Naive CD4 T-cell activation identifies MS patients having rapid transition to progressive MS.
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.
From Neuroscience (E.Z., L.F.-G.), Department of Pathology (D.G.H.), and McGill Centre for Bioinformatics (M.H.), McGill University, Montreal; Neurology (J.A., A.B.-O., Y.L.), Montreal Neurological Hospital, Montreal, Canada; and Neurology (S.B.), UCSF, San Francisco, CA.
Evelyn
E
Zastepa
Leslie
L
Fitz-Gerald
Michael
M
Hallett
Jack
J
Antel
Amit
A
Bar-Or
Sergio
S
Baranzini
Yves
Y
Lapierre
David G
DG
Haegert
D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology; D008213:Lymphocyte Activation / Q000502:physiology*; D008875:Middle Aged; D020528:Multiple Sclerosis, Chronic Progressive / Q000175:diagnosis / Q000276:immunology*; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000175:diagnosis / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism
D011948:Receptors, Antigen, T-Cell