Siglec Modulation of Inflammation in Humans and Mice

唾液酸（Sias）存在于脊椎动物聚糖链的远端，介导许多生物学作用， 包括通过称为Siglecs（Sia-recognizing Ig-like lectins）的固有Sia-recognizing受体结合。我们 我假设灵长类动物和啮齿类动物中的CD 33相关Siglecs亚群（CD 33 rSiglecs） 将宿主Sias识别为“自身”，从而抑制免疫细胞的反应性。我们还假设， 表达Sia的细菌病原体利用这一机制下调先天免疫， 对他们的反应。我们之前发现了一种人类特有的进化缺失， 哺乳动物Sia N-羟乙酰神经氨酸（NeuSGc）。这将导致失去最佳的 CD 33 rSiglec配体。这些凝集素中的多种人类特异性遗传变化和调整 显然，随后发生了，使人类免疫系统处于一种改变的状态，相对于我们伟大的人类， 猿类进化上的亲戚这些差异的生物学和病理学后果正在被 通过比较人类和类人猿进行研究，但许多实际，道德和财政问题限制了这一点 approach.因此，我们建议使用转基因小鼠来模拟和比较人类和黑猩猩 唾液酸和CD 33 rSiglec生物学，阐明遗传变化导致的功能后果 在人类进化过程中。正在测试的总体假设是，人类发展的倾向 涉及先天性和适应性免疫细胞的炎性疾病，以及表达Sia的 细菌与某些CD 33 rSiglecs中的人类特异性进化变化有关。其中包括人类特异性 中性粒细胞和单核细胞上Siglec-9的Sia结合特性的变化; Siglec-11和Siglec-12在巨噬细胞上的性质、表达和功能; Siglec-11在人脑上的性质、表达和功能 小胶质细胞，以及Siglec-5对人T细胞的选择性下调。我们将使用各种 基因修饰的小鼠以模拟组成型CD 33 rSiglec“暴露”的祖先人类状况。 骨髓单核细胞;人类和黑猩猩Siglec-9的当前功能状态;人类特异性 巨噬细胞上Siglec-11和Siglec-12的变化;小胶质细胞中人特异性Siglec-11的表达;以及 T淋巴细胞上Siglec-5表达的祖先类人猿状态。这些研究将在野生型 小鼠，以及相关鼠CD 33 rSiglecs缺陷株。适当研究先天和 适应性免疫反应以及Sia表达细菌病原体的挑战将测试 原始假设这些研究涉及与其他计划成员的合作，并利用所有核心 在节目中的服务。重要的是，即使一些采取的方法不能准确地反映人类 进化，结果将阐明各种一般的基本原则，关于生物学的 先天性和适应性免疫血细胞上的CD 33 rSiglecs。

Sialic acids (Sias) presented at the distal ends of vertebrate glycan chains mediate many biological roles, including binding by intrinsic Sia-recognizing receptors called Siglecs (Sia-recognizing Ig-like lectins). We have hypothesized that the CD33-related subset of Siglecs (CD33rSiglecs) in primates and rodents recognize host Sias as "self, thereby dampening the reactivity of immune cells. We also hypothesize that Sia-expressing bacterial pathogens take advantage of this mechanism to down-regulate innate immune reactivity against them. We earlier discovered a human-specific evolutionary loss of the common mammalian Sia N-glycolylneuraminic acid (NeuSGc). This would have resulted in loss of optimal CD33rSiglec ligands. A variety of human-specific genetic changes and adjustments in these lectins apparently then ensued, leaving the human immune system in an altered state relative to that of our great ape evolutionary relatives. The biological and pathological consequences of these differences are being studied by comparing humans and great apes, but many practical, ethical and fiscal issues limit this approach. We therefore propose to use transgenic mice to model and compare human and chimpanzee sialic acid and CD33rSiglec biology, elucidating functional consequences resulting from genetic changes during human evolution. The overall hypothesis being tested is that the human propensity to develop inflammatory diseases involving innate and adaptive immune cells, as well as infections by Sia-expressing bacteria are related to human-specific evolutionary changes in certain CD33rSiglecs. These include humanspecific changes in Sia-binding properties of Siglec-9 on neutrophils and monocytes; in the binding properties, expression and function of Siglec-11 and -12 on macrophages; of Siglec-11 on human brain microglia, and the selective down-regulation of Siglec-5 on human T cells. We will use a variety of genetically modified mice to mimic the ancestral human condition of constitutive CD33rSiglec "unmasking" in myelomonocytic cells; the current functional states of human and chimpanzee Siglec-9; human-specific changes in Siglec-11 and -12 on macrophages; human-specific Siglec-11 expression in microglia; and, the ancestral great ape state of Siglec-5 expression on T lymphocytes. These studies will be done in wild-type mice, and in strains deficient in the relevant murine CD33rSiglecs. Appropriate studies of innate and adaptive immune responses as well as challenges with Sia-expressing bacterial pathogens will test the original hypotheses. These studies involve collaborations with other program members and utilize all Core services in the program. Importantly, even if some of the taken approaches fail to accurately mirror human evolution, the results will illuminate various general underlying principles regarding the biology of CD33rSiglecs on innate and adaptive immune blood cells.