Objective: Our objective was to determine whether altered naive CD4 T-cell biology contributes to development of disease progression in secondary progressive multiple sclerosis (SPMS). Methods: We compared the naive CD4 T-cell gene expression profiles of 19 patients with SPMS and 14 healthy controls (HCs) using a whole-genome microarray approach. We analyzed surface protein expression of critical genes by flow cytometry after T-cell receptor (TCR) stimulation of naive CD4 T cells isolated from HCs and patients with SPMS. Results: Hierarchical clustering segregated patients with SPMS into 2 subgroups: SP-1, which had a short duration of relapsing-remitting multiple sclerosis (MS), and SP-2, which had a long duration of relapsing-remitting MS. SP-1 patients upregulated numerous immune genes, including genes within TCR and toll-like receptor (TLR) signaling pathways. SP-2 patients showed immune gene downregulation in comparison with HCs. We identified an SP-1-specific transcriptional signature of 3 genes (TLR4, TLR2, and chemokine receptor 1), and these genes had higher surface protein expression in SP-1 than in SP-2. After TCR stimulation for 48 hours, only SP-1 showed a progressive linear increase in TLR2 and TLR4 protein expression. Conclusions: Differences in naive CD4 T-cell biology, notably of TCR and TLR signaling pathways, identified patients with MS with more rapid conversion to secondary progression, a critical determinant of long-term disability in MS.
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