Gene expression changes in multiple sclerosis relapse suggest activation of T and non-T cells

Abstract

A defining feature of multiple sclerosis (MS) is the occurrence of clinical relapses separated by periods of clinical stability. Better understanding of the events underlying clinical relapse might suggest new approaches to treatment. The objective of this study was to measure changes in the expression of RNA in the blood during relapse. We used microarrays to measure mRNA expression in paired samples from 14 MS patients during clinical relapse and while stable. Seventy-one transcripts changed expression at the P < 0.001 significance level. The most notable finding was decreased expression of transcripts with regulatory function, expressed primarily in non-T cells. These decreased transcripts included the interleukin-1 receptor antagonist, which had a corresponding decrease in the protein concentration in serum. Transcripts with increased expression were expressed primarily in T cells. Pathways analysis suggested involvement of the cytokine network, coagulation and complement cascades, IL-10 signaling and NF-κB signaling. We conclude that there are alterations of mRNA expression in both T cells and non-T cells during MS relapse.

Figure 1

Changes in expression in T versus non-T cells. (A) The ratio of relapse versus stable and non-T versus T expression for the 71 transcripts with significance of P < 0.001. The ratio of relapse to stable is on the y axis on a linear scale, the ratio of non-T to T is on the x axis on a logarithmic scale. (B) Ratio of relapse to stable versus non-T to T for the 100 transcripts with the highest bias to expression in non-T cells. There is no general decrease in transcripts expressed in non-T cells.

Figure 2

Ingenuity pathways. Bar denotes statistical significance, squares indicate the fraction of transcripts in that pathway that are changed.

Figure 3

Hierarchical clustering. Dendrogram constructed using BRB ArrayTools with centered correlation and average linkage. The branch labels give the experiment number (–5), the subject number (–14), clinical status, treatment, and gender. The samples from the first two experiments formed large clusters. For 11 of the subjects, the nearest neighbor for the stable sample is the corresponding relapse sample from that subject. There was no tendency to cluster by clinical status, treatment, or gender. S, stable; R, relapse; I, interferon; G, glatiramer; N, no treatment; m, male; f, female.