Pan IgG repertoire in AlphaGal KO mice

Most mammals carry a functional N-acetyllactosaminide alpha-1,3-galactosyltransferase 1 (GGTA1) gene, which encodes the enzyme synthetizing Galα1-3Galβ1-4Glc (αGal). In contrast, anthropoid monkeys, including humans, carry loss-of-function mutations in GGTA1 and lack αGal (1, 2). Natural selection and fixation of these mutations allowed for the emergence of αGal-specific immunity, enhancing resistance to pathogens expressing αGal (3-5). Here we demonstrate that loss of Ggta1 function in mice enhances resistance to bacterial sepsis, irrespectively of αGal-specific immunity. This is owed instead to enhanced IgG bactericidal activity, driven by improved IgG binding to the Fc gamma receptor IV (FcRIV). As a trade-off, Ggta1 loss of function causes earlier onset of reproductive senescence, a major fitness cost at play during the early stages of hominidae evolution.

大多数哺乳动物携带功能性的N-乙酰乳糖胺α-1,3-半乳糖基转移酶1 (GGTA1) 基因，该基因编码合成Galα1-3Galβ1-4Glc (αGal) 的酶。相比之下，灵长类动物，包括人类，在GGTA1基因中存在功能丧失的突变，且缺乏αGal (1, 2)。自然选择和这些突变的固定化导致了αGal特异性免疫力的产生，增强了对抗表达αGal的病原体的抵抗力 (3-5)。本研究表明，小鼠Ggta1功能的丧失增强了对抗细菌败血症的抵抗力，不论是否具有αGal特异性免疫力。这一效应归因于增强的IgG杀菌活性，这是由于IgG与Fcγ受体IV (FcRIV) 结合能力的提高。作为权衡，Ggta1功能丧失导致繁殖衰老的早期发生，这是在人类进化早期阶段所承受的主要适应性代价。