospinal secondary to an inflammatory response against infected T-cells. In the present work, we aimed to evaluate biomarkers of neurodegeneration and neuroinflammation in the definition of HAM/TSP prognosis. Neurofilament light (NfL) and phosphorylated heavy (pNfH) chains, total Tau protein, cellular prion protein (PrPc), inflammatory chemokines, and neopterin were quantified in paired cerebrospinal fluid (CSF) and serum samples from HAM/TSP patients (n=21), HTLV-1 asymptomatic carriers (AC) (n=13), and HTLV-1 seronegative individuals with non-inflammatory non-degenerative neurological disease (normal-pressure hydrocephalus) (n=9) as a control group. HTLV-1 proviral load in peripheral blood mononuclear cells and the expression of chemokine receptors CCR4, CCR5, and CXCR3 in infected CD4+ T-cells (HTLV-1 Tax+ cells) were also assessed. CSF levels of Tau, NfL, and pNfH were similar between groups, but PrPc and neopterin were elevated in HAM/TSP patients. Most individuals in the control group and all HTLV-1 AC had CSF/serum neopterin ratio < 1.0, and two-thirds of HAM/TSP patients had ratio values > 1.0, which positively correlated with the speed of disease progression and pNfH levels, indicating active neuroinflammation. HAM/TSP patients showed high serum levels of CXCR3-binding chemokines (CXCL9, CXCL10, and CXCL11) and elevated CSF levels of CCL2, CCL3, CCL4, CCL17, CXCL5, CXCL10, and CXCL11. Indeed, CXCL10 concentration in CSF of HAM/TSP patients was 5.8-fold and 8.7-fold higher in than in HTLV-1 AC and controls, respectively, and correlated with CSF cell counts. HAM/TSP patients with typical/rapid disease progression had CSF/serum CXCL10 ratio > 1.0 and a higher frequency of CXCR3+Tax+CD4+ T-cells in blood, which indicated a positive gradient for the migration of infected cells and infiltration into the central nervous system. In conclusion, the slow progression of HAM/TSP abrogates the usefulness of biomarkers of neuronal injury for the disease prognosis. Thus, markers of inflammation provide stronger evidence for HAM/TSP progression, particularly the CSF/serum neopterin ratio, which may contribute to overcome differences between laboratory assays.

Highlights

HTLV-1 infection is endemic in Japan, the Caribbean, Middle East, sub-Saharan Africa, Australia, and South America, in Brazil, and it is estimated that 5 to 10 million people are infected worldwide [1]
Patients with the following criteria were enrolled in the study: individuals older than 18 years; without a history of autoimmune diseases, lymphoproliferative diseases (ATLL or cutaneous lymphoma), and inflammatory disorders other than HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP); without diagnostic of other illnesses associated with motor impairment, such as Parkinson’s disease, rheumatoid arthritis, ankylosing spondylitis; not submitted to therapy with corticosteroids or other immunomodulatory drugs throughout one year preceding the time at sample collection; no history of pressure ulcers; no concurrent chronic infections such as HTLV-2, HIV, HBV and/or HCV
HAM/TSP is a chronic demyelinating inflammatory disease that typically presents with a slow course

Summary

Introduction

HTLV-1 infection is endemic in Japan, the Caribbean, Middle East, sub-Saharan Africa, Australia, and South America, in Brazil, and it is estimated that 5 to 10 million people are infected worldwide [1]. Only 0.5−5% of infected individuals develop a neurological disease known as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) after 20 to 40 years of infection [2, 3]. HAM/TSP is an inflammatory disorder that affects the spinal cord, causing axonal degeneration and perivascular demyelination that results in a slowly progressive neurological disability and motor impairment without signs of remission [2, 3]. A fast decline of the neurological condition can be observed in a small proportion of cases, with loss of motor function and restriction to a wheelchair within two years from symptoms onset [5]. Muscle weakness and spasticity are potential predictors of HAM/TSP progression, a proportion of patients can present with an incomplete pyramidal syndrome, raising the need for laboratory markers to confirm the disease diagnosis [8, 9]

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