Galili Uri
Department of Surgery, University of Massachusetts Medical School, Worcester, MA, USA.
Xenotransplantation. 2013 Sep-Oct;20(5):267-76. doi: 10.1111/xen.12051. Epub 2013 Aug 22.
Anti-Gal is the most abundant natural antibody in humans and Old World primates (apes and Old World monkeys). Its ligand, the α-gal epitope (Galα1-3Galβ1-4GlcNAc-R), is abundant in nonprimate mammals, prosimians and New World monkeys whereas it is absent in humans and Old World primates as a result of inactivation of the α1,3galactosyltransferase (α1,3GT) gene in ancestral Old World primates, as recent as 20-28 million years ago. Since anti-Gal has been a "forbidden" autoantibody for >140 million years of evolution in mammals producing α-gal epitopes it was of interest to determine whether ancestral Old World primates could produce anti-Gal once α-gal epitopes were eliminated, i.e. did they carry anti-Gal encoding immunoglobulin genes, or did evolutionary selection eliminate these genes that may be detrimental in mammals synthesizing α-gal epitopes. This question was studied by evaluating anti-Gal prodution in α1,3GT knockout (GT-KO) pigs recently generated from wild-type pigs in which the α-gal epitope is a major self-antigen.
Anti-Gal antibody activity in pig sera was assessed by ELISA, flow cytometry and complement mediated cytolysis and compared to that in human sera.
The study demonstrates abundant production of the natural anti-Gal antibody in GT-KO pigs at titers even higher than in humans. The fine specificity of GT-KO pig anti-Gal is identical to that of human anti-Gal.
Pigs and probably other mammals producing α-gal epitopes carry immunoglobulin genes encoding anti-Gal as an autoantibody. Once the α-gal epitope is eliminated in GT-KO pigs, they produce anti-Gal. These findings strongly suggest that similar to GT-KO pigs, inactivation of the α1,3GT gene in ancestral Old World primates enabled the immediate production of anti-Gal, possibly as a protective antibody against detrimental microbial agents carrying α-gal epitopes.
抗半乳糖（Anti-Gal）是人类和旧世界灵长类动物（猿类和旧世界猴）中最丰富的天然抗体。其配体，α-半乳糖表位（Galα1-3Galβ1-4GlcNAc-R），在非灵长类哺乳动物、原猴亚目动物和新世界猴中含量丰富，而在人类和旧世界灵长类动物中不存在，这是由于在距今2000万至2800万年前的旧世界灵长类动物祖先中，α1,3-半乳糖基转移酶（α1,3GT）基因失活所致。由于在产生α-半乳糖表位的哺乳动物中，抗半乳糖在超过1.4亿年的进化过程中一直是一种“禁忌”自身抗体，因此，确定一旦α-半乳糖表位被消除，旧世界灵长类动物祖先是否能够产生抗半乳糖很有意义，也就是说，它们是否携带编码抗半乳糖的免疫球蛋白基因，或者进化选择是否消除了这些在合成α-半乳糖表位的哺乳动物中可能有害的基因。通过评估最近从野生型猪培育出的α1,3GT基因敲除（GT-KO）猪中的抗半乳糖产生情况，对这个问题进行了研究，在野生型猪中，α-半乳糖表位是一种主要的自身抗原。
通过酶联免疫吸附测定（ELISA）、流式细胞术和补体介导的细胞溶解来评估猪血清中的抗半乳糖抗体活性，并与人类血清中的进行比较。
该研究表明，GT-KO猪中天然抗半乳糖抗体大量产生，其滴度甚至高于人类。GT-KO猪抗半乳糖的精细特异性与人类抗半乳糖相同。
猪以及可能其他产生α-半乳糖表位的哺乳动物携带编码抗半乳糖作为自身抗体的免疫球蛋白基因。一旦GT-KO猪中的α-半乳糖表位被消除，它们就会产生抗半乳糖。这些发现强烈表明，与GT-KO猪类似，旧世界灵长类动物祖先中α1,3GT基因的失活使得抗半乳糖能够立即产生，可能作为一种针对携带α-半乳糖表位的有害微生物的保护性抗体。
