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.
Many people tell us that CD4 T cells are not important in MS because trials with a depleting CD4 specific antibody failed to affect MS (did it really? or was the trial design flawed?). However any immunologist will tell you that they are in the centre of the immunological universe because they help the other aspects of the immune response to do their thing. In this study they looked at T cell function and they found certain proteins at higher level on T cells from progressive MSers that progressed more rapidly. What were they doing. Simple answer is I don't know, but Toll-like receptors are involved in the recognition of microbes, so are infections important to the speed of progression. However blocking CD4 activity does not stop progression, the question is whether it changes the slope, we will get this answer from the SP1and tysabri trials.