Role of Th17 cells in the pathogenesis of CNS inflammatory demyelination

Abstract

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). The etiology of MS is not well understood, but it is believed that myelin-specific CD4(+) T cells play a central role in initiating and orchestrating CNS inflammation. In this scenario, CD4(+) T cells, activated in the periphery, infiltrate the CNS, where, by secreting cytokines and chemokines, they start an inflammatory cascade. Given the central role of CD4(+) T cells in CNS autoimmunity, they have been studied extensively, principally by using experimental autoimmune encephalomyelitis (EAE), an animal model of MS. In the late 1980s, CD4(+) T cells, based on their cytokine production, were divided into two helper lineages, Th1 and Th2 cells. It was postulated that Th1 cells, which produce IFN-γ, mediate inflammation of the CNS in MS/EAE, while Th2 cells, which produce IL-4, have a beneficial effect in disease, because of their antagonistic effect on Th1 cells. The Th1/Th2 paradigm remained the prevailing view of MS/EAE pathogenesis until 2005, when a new lineage, Th17, was discovered. In a relatively short period of time it became apparent that Th17 cells, named after their hallmark cytokine, IL-17A, play a crucial role in many inflammatory diseases, including EAE, and likely in MS as well. The Th17 paradigm developed rapidly, initiating the debate of whether Th1 cells contribute to EAE/MS pathogenesis at all, or if they might even have a protective role due to their antagonistic effects on Th17 cells. Numerous findings support the view that Th17 cells play an essential role in autoimmune CNS inflammation, perhaps mainly in the initial phases of disease. Th1 cells likely contribute to pathogenesis, with their role possibly more pronounced later in disease. Hence, the current view on the role of Th cells in MS/EAE pathogenesis can be called the Th17/Th1 paradigm. It is certain that Th17 cells will continue to be the focus of intense investigation aimed at elucidating the pathogenesis of CNS autoimmunity.

Keywords: APC; CNS; EAE; GM-CSF; IFN; IL; IL-23; IL-27; MBP; MOG; MS; Multiple sclerosis; NO; TNF; Th1; Th17; Th9; Treg; Tregs; WT; antigen presenting cells; central nervous system; experimental allergic encephalomyelitis; granulocyte macrophage colony-stimulating factor; interferon; interleukin; multiple sclerosis; myelin basic protein; myelin oligodendrocyte glycoprotein; nitric oxide; regulatory T cells; tumor necrosis factor; wild-type; γδ T cell.

Copyright © 2013 Elsevier B.V. All rights reserved.

Figures

Figure 1

Effect of IL-12 and of neutralizing anti-IL-12p40 mAb on the course of relapsing EAE. After recovery from the initial attack of EAE, mice were treated as indicated by the arrow. IL-12 treatment induced immediate relapses and worsening later relapses. Anti-IL-12p40 Ab prevented spontaneous relapses. Results are shown as mean × SD of clinical scores. The course of EAE in mice treated with control rat IgG overlaps completely with that of mice receiving no treatment and is not shown. (Figure first published in Journal of Immunology, 161:5097-5104, 1998, Constantinescu C et al., Antibodies against interleukin-12 prevent superantigen-induced and spontaneous relapses of experimental autoimmune encephalomyelitis. Copyright 1998. The American Association of Immunologists, Inc.)

Figure 2

IL-12p35−/− are susceptible to EAE, while IL-12p40−/− mice are resistant. Female WT, IL-12p35−/−, and IL-12p40−/− mice were immunized with MOG35-55 in CFA. Data represent the mean clinical scores × SEM. The overall clinical score was not significantly different between WT and IL-12p35−/− mice. (Figure first published in the Journal of Immunology, 169: 7104-7110, 2002, Gran B. et al., IL-12p35-deficient mice are susceptible to experimental autoimmune encephalomyelitis: Evidence for redundancy in the IL-12 system in the induction of central nervous system autoimmune demyelination. Copyright 2002. The American Association of Immunologists, Inc.)

Figure 3

IL-12Rβ2−/− mice develop severe EAE. Female WT and IL-12Rβ2−/− mice were immunized with MOG35-55 peptide in CFA. Data represent mean clinical score × SD. The overall clinical score was significantly different between WT and IL-12Rβ2−/− mice (p < 0.001). (Figure first published in Journal of Immunology, 2003, 170(4):2153-60, Zhang G-X et al., Induction of experimental autoimmune encephalomyelitis in IL-12 receptor-beta2-deficient mice: IL-12 responsiveness is not required in the pathogenesis of inflammatory demyelination in the central nervous system. Copyright 2003. The American Association of Immunologists, Inc.)

Figure 4

GM-CSF production by Th1 and Th17 cells is required for their encephalitogenicity. WT or Csf2−/− MBP(Ac1-11) TCR-transgenic splenocytes were activated with MBP(Ac1-11) in the presence of IL-12 (Th1 conditions) or TGF-β plus IL-6, anti-IFN-γ and anti-IL-4 (Th17 conditions), then allowed to ‘rest’ for 2 days in the presence of IL-2; they were then reactivated for 72 h with MBP(Ac1-11) in the presence of IL-12 (Th1 conditions) or IL-23 (Th17 conditions). Clinical scores of mice that received 5 × 106 MBP(Ac1-11)-specific WT or Csf2−/− Th1 or Th17 cells are shown. (Figure first published in: Nature Immunology, 2011 Jun;12(6):568-75. El-Behi M, et al., The encephalitogenicity of T(H)17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM-CSF.)

Figure 5

Exogenous IL-27 suppresses actively induced EAE. EAE was induced in C57BL/6 mice with MOG35-55 and osmotic pumps (7-day delivery capacity) containing either rmIL-27 or PBS were implanted s.c. on day 11. Mice that did not undergo surgery were also assessed. (Figure first published in Journal of Immunology 179:3268-75, 2007, Fitzgerald DC et al., Suppressive effect of IL-27 on encephalitogenic Th17 cells and the effector phase of experimental autoimmune encephalomyelitis (EAE). Copyright 2007. The American Association of Immunologists, Inc.)

Figure 6

Th1/Th17 paradigm of CNS inflammatory demyelination. In the peripheral immune system, IL-12 and IL-23, produced by dendritic cells, induces the differentiation of Th1 and Th17 cells, respectively. IL-12 is not strictly required and may actually play an immunoregulatory role in development of EAE, as mice that do not produce, or cannot respond to, IL-12 develop severe EAE. Activated Th1 and Th17 cells migrate into the CNS across the blood-brain barrier. In the CNS, myelin-reactive Th cells interact with resident microglia and are reactivated upon recognition of myelin antigens. Activated effector Th cells produce cytokines and chemokines that lead to an inflammatory pathological cascade in the CNS and damage to the myelin sheath and neuronal axons. (Figure first published in Drug News & Perspectives 19(2):77-83, 2006, Touil T et al., Pathophysiology of Interleukin-23 in experimental autoimmune encephalomyelitis. Copyright © 2006 Prous Science, S.A.U. or its licensors. All rights reserved.)