Departments of Medicine and Cellular and Molecular Medicine, Glycobiology Research and Training Center (GRTC) and Center for Academic Research and Training in Anthropogeny (CARTA), University of California, San Diego, La Jolla, CA, 92093-0687, USA.
J Autoimmun. 2017 Sep;83:134-142. doi: 10.1016/j.jaut.2017.07.011. Epub 2017 Jul 26.
Given varied intrinsic and extrinsic challenges to the immune system, it is unsurprising that each evolutionary lineage evolves distinctive features of immunoreactivity, and that tolerance mechanisms fail, allowing autoimmunity. Humans appear prone to many autoimmune diseases, with mechanisms both genetic and environmental. Another rapidly evolving biological system involves sialic acids, a family of monosaccharides that are terminal caps on cell surface and secreted molecules of vertebrates, and play multifarious roles in immunity. We have explored multiple genomic changes in sialic acid biology that occurred in human ancestors (hominins), some with implications for enhanced immunoreactivity, and hence for autoimmunity. Human ancestors lost the enzyme synthesizing the common mammalian sialic acid Neu5Gc, with an accumulation of the precursor sialic acid Neu5Ac. Resulting changes include an enhanced reactivity by some immune cells and increased ability of macrophages to kill bacteria, at the cost of increased endotoxin sensitivity. There are also multiple human-specific evolutionary changes in inhibitory and activating Siglecs, immune cell receptors that recognize sialic acids as "self-associated molecular patterns" (SAMPs) to modulate immunity, but can also be hijacked by pathogen molecular mimicry of SAMPs. Altered expression patterns and fixed or polymorphic SIGLEC pseudogenization in humans has modulated both innate and adaptive immunity, sometimes favoring over-reactivity. Meanwhile, dietary intake of Neu5Gc (derived primarily from red meats) allows metabolic incorporation of this non-human molecule into human cells--apparently the first example of "xeno-autoimmunity" involving "xeno-autoantigen" interactions with circulating "xeno-autoantibodies". Taken together, some of these factors may contribute to the apparent human propensity for autoimmunity.
鉴于免疫系统面临着各种内在和外在的挑战，每个进化谱系进化出独特的免疫反应特征，以及耐受机制失效导致自身免疫，这并不奇怪。人类似乎容易患上许多自身免疫性疾病，其机制既有遗传的也有环境的。另一个快速进化的生物学系统涉及唾液酸，这是一类单糖，是脊椎动物细胞表面和分泌分子的末端帽，在免疫中发挥着多种作用。我们探索了人类祖先（人科动物）中发生的唾液酸生物学的多种基因组变化，其中一些与增强的免疫反应有关，因此也与自身免疫有关。人类祖先失去了合成常见哺乳动物唾液酸 Neu5Gc 的酶，导致前体唾液酸 Neu5Ac 积累。由此产生的变化包括一些免疫细胞的反应性增强，以及巨噬细胞杀死细菌的能力增强，代价是对内毒素的敏感性增加。在抑制性和激活型 Siglec 上也有多种人类特有的进化变化，Siglec 是免疫细胞受体，它将唾液酸识别为“自身相关分子模式”（SAMPs）以调节免疫，但也可以被病原体 SAMPs 分子模拟劫持。人类 Siglec 的表达模式改变和固定或多态性假基因化调节了先天和适应性免疫，有时会导致过度反应。同时，Neu5Gc（主要来源于红肉）的饮食摄入允许这种非人类分子在人类细胞中进行代谢掺入——这显然是涉及“异种自身抗原”与循环“异种自身抗体”相互作用的“异种-autoimmunity”的第一个例子。总之，这些因素中的一些可能导致人类自身免疫的明显倾向。
