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α1,3Galactosyltransferase knockout pigs produce the natural anti‐Gal antibody and simulate the evolutionary appearance of this antibody in primates

2013; Wiley; Volume: 20; Issue: 5 Linguagem: Inglês

10.1111/xen.12051

1399-3089

Uri Galili,

Animal Genetics and Reproduction

Abstract Background Anti‐ G al is the most abundant natural antibody in humans and O ld W orld primates (apes and O ld W orld monkeys). Its ligand, the α‐gal epitope ( G alα1‐3 G alβ1‐4 G lc NA c‐ R ), is abundant in nonprimate mammals, prosimians and N ew W orld monkeys whereas it is absent in humans and O ld W orld primates as a result of inactivation of the α1,3galactosyltransferase (α1, 3G T) gene in ancestral O ld W orld primates, as recent as 20–28 million years ago. Since anti‐ G al 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 O ld W orld primates could produce anti‐ G al once α‐gal epitopes were eliminated, i.e. did they carry anti‐ G al 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‐ G al prodution in α1,3 GT knockout ( GT ‐ KO ) pigs recently generated from wild‐type pigs in which the α‐gal epitope is a major self‐antigen. Methods Anti‐ G al antibody activity in pig sera was assessed by ELISA , flow cytometry and complement mediated cytolysis and compared to that in human sera. Results The study demonstrates abundant production of the natural anti‐ G al antibody in GT ‐ KO pigs at titers even higher than in humans. The fine specificity of GT ‐ KO pig anti‐ G al is identical to that of human anti‐ G al. Conclusions Pigs and probably other mammals producing α‐gal epitopes carry immunoglobulin genes encoding anti‐ G al as an autoantibody. Once the α‐gal epitope is eliminated in GT ‐ KO pigs, they produce anti‐ G al. These findings strongly suggest that similar to GT ‐ KO pigs, inactivation of the α1,3 GT gene in ancestral O ld W orld primates enabled the immediate production of anti‐ G al, possibly as a protective antibody against detrimental microbial agents carrying α‐gal epitopes.