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.

多数哺乳动物携带具有功能活性的N-乙酰乳糖胺α-1,3-半乳糖基转移酶1（N-acetyllactosaminide alpha-1,3-galactosyltransferase 1，GGTA1）基因，该基因编码合成Galα1-3Galβ1-4Glc（αGal）的酶。与之相对，包括人类在内的类人猿的GGTA1基因携带功能丧失型突变，且无法表达αGal（1, 2）。这类突变经自然选择并被固定后，使得αGal特异性免疫得以产生，进而增强宿主对表达αGal的病原体的抵抗能力（3-5）。本研究证实，小鼠体内Ggta1功能丧失可提升其对细菌性败血症的抵抗能力，且该效应不依赖于αGal特异性免疫。其本质并非源于αGal特异性免疫，而是得益于IgG杀菌活性的增强——这一增强由IgG与Fcγ受体IV（Fc gamma receptor IV，FcγRIV）的结合能力提升所驱动。作为一种进化权衡，Ggta1功能丧失会导致生殖衰老提前发生，这是人科（hominidae）演化早期所面临的一项显著适合度代价。