Börnsen Lars, Romme Christensen Jeppe, Ratzer Rikke, Hedegaard Chris, Søndergaard Helle B, Krakauer Martin, Hesse Dan, Nielsen Claus H, Sorensen Per S, Sellebjerg Finn
Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
Institute for Inflammation Research, Department of Rheumatology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
PLoS One. 2015 Mar 4;10(3):e0118830. doi: 10.1371/journal.pone.0118830. eCollection 2015.
Autoreactive CD4+ T-cells are considered to play a major role in the pathogenesis of multiple sclerosis. In experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis, exogenous and endogenous type I interferons restrict disease severity. Recombinant interferon-β is used for treatment of multiple sclerosis, and some untreated multiple sclerosis patients have increased expression levels of type I interferon-inducible genes in immune cells. The role of endogenous type I interferons in multiple sclerosis is controversial: some studies found an association of high expression levels of interferon-β-inducible genes with an increased expression of interleukin-10 and a milder disease course in untreated multiple sclerosis patients, whereas other studies reported an association with a poor response to treatment with interferon-β. In the present study, we found that untreated multiple sclerosis patients with an increased expression of interferon-β-inducible genes in peripheral blood mononuclear cells and interferon-β-treated multiple sclerosis patients had decreased CD4+ T-cell reactivity to the autoantigen myelin basic protein ex vivo. Interferon-β-treated multiple sclerosis patients had increased IL10 and IL27 gene expression levels in monocytes in vivo. In vitro, neutralization of interleukin-10 and monocyte depletion increased CD4+ T-cell reactivity to myelin basic protein while interleukin-10, in the presence or absence of monocytes, inhibited CD4+ T-cell reactivity to myelin basic protein. Our findings suggest that spontaneous expression of interferon-β-inducible genes in peripheral blood mononuclear cells from untreated multiple sclerosis patients and treatment with interferon-β are associated with reduced myelin basic protein-induced T-cell responses. Reduced myelin basic protein-induced CD4+ T-cell autoreactivity in interferon-β-treated multiple sclerosis patients may be mediated by monocyte-derived interleukin-10.
自身反应性CD4 + T细胞被认为在多发性硬化症的发病机制中起主要作用。在实验性自身免疫性脑脊髓炎（一种多发性硬化症的动物模型）中，外源性和内源性I型干扰素可限制疾病严重程度。重组干扰素-β用于治疗多发性硬化症，一些未经治疗的多发性硬化症患者免疫细胞中I型干扰素诱导基因的表达水平升高。内源性I型干扰素在多发性硬化症中的作用存在争议：一些研究发现，在未经治疗的多发性硬化症患者中，干扰素-β诱导基因的高表达水平与白细胞介素-10表达增加及病情较轻相关，而其他研究则报道其与对干扰素-β治疗反应不佳有关。在本研究中，我们发现外周血单个核细胞中干扰素-β诱导基因表达增加的未经治疗的多发性硬化症患者以及接受干扰素-β治疗的多发性硬化症患者，其离体CD4 + T细胞对自身抗原髓鞘碱性蛋白的反应性降低。接受干扰素-β治疗的多发性硬化症患者体内单核细胞中的IL10和IL27基因表达水平升高。在体外，白细胞介素-10的中和及单核细胞的清除增加了CD4 + T细胞对髓鞘碱性蛋白的反应性，而无论有无单核细胞存在，白细胞介素-10均抑制CD4 + T细胞对髓鞘碱性蛋白的反应性。我们的研究结果表明，未经治疗的多发性硬化症患者外周血单个核细胞中干扰素-β诱导基因的自发表达以及干扰素-β治疗与髓鞘碱性蛋白诱导的T细胞反应减少有关。接受干扰素-β治疗的多发性硬化症患者中髓鞘碱性蛋白诱导的CD4 + T细胞自身反应性降低可能由单核细胞衍生的白细胞介素-10介导。
