Human T-lymphotropic virus type 1–associated (HTLV-1–associated) myelopathy (HAM, also known as tropical spastic paraparesis) is a rare neurodegenerative disease with largely elusive molecular mechanisms, impeding targeted therapeutic advancements. This study aimed to identify the critical molecule responsible for neuronal damage in HAM, its source, and the regulatory mechanisms controlling its expression. Utilizing patient-derived cells and established cell lines, we discovered that HTLV-1 Tax, in conjunction with specificity protein 1 (Sp1), enhanced the expression of repulsive guidance molecule A (RGMa), a protein known to contribute to neuronal damage. RGMa expression was specifically upregulated in HTLV-1–infected cells from patients with HAM, particularly in those expressing HTLV-1 Tax. Furthermore, in CD4 ⁺ cells from patients with HAM, the level of H3K27me3 methylation upstream of the RGMA gene locus was reduced, making RGMA more prone to constitutive expression. We demonstrated that HTLV-1–infected cells in HAM inflict neuronal damage via RGMa. Crucially, the neutralizing antibody against RGMa, unasnemab (MT-3921), effectively mitigated this damage in a dose-responsive manner, highlighting RGMa’s pivotal role in neuronal damage and its potential as a therapeutic target for alleviating neuronal damage in HAM.

The diagnostic accuracy of cerebrospinal fluid (CSF) anti-human T-cell leukemia virus type I (HTLV-1) antibody testing for HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM) remains unclear. Therefore, we measured the anti-HTLV-1 antibody levels in CSF using various test kits, evaluated the stability of CSF antibodies, and performed a correlation analysis using the particle agglutination (PA) method, as well as a receiver operating characteristic (ROC) analysis between patients with HAM and carriers. The CSF anti-HTLV-1 antibody levels were influenced by freeze–thaw cycles but remained stable when the CSF was refrigerated at 4 °C for up to 48 h. Measurements from 92 patients (69 patients with HAM and 23 carriers) demonstrated a strong correlation (r > 0.9) with the PA method across all six quantifiable test kits. All six test kits, along with CSF neopterin and CXCL10, exhibited areas under the ROC curve greater than 0.9, indicating a high diagnostic performance for HAM. Among these, five test kits, Lumipulse and Lumipulse Presto HTLV-I/II, HISCL-UD (a kit under development), HTLV-Abbott, and Elecsys HTLV-I/II, established a cutoff with 100% sensitivity and maximum specificity, achieving a sensitivity of 100% and a specificity ranging from 43.5% to 56.5%. This cutoff value, in combination with clinical findings, will aid in the accurate diagnosis of HAM.