Department of Microbiology and Immunology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA.
Department of Microbiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA.
Immunohorizons. 2022 Dec 1;6(12):807-816. doi: 10.4049/immunohorizons.2200088.
Circulating IgM present in the body prior to any apparent Ag exposure is referred to as natural IgM. Natural IgM provides protective immunity against a variety of pathogens. Salmonella enterica serovar Typhi (S. Typhi) is the causative agent of typhoid fever in humans. Because mice are not permissive to S. Typhi infection, we employed a murine model of typhoid using S. enterica serovar Typhimurium expressing the Vi polysaccharide (ViPS) of S. Typhi (S. Typhimurium strain RC60) to evaluate the role of natural IgM in pathogenesis. We found that natural mouse IgM binds to S. Typhi and S. Typhimurium. The severity of S. Typhimurium infection in mice is dependent on presence of the natural resistance-associated macrophage protein 1 (Nramp1) allele; therefore, we infected mice deficient in secreted form of IgM (sIgM) on either a Nramp1-resistant (129S) or -susceptible (C57BL/6J) background. We found that the lack of natural IgM results in a significantly increased susceptibility and an exaggerated liver pathology regardless of the route of infection or the Nramp1 allele. Reconstitution of sIgM-/- mice with normal mouse serum or purified polyclonal IgM restored the resistance to that of sIgM+/+ mice. Furthermore, immunization of sIgM-/- mice with heat-killed S. Typhi induced a significantly reduced anti-ViPS IgG and complement-dependent bactericidal activity against S. Typhi in vitro, compared with that of sIgM+/+ mice. These findings indicate that natural IgM is an important factor in reducing the typhoid severity and inducing an optimal anti-ViPS IgG response to vaccination.
体内在任何明显抗原暴露之前存在的循环 IgM 被称为天然 IgM。天然 IgM 提供针对多种病原体的保护性免疫。沙门氏菌血清型 Typhi（S. Typhi）是人类伤寒的病原体。由于小鼠不允许 S. Typhi 感染，我们使用表达 S. Typhi Vi 多糖（ViPS）的鼠伤寒沙门氏菌（S. Typhimurium 菌株 RC60）的小鼠模型来评估天然 IgM 在发病机制中的作用。我们发现天然小鼠 IgM 与 S. Typhi 和 S. Typhimurium 结合。S. Typhimurium 感染小鼠的严重程度取决于天然抗性相关巨噬细胞蛋白 1（Nramp1）等位基因的存在；因此，我们感染了缺乏分泌型 IgM（sIgM）的小鼠，这些小鼠在 Nramp1 抗性（129S）或易感（C57BL/6J）背景下。我们发现，无论感染途径或 Nramp1 等位基因如何，缺乏天然 IgM 都会导致显着增加的易感性和夸大的肝脏病理学。用正常小鼠血清或纯化的多克隆 IgM 重建 sIgM-/-小鼠的 sIgM 会恢复对 sIgM+/+小鼠的抵抗力。此外，与 sIgM+/+ 小鼠相比，sIgM-/- 小鼠用热灭活的 S. Typhi 免疫接种会导致针对 S. Typhi 的体外抗-ViPS IgG 和补体依赖性杀菌活性显着降低。这些发现表明，天然 IgM 是减轻伤寒严重程度和诱导针对疫苗接种的最佳抗-ViPS IgG 反应的重要因素。
