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New pieces in the puzzle: How does interferon‐β really work in multiple sclerosis?

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Although the etiology of MS is still unknown, there is good circumstantial evidence that T cells reacting against myelin antigens are key players in the initiation of the pathogenic process. For many years, the major role in the induction of organ-specific autoimmunity was attributed to interferon (IFN)producing T helper 1 (TH1) lymphocytes, as they were found in CNS perivascular infiltrates, and increased amounts of IFNcould be detected in the CNS, cerebrospinal fluid (CSF), and peripheral blood of MS patients during episodes of active disease. However, a new subset of T cells, named TH17 after its signature cytokine interleukin (IL)-17, has recently been identified that shows highly inflammatory properties and induces severe immunopathology in various animal models of human autoimmune diseases. TH17 cells appear to pass through 3 distinct steps during T-cell differentiation: induction, amplification, and stabilization. TGF, together with the proinflammatory cytokine IL-6, is crucial for inducing differentiation of TH17 cells, IL-21 amplifies their expansion, and IL-23 further expands and stabilizes their function (see figure). Several independent groups showed the significance of this T-cell subset in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model for MS. In this issue of Annals of Neurology, Durelli et al show that active MS patients exhibit an approximately 7-fold increase in the frequency of TH17 cells in comparison to inactive MS patients or healthy subjects. A longitudinal follow-up of MS patients showed a close correlation between IL-17 levels and disease activity. These data confirm and complement previous studies that reported elevated levels of IL-17 in blood mononuclear cells, CSF, and active CNS lesions of MS patients. IFN, a type I interferon, is a first-line therapy in the treatment of relapsing-remitting MS. It has been proven to be beneficial for the treatment of MS, as demonstrated by decreased inflammatory lesion formation in the CNS, reduced relapse rate, and potentially diminished progression of sustained disability. However, both the underlying mode of action of this agent and the physiological role of endogenous type I IFNs in the pathogenesis of autoimmune disease remain elusive. Several mechanisms have been proposed, including inhibition of antigen processing and presentation, inhibition of T-cell proliferation, modulation of cytokine production, and downregulation of matrix metalloproteinases as well as adhesion molecules, which would result in inhibition of lymphocyte migration across the blood-brain barrier. In this issue of Annals of Neurology, Durelli et al investigated the effect of IFNon different subsets of T cells, namely TH0, TH1, and TH17 cells. Interestingly, among the T-cell subsets, TH17 cells were most susceptible to IFN–mediated effects, presumably owing to a higher expression of the IFN type I receptor chain 1 (IFNAR1) in TH17 cells as compared to TH1 cells. Addition of IFNinhibited IL-17 production within the CD4 CD45RO T-cell compartment, whereas IFNproduction in TH1 cells was not affected. As a possible mechanism, the authors proposed that IFNmediated apoptosis in TH17 cells, leading to a preferential loss of IL-17–producing T cells. However, as total peripheral mononuclear cells were used in this study, effects on other cell types, notably antigen-presenting cells (APCs), cannot be ruled out. This is of particular interest, as several recent reports suggested that the inhibitory effect of IFNis mediated via APCs. Shinohara et al showed that engagement of type I interferon receptors on dendritic cells inhibits TH17 development via production of IL-27. This is in line with another report that states that activation of various Toll-like receptors (TLRs) provoke IL-27 production by human macrophages, which is mediated by IFN–driven transactivation of the p28 subunit of IL-27. Two other studies further explored the role of IFNAR expression on different cell types, and clearly demonstrated that absence of IFNAR on myeloid cells led to severe EAE with an enhanced effector phase and increased lethality, whereas mice with B or T lymphocyte–specific IFNAR ablation showed normal EAE. Overall, these results suggest that IFNmight induce upregulation of IL-27 in innate immune cells via modulation of TLR signaling pathways. IL-27 is known to inhibit the development of TH17 cells in a cell-intrinsic manner possibly involving STAT1. This pathway, together with a more direct inhibition of TH17 cells by IFNas implied by the present study, suggests a preferential susceptibility of TH17 cells to IFN–mediated immunomodulation. If this is true, we might—based on the efficacy of type I interferons in treating inflammatory features of MS—hypothesize that TH17 cells play a relevant role in driving inflammation and immunopathology in MS. But initial trials to block the generation of both TH1 and TH17 cells by administration of a neutralizing anti–IL-12/IL-23 p40 antibody showed no inhibition of disease activity in patients with relapsing-remitting MS. However, this failure does not exclude the possibility that IL-17 and TH17 cells play a role in the pathogenesis of MS. In fact, other incidents, such as poor CNS availability of the antibody or the fact that crucial steps in T-cell differentiation happen at an earlier stage of the disease, might have influEDITORIALS