Evidence that an expansion of peripheral Th17 cells, a Th subset that can infiltrate brain parenchyma and damage cells, is associated with disease activity in MS. The greater IFN-alphaR1 level expressed by Th17 compared with Th1 cells might make them a selective target for IFN-beta therapy.

ContributorsGIW wrote and revised the manuscript in response to co-author comments. He finalized all the figures and tables, performed the literature search, and assisted with data interpretation. HJK critically reviewed the manuscript and made important suggestions to improve it. He assisted with data interpretation. IBA performed the data analysis, constructed the figures and tables, and made important suggestions to improve the manuscript. H-CK assisted with the data analysis and also reviewed the manuscript. GRC critically reviewed the manuscript and made important suggestions to improve it. He assisted with data interpretation. All other authors were given the opportunity to review the manuscript and make suggestions which GIW received, either revising the paper or providing explanations. All who are not deceased were involved with approval of the manuscript.

No abstract

At present, two types of recombinant human interferon (IFN)-beta are in clinical use. IFN-beta1a is produced in genetically engineered Chinese hamster ovary cells, and its amino acid sequence and glycosylation pattern are identical to those of endogenous human IFN-beta. The beneficial effect of IFN-beta in multiple sclerosis (MS) probably results from different mechanisms of action, such as a direct effect on plasma cells modulating IgG synthesis, an increase of interleukin (IL)-10 levels, the inhibition of IL-1beta and tumour necrosis factor alpha, the stimulation of IL-1 receptor antagonist production, the inhibition of proliferation of leukocytes, a decreased antigen presentation in microglia, a reduction of T cell migration into the brain by inhibition of the activity of T cell matrix metalloproteinases, and a downregulation of adhesion molecules. IFN-beta1a has been shown by several multicenter controlled trials to be effective in relapsing-remitting MS. It reduces relapse rate by 30-50%, magnetic resonance imaging signs of disease activity in 30-80% and disability progression by 30%. It is also effective in preventing conversion to clinically definite MS when given at the time of a first demyelinating event (i.e., at the very beginning of the clinical disease). No clear evidence of the persistence of the efficacy over the long-term has stood out from a systematic analysis of published trials. A Cochrane review concluded that, in fact, the clinical effect beyond the first year of treatment is not clear. Finally, no efficacy has been shown in secondary progressive or primary progressive MS. However, IFN-beta1a is very well tolerated and the most frequent side effects are mild (local skin reaction and flu-like symptoms) and decline in frequency or disappear after the first 3-6 months of treatment. Although the optimal frequency between once weekly or multiple weekly administrations is still controversial, all protocols require multiple monthly injections. Some patients might find it hard to cope with such a treatment regimen over the long term. Ongoing trials with new powerful immunomodulatory drugs, such as monoclonal antibodies, that require only monthly or bimonthly parenteral administrations will probably offer a better tolerated treatment option in the near future.

IFN-β inhibits the expansion of Th17 cells in active multiple sclerosis (AMS), and this might contribute to improve the clinical symptoms. The effectiveness of this inhibition, however, requires intact IFN-γ signaling in T cells. In this study, we report that both mRNA and cell surface expression of the signaling chain of the IFN-γ receptor (IFN-γR2) and its cognate tyrosine kinase JAK2 are enhanced in peripheral blood Th17 cells and clones from patients with AMS compared with those with inactive multiple sclerosis (IMS) or healthy subjects (HS). IFN-γ decreased the frequency of Th17 peripheral cells and proliferation of Th17 clones from AMS patients. Stimulation of PBMCs from HS in Th17-polarizing conditions resulted in the enhancement of JAK2 expression and accumulation of cell surface IFN-γR2. The role of JAK2 in the modulation of IFN-γR2 was demonstrated as its transduction prevented rapid internalization and degradation of IFN-γR2 in JAK2-deficient γ2A cells. In conclusion, these data identify JAK2 as a critical factor that stabilizes IFN-γR2 surface expression in Th17 cells from AMS patients, making them sensitive to IFN-γ. These data may have clinical implications for a better use of IFNs in multiple sclerosis and possibly other inflammatory diseases.