Experimental autoimmune myocarditis in A/J mice is an interleukin-4-dependent disease with a Th2 phenotype
Experimental autoimmune myocarditis in A/J mice is an interleukin-4-dependent disease with a Th2 phenotype
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DOI：
10.1016/s0002-9440(10)61685-9
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发表时间：
2001-07-01
影响因子：
6
通讯作者：
Rose, NR
中科院分区：
文献类型：
--
作者：
Afanasyeva, M;Wang, Y;Rose, NR
人类心肌炎通常与自身免疫过程有关，在该过程中，心肌肌球蛋白(CM)是主要的自身抗原。用CM免疫小鼠诱导实验性自身免疫性心肌炎(EAM)。我们发现，A/J小鼠的EAM表现为Th2样表型，表现为心脏病变的组织学图像(嗜酸性粒细胞和巨细胞)和体液反应(IgG1反应与疾病的关联和总IgE的上调)。用抗IL-4单抗阻断IL-4可减轻EAM的严重程度。这种严重程度的降低与从Th2样表型转变为Th1样表型有关，表现为CM特异性IgG1减少；CM特异性IgG2a增加；总IgE应答减少；IL-4、IL-5和IL-13减少；以及体外干扰素(IFN)-γ产生显著增加。基于后一项发现，我们假设干扰素-伽马可以限制疾病。事实上，用单抗阻断干扰素-γ会加剧疾病。联合应用抗干扰素-γ单抗可阻断IL-4的拮抗作用。因此，EAM代表了一种与Th2表型相关的器官特异性自身免疫性疾病的模型，在该模型中，IL-4促进了疾病的发生，而干扰素-γ限制了疾病的发生。抑制干扰素-γ至少代表了IL-4促进EAM的机制之一。
Myocarditis in humans is often associated with an autoimmune process in which cardiac myosin (CM) is a major autoantigen. Experimental autoimmune myocarditis (EAM) is induced in mice by immunization with CM. We found that EAM in A/J mice exhibits a Th2-like phenotype demonstrated by the histological picture of the heart lesions (eosinophils and giant cells) and by the humoral response (association of IgG1 response with disease and up-regulation of total IgE). Blocking interleukin (IL)-4 with anti-IL-4 monoclonal antibody (mAb) reduced the severity of EAM. This reduction in severity was associated with a shift from a Th2-like to a Th1-like phenotype represented by a reduction in CM-specific IgG1; an increase in CM-specific IgG2a; an abrogation of total IgE response; a decrease in IL-4, IL-5, and IL-13; as well as a dramatic increase in interferon (IFN)-gamma production in vitro. Based on the latter finding, we hypothesized that IFN-gamma limits disease. Indeed, IFN-gamma blockade with a mAb exacerbated disease. The ameliorating effect of IL-4: blockade was abrogated by co-administration of anti-IFN-gamma mAb. Thus, EAM represents a model of an organ-specific autoimmune disease associated with a Th2 phenotype, in which IL-4 promotes the disease and IFN-gamma limits it. Suppression of IFN-gamma represents at least one of the mechanisms by which IL-4 promotes EAM.