Leishmania mexicana infection induces IgG to parasite surface glycoinositol phospholipids that can induce IL-10 in mice and humans.
Leishmania mexicana infection induces IgG to parasite surface glycoinositol phospholipids that can induce IL-10 in mice and humans.
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DOI：
10.1371/journal.pntd.0002224
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发表时间：
2013
影响因子：
3.8
通讯作者：
Buxbaum LU
中科院分区：
文献类型：
--
作者：
Buxbaum LU
感染细胞内原生动物寄生虫墨西哥利什曼原虫导致C57 BL/6小鼠慢性疾病，其中皮肤病变持续数月，寄生虫负荷高（107-108个寄生虫）。这种慢性疾病过程需要宿主IL-10和FcγRIII。当利什曼原虫无鞭毛体从细胞释放时，表面结合的IgG可以诱导IL-10并抑制巨噬细胞产生IL-12。这些变化减少了T细胞的IFN-γ和感染细胞中一氧化氮的产生，这两者都是控制利什曼原虫所必需的。然而，抗体靶点和抗体产生的动力学是未知的。有几个小组在鉴定结合IgG的无鞭毛体表面蛋白方面一直不成功。我们现在表明，糖肌醇磷脂（GIPL）的L。在感染6周时，小鼠IgG 1可识别出Mexicana，在12 - 16周之间快速增加，这与C57 BL/6小鼠慢性疾病的发生时间与Fcγ RIII缺陷小鼠的愈合时间一致。TLC上的单个显著斑点被IgG识别，糖脂是含有支链甘露糖结构的糖基磷脂酰肌醇。我们表明，GIPL（sn-2脂肪酸）的脂质结构是抗体识别所必需的。这种GIPL在L. mexicana无鞭毛体，在静止期前鞭毛体中罕见，在L.主要，与慢性疾病中GIPL抗体的作用一致。小鼠单克隆抗GIPL IgG识别寄生虫表面上的GIPL，并从巨噬细胞诱导IL-10。目前的工作也将这种小鼠分析扩展到人类，发现L。患有局部和弥漫性皮肤利什曼病的墨西哥感染的人具有识别GIPL的抗体，其可以结合到无鞭毛体的表面，并且可以从人单核细胞诱导IL-10。目标糖脂的进一步表征将对药物和疫苗开发具有重要意义，并将阐明糖脂在感染免疫学中的作用。 墨西哥利什曼原虫是一种单细胞寄生虫，可引起人类和小鼠的慢性皮肤病。寄生虫表面的抗体导致产生一种名为白细胞介素-10（IL-10）的蛋白质，这种蛋白质阻止杀死寄生虫和解决皮肤病变所需的有效免疫反应。在小鼠中，需要IL-10来维持慢性、不愈合的病变。这些抗体的寄生虫表面靶点尚未确定。使用生物化学和免疫学技术，我们已经表明，抗体结合寄生虫表面糖脂（分子与糖锚定的膜脂质），而不是蛋白质的目标。我们已经确定了这些糖脂的一些基本结构特征，并表明它们的抗体结合寄生虫的表面，并可以诱导小鼠细胞中的IL-10。我们已经将这项工作扩展到人类，表明感染这种寄生虫的人也会产生与这些糖脂和寄生虫表面结合的抗体，并且可以从人类白色血细胞中诱导IL-10。这些糖脂的进一步表征可能对开发用于这种和相关寄生虫感染的药物或疫苗具有重要意义，并且可能揭示糖脂诱导抗体反应的免疫途径。
Infection with the intracellular protozoan parasite Leishmania mexicana causes chronic disease in C57BL/6 mice, in which cutaneous lesions persist for many months with high parasite burdens (107–108 parasites). This chronic disease process requires host IL-10 and FcγRIII. When Leishmania amastigotes are released from cells, surface-bound IgG can induce IL-10 and suppress IL-12 production from macrophages. These changes decrease IFN-γ from T cells and nitric oxide production in infected cells, which are both required for Leishmania control. However, antibodies targets and the kinetics of antibody production are unknown. Several groups have been unsuccessful in identifying amastigote surface proteins that bind IgG. We now show that glycoinositol phospholipids (GIPLs) of L. mexicana are recognized by mouse IgG1 by 6 weeks of infection, with a rapid increase between 12 and 16 weeks, consistent with the timing of chronic disease in C57BL/6 mice vs. healing in FcγRIII-deficient mice. A single prominent spot on TLC is recognized by IgG, and the glycolipid is a glycosyl phosphatidylinositol containing a branched mannose structure. We show that the lipid structure of the GIPL (the sn-2 fatty acid) is required for antibody recognition. This GIPL is abundant in L. mexicana amastigotes, rare in stationary-phase promastigotes, and absent in L. major, consistent with a role for antibodies to GIPLs in chronic disease. A mouse monoclonal anti-GIPL IgG recognizes GIPLs on the parasite surface, and induces IL-10 from macrophages. The current work also extends this mouse analysis to humans, finding that L. mexicana-infected humans with localized and diffuse cutaneous leishmaniasis have antibodies that recognize GIPLs, can bind to the surface of amastigotes, and can induce IL-10 from human monocytes. Further characterization of the target glycolipids will have important implications for drug and vaccine development and will elucidate the poorly understood role of glycolipids in the immunology of infections. Leishmania mexicana is a single-celled parasite that causes chronic skin disease in humans and mice. Antibodies on the surface of parasites lead to the production of a protein called interleukin-10 (IL-10), which blocks an effective immune response needed to kill parasites and resolve skin lesions. In mice, IL-10 is required to maintain chronic, non-healing lesions. Parasite surface targets of these antibodies have not been identified. Using biochemical and immunologic techniques, we have shown that antibodies bind to parasite surface glycolipids (molecules with sugars that are anchored to the membrane by lipids), rather than to protein targets. We have determined some basic structural features of these glycolipids and shown that antibodies to them bind the surface of parasites and can induce IL-10 from mouse cells. We have extended this work to humans by showing that people infected with this parasite also make antibodies that bind to these glycolipids and to the surface of parasites, and that can induce IL-10 from human white blood cells. Further characterization of these glycolipids may have important implications for the development of a drug or vaccine for this and related parasite infections, and may shed light on poorly understood immunologic pathways by which glycolipids induce antibody responses.
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