Pastrana D V, Raghavan N, FitzGerald P, Eisinger S W, Metz C, Bucala R, Schleimer R P, Bickel C, Scott A L
Department of Molecular Microbiology and Immunology, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, Maryland 21205, USA.
Infect Immun. 1998 Dec;66(12):5955-63. doi: 10.1128/IAI.66.12.5955-5963.1998.
Filarial nematode parasites establish long-term chronic infections in the context of an antiparasite immunity that is strongly biased toward a Th2 response. The mechanisms that lead to this Th2 bias toward filarial antigens are not clear, but one possibility is that the parasites produce molecules that have the capacity to proactively modify their immunological environment. Here we report that filarial parasites of humans secrete a homologue of the human proinflammatory cytokine macrophage migration inhibitory factor (MIF) that has the capability of modifying the activity of human monocytes/macrophages. A cDNA clone isolated from a Brugia malayi infective-stage larva expression library encoded a 12.5-kDa protein product (Bm-MIF) with 42% identity to human and murine MIF. MIF homologues were also found to be expressed in the related filarial species Wuchereria bancrofti and Onchocerca volvulus. Bm-mif was transcribed by adult and larval parasites, and the protein product was found in somatic extracts and in the parasite's excretory-secretory products. Immunohistocytochemistry revealed that Bm-MIF was localized to cells of the hypodermis/lateral chord, the uterine wall, and larvae developing in utero. Unexpectedly, the activities of recombinant Bm-MIF and human MIF on human monocytes/macrophages were found to be similar. When placed with monocytes/macrophages in a cell migration assay, Bm-MIF inhibited random migration. When placed away from cells, Bm-MIF induced an increase in monocyte/macrophage migration that was specifically inhibited by neutralizing anti-Bm-MIF antibodies. Bm-MIF is the first demonstration that helminth parasites produce cytokine homologues that have the potential to modify host immune responses to promote parasite survival.
丝虫线虫寄生虫在强烈偏向Th2反应的抗寄生虫免疫环境中建立长期慢性感染。导致对丝虫抗原产生这种Th2偏向的机制尚不清楚，但一种可能性是寄生虫产生能够主动改变其免疫环境的分子。在这里，我们报告人类丝虫寄生虫分泌一种人类促炎细胞因子巨噬细胞迁移抑制因子（MIF）的同源物，它具有改变人类单核细胞/巨噬细胞活性的能力。从马来布鲁线虫感染期幼虫表达文库中分离出的一个cDNA克隆编码一种12.5 kDa的蛋白质产物（Bm-MIF），与人类和小鼠MIF有42%的同源性。在相关的丝虫物种班氏吴策线虫和盘尾丝虫中也发现了MIF同源物的表达。Bm-mif由成虫和幼虫寄生虫转录，蛋白质产物存在于体细胞提取物和寄生虫的排泄-分泌产物中。免疫组织化学显示，Bm-MIF定位于皮下/侧索细胞、子宫壁以及子宫内发育的幼虫。出乎意料的是，发现重组Bm-MIF和人类MIF对人类单核细胞/巨噬细胞的活性相似。在细胞迁移试验中，当与单核细胞/巨噬细胞一起放置时，Bm-MIF抑制随机迁移。当远离细胞放置时，Bm-MIF诱导单核细胞/巨噬细胞迁移增加，而这种增加被中和抗Bm-MIF抗体特异性抑制。Bm-MIF首次证明了蠕虫寄生虫产生具有改变宿主免疫反应以促进寄生虫生存潜力的细胞因子同源物。
