Department of Internal Medicine, Division of Nephrology, Center of Immunology, Inflammation and Regenerative Medicine, University of Virginia Health Center, Charlottesville, VA, USA.
Curr Top Microbiol Immunol. 2017;408:89-117. doi: 10.1007/82_2017_37.
Natural IgM autoantibodies (IgM-NAA) are rapidly produced to inhibit pathogens and abrogate inflammation mediated by invading microorganisms and host neoantigens. IgM-NAA achieve this difficult task by being polyreactive with low binding affinity but with high avidity, characteristics that allow these antibodies to bind antigenic determinants shared by pathogens and neoantigens. Hence the same clones of natural IgM can bind and mask host neoantigens as well as inhibit microorganisms. In addition, IgM-NAA regulate the inflammatory response via mechanisms involving binding of IgM to apoptotic cells to enhance their removal and binding of IgM to live leukocytes to regulate their function. Secondly, we review how natural IgM prevents autoimmune disorders arising from pathogenic IgG autoantibodies as well as by autoreactive B and T cells that have escaped tolerance mechanisms. Thirdly, using IgM knockout mice, we show that regulatory B and T cells require IgM to effectively regulate inflammation mediated by innate, adaptive and autoimmune mechanisms. It is therefore not surprising why the host positively selects such autoreactive B1 cells that generate protective IgM-NAA, which are also evolutionarily conserved. Fourthly, we show that IgM anti-leukocyte autoantibodies (IgM-ALA) levels and their repertoire can vary in normal humans and disease states and this variation may partly explain the observed differences in the inflammatory response after infection, ischemic injury or after a transplant. Finally we also show how protective IgM-NAA can be rendered pathogenic under non-physiological conditions. IgM-NAA have therapeutic potential. Polyclonal IgM infusions can be used to abrogate ongoing inflammation. Additionally, inflammation arising after ischemic kidney injury, e.g., during high-risk elective cardiac surgery or after allograft transplantation, can be prevented by pre-emptively infusing polyclonal IgM, or DC pretreated ex vivo with IgM, or by increasing in vivo IgM with a vaccine approach. Cell therapy with IgM pretreated cells, is appealing as less IgM will be required.
天然 IgM 自身抗体（IgM-NAA）迅速产生，以抑制病原体并消除由入侵微生物和宿主新抗原引起的炎症。IgM-NAA 通过与低亲和力但高亲和力的多反应性来实现这一艰巨任务，这些特性使这些抗体能够结合病原体和新抗原共有的抗原决定簇。因此，相同的天然 IgM 克隆可以结合并掩盖宿主新抗原，同时抑制微生物。此外，IgM-NAA 通过涉及 IgM 与凋亡细胞结合以增强其清除和与活白细胞结合以调节其功能的机制来调节炎症反应。其次，我们回顾了天然 IgM 如何防止源自致病性 IgG 自身抗体以及逃避耐受机制的自身反应性 B 和 T 细胞引起的自身免疫疾病。第三，使用 IgM 敲除小鼠，我们表明调节性 B 和 T 细胞需要 IgM 才能有效调节先天、适应性和自身免疫机制介导的炎症。因此，宿主积极选择产生保护性 IgM-NAA 的这种自身反应性 B1 细胞并不奇怪，这些细胞也在进化上得到了保守。第四，我们表明，在正常人和疾病状态下，IgM 抗白细胞自身抗体（IgM-ALA）水平及其库可以变化，这种变化可能部分解释了感染、缺血性损伤或移植后观察到的炎症反应差异。最后，我们还表明，在非生理条件下，保护性 IgM-NAA 如何变得具有致病性。IgM-NAA 具有治疗潜力。多克隆 IgM 输注可用于消除持续的炎症。此外，在缺血性肾损伤后（例如，在高风险择期心脏手术或同种异体移植后）出现的炎症可以通过预先输注多克隆 IgM、或用 IgM 预处理的 DC 进行预先处理、或通过疫苗接种方法增加体内 IgM 来预防。用预先用 IgM 处理的细胞进行细胞治疗很有吸引力，因为所需的 IgM 较少。
