Role of Natural Autoantibodies and Natural IgM Anti-Leucocyte Autoantibodies in Health and Disease.
Role of Natural Autoantibodies and Natural IgM Anti-Leucocyte Autoantibodies in Health and Disease.
复制标题
DOI：
10.3389/fimmu.2016.00198
复制
发表时间：
2016
影响因子：
7.3
通讯作者：
Lobo PI
中科院分区：
文献类型：
--
作者：
Lobo PI
我们回顾了多反应性天然IgM自身抗体（IgM-NAA）如何保护宿主免受入侵微生物和宿主新抗原的侵害，这些新抗原不断由氧化机制和细胞凋亡产生。其次，我们讨论了IgM-NAA和IgM抗白细胞抗体（IgM-ALA）如何通过抗独特型机制抑制自身免疫性炎症，增强凋亡细胞的清除，掩蔽新抗原，调节树突状细胞（DC）和效应细胞的功能。第三，我们回顾了天然IgM如何预防由致病性IgG自身抗体引起的自身免疫性疾病，由遗传机制触发（例如，SLE）或微生物，以及逃避耐受机制的自身反应性B和T细胞。在IgM基因敲除小鼠中的研究已经清楚地表明，调节性B和T细胞需要IgM来有效地调节由先天性、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IgM-NAA的自身反应性B1细胞并不奇怪，IgM-NAA也是进化上保守的。第四，我们表明，IgM-ALA水平和他们的剧目可以在正常人和疾病状态不同，这种变化可能部分解释感染后，缺血性损伤，或移植后的炎症反应观察到的差异。我们还展示了如何保护性IgM-NAA可以在非生理条件下致病。我们还综述了血浆中比IgM-NAA更丰富的IgG-NAA。然而，我们需要了解IgG-NAA的（Fab）2区域在非疾病状态下是否具有生理相关性，如在血浆中，它们的功能活性被具有抗独特型活性的IgM-NAA阻断。一些IgG-NAA是由B2细胞产生的，这些细胞已经逃脱了耐受机制，我们展示了如何调节这种致病性IgG-NAA来预防自身免疫性疾病。IgG NAA的Fc区可通过与激活性和抑制性FcγR结合而影响体内炎症和B细胞功能。IgM-NAA具有治疗潜力。多克隆IgM输注可用于消除正在进行的炎症。此外，缺血性肾损伤后出现的炎症，例如，在高风险选择性心脏手术期间或同种异体移植后，可以通过预先输注多克隆IgM或用IgM离体预处理的DC或通过用疫苗方法增加体内IgM来预防。细胞疗法很有吸引力，因为需要更少的IgM。
We review how polyreactive natural IgM autoantibodies (IgM-NAA) protect the host from invading micro-organisms and host neo-antigens that are constantly being produced by oxidation mechanisms and cell apoptosis. Second, we discuss how IgM-NAA and IgM anti-leukocyte antibodies (IgM-ALA) inhibits autoimmune inflammation by anti-idiotypic mechanisms, enhancing removal of apoptotic cells, masking neo-antigens, and regulating the function of dendritic cells (DC) and effector cells. Third, we review how natural IgM prevents autoimmune disorders arising from pathogenic IgG autoantibodies, triggered by genetic mechanisms (e.g., SLE) or micro-organisms, as well as by autoreactive B and T cells that have escaped tolerance mechanisms. Studies in IgM knockout mice have clearly demonstrated 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 IgM-NAA, which are also evolutionarily conserved. Fourth, we show that 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. We also show how protective IgM-NAA can be rendered pathogenic under non-physiological conditions. We also review IgG-NAA that are more abundant than IgM-NAA in plasma. However, we need to understand if the (Fab)2 region of IgG-NAA has physiological relevance in non-disease states, as in plasma, their functional activity is blocked by IgM-NAA having anti-idiotypic activity. Some IgG-NAA are produced by B2 cells that have escaped tolerance mechanisms and we show how such pathogenic IgG-NAA are regulated to prevent autoimmune disease. The Fc region of IgG-NAA can influence inflammation and B cell function in vivo by binding to activating and inhibitory FcγR. IgM-NAA has therapeutic potential. Polyclonal IgM infusions can be used to abrogate on-going 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 is appealing as less IgM will be required.