Somatic Antigens of Tropical Liver Flukes Ameliorate Collagen-Induced Arthritis in Wistar Rats

Parasitic helminths polarize immune response of their vertebrate hosts towards anti-inflammatory Th2 type and therefore it is hypothesized that they may suppress the inflammatory conditions in autoimmune disorders. The present study was undertaken to investigate in vivo immunomodulatory and therapeutic potential of somatic antigens (Ag) of liver infecting digenetic trematodes [Fasciola gigantica (Fg) and Gigantocotyle explanatum (Ge)] in collagen-induced arthritic (CIA) Wistar rats. The CIA rats were administered subcutaneously with different doses (50 μg, 100 μg and 150 μg) of somatic antigens of Fg and Ge, daily for 21 days, the time period required to establish infection in natural host (Bubalus bubalis). Thereafter, the control, diseased and treated rats were compared for different parameters viz. hind paw thickness; serum interleukins, IL-4 and IL-10, tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ); expression level of matrix metalloproteinases (MMPs) -2, -9, -13 and nitric oxide (NO) in knee joints and patellar morphology. The CIA rats treated with different antigens, Fg-Ag and Ge-Ag, show significant amelioration of the disease by down regulation of serum TNF-α and IFN-γ (p< 0.05) and upregulation of IL-4 and IL-10 cytokines (p< 0.05); inhibition (p< 0.05) of MMPs (-2,-9,-13) and NO in knee joints and improved patellar morphology with decreased synovial hypertrophy and reduced infiltration of ploymorphonuclear cells. The activity of pro as well as active MMPs (-2 and -9) and active MMP-13 in knee joints of CIA rats was very high compared to the control and treatment groups, suggesting the extent of collagen degradation in CIA rats. Interestingly, the highest dose (150 μg) of Ge-Ag almost wiped out MMP-13 expression. The overall findings suggest that the somatic proteins of Ge-Ag appeared to be therapeutically more effective than Fg-Ag, reflecting interspecific molecular differences which could contribute to the ability of these worms to successfully ameliorate the pathology of CIA.

寄生性蠕虫可将脊椎动物宿主的免疫应答极化为抗炎性辅助性T细胞2型（Th2），因此有假说提出，这类蠕虫可抑制自身免疫性疾病中的炎症状态。本研究旨在探究感染肝脏的复殖目吸虫[大片吸虫（Fasciola gigantica, Fg）与巨孔吸虫（Gigantocotyle explanatum, Ge）]的体细胞抗原（Ag）在胶原诱导性关节炎（CIA）Wistar大鼠体内的免疫调节活性与治疗潜力。研究人员向胶原诱导性关节炎模型Wistar大鼠皮下注射不同剂量（50μg、100μg及150μg）的Fg与Ge体细胞抗原，每日给药，持续21天——该时长为天然宿主水牛（Bubalus bubalis）建立感染所需的时间。随后，研究人员对对照组、疾病模型组与给药组大鼠的多项指标进行对比分析，具体包括：后足爪厚度；血清白细胞介素4（IL-4）、白细胞介素10（IL-10）、肿瘤坏死因子-α（TNF-α）与干扰素-γ（IFN-γ）水平；膝关节中基质金属蛋白酶（MMPs）-2、-9、-13的表达水平及一氧化氮（NO）含量，以及髌骨形态学特征。经Fg-Ag与Ge-Ag两种抗原处理的CIA模型大鼠，其疾病症状均得到显著改善：血清TNF-α与IFN-γ水平显著下调（p<0.05），IL-4与IL-10细胞因子水平显著上调（p<0.05）；膝关节内基质金属蛋白酶-2、-9、-13及一氧化氮的活性受到显著抑制（p<0.05），同时滑膜增生减轻、多形核细胞浸润减少，髌骨形态学得到有效改善。与对照组及给药组相比，未给药的CIA模型大鼠膝关节内的酶原型及活化型基质金属蛋白酶-2、-9，以及活化型基质金属蛋白酶-13的活性显著升高，这反映出CIA模型大鼠体内胶原降解的严重程度。值得注意的是，150μg的最高剂量Ge-Ag几乎完全消除了MMP-13的表达。本研究整体结果表明，Ge-Ag的体细胞蛋白在治疗效果上优于Fg-Ag，这一现象反映出两种蠕虫的种间分子差异，而该差异可能是二者能够有效改善CIA病理进程的核心原因。