A detrimental role for IgG and FcgammaR in Leishmania mexicana infection
A detrimental role for IgG and FcgammaR in Leishmania mexicana infection
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DOI：
10.1007/s12026-008-8074-5
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发表时间：
2008-10-01
影响因子：
4.4
通讯作者：
Buxbaum, Laurence U.
中科院分区：
文献类型：
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作者：
Buxbaum, Laurence U.
细胞内的原生动物寄生虫利什曼原虫导致利什曼病，利什曼病是仅次于疟疾的全球第二大寄生虫病杀手。由于利什曼病的药物治疗是有毒的，耐药性正在增长，疫苗是对抗这种疾病的重要武器。不幸的是，目前还没有针对任何人类寄生虫感染的有效疫苗。更糟糕的是，几乎所有机制已知的有效疫苗都是通过诱导保护性抗体发挥作用的。墨西哥利什曼原虫主要引起慢性皮肤病。抗体不仅不能有效杀死利什曼原虫，因为它隐藏在宿主细胞的寄生虫空泡中，而且新的研究表明，免疫球蛋白抗体可能通过产生免疫抑制白介素10反应而在抑制宿主免疫反应方面起关键作用。IL-10能够减少所需的Th1产生的干扰素-γ，并下调一氧化氮的产生，一氧化氮是杀死寄生虫所必需的效应机制。我们一直在研究寄主用来部分控制墨西哥乳杆菌感染的途径，包括STAT4、干扰素-γ和诱导型一氧化氮合酶，但发现IL-12途径被IL-10抑制。我们现在正在研究与寄生虫结合的免疫球蛋白可以通过Fc-Gamma R连接诱导IL-10的机制，以及这如何抑制愈合的免疫反应。我们正在研究哪些免疫球蛋白亚型与哪些Fc-γ受体结合，以及巨噬细胞是否是慢性疾病所必需的IL-10来源。阐明这些机制可能有助于我们设计不会诱导抗体介导的免疫抑制IL-10反应的疫苗。
The intracellular protozoan parasite Leishmania causes leishmaniasis, which is the second biggest killer worldwide among parasitic diseases, after malaria. As drug therapy for leishmaniasis is toxic and resistance is growing, a vaccine is an important weapon against this disease. Unfortunately, no effective vaccine exists for any human parasitic infection. Worse yet, nearly all effective vaccines whose mechanisms are known work through the induction of protective antibodies. Leishmania mexicana causes primarily chronic cutaneous disease. Not only are antibodies not effective at killing Leishmania, as it hides inside the parasitophorous vacuole of the host cell, but new research indicates that IgG antibodies may be crucial in suppressing the host immune response by generating an immunosuppressive interleukin-10 response. IL-10 is able to decrease the needed Th1-generated IFN-gamma and downregulates production of nitric oxide, a required effector mechanism of parasite killing. We have been studying the pathways that the host uses to partially control L. mexicana infection, which include STAT4, IFN-gamma, and inducible nitric oxide synthase, but found that the IL-12 pathway is suppressed by IL-10. We are now studying the mechanisms by which IgG, bound to parasites, can induce IL-10 through Fc gamma R ligation and how this suppresses a healing immune response. We are examining which IgG isotypes bind to which Fc gamma Rs and whether macrophages are the necessary source of IL-10 for chronic disease. Elucidation of these mechanisms may help us to design vaccines that will not induce antibody-mediated immunosuppressive IL-10 responses.