Anti‐ G al: an abundant human natural antibody of multiple pathogeneses and clinical benefits

Summary Anti‐ G al is the most abundant natural antibody in humans, constituting ~ 1% of immunoglobulins. Anti‐ G al is naturally produced also in apes and O ld W orld monkeys. The ligand of anti‐ G al is a carbohydrate antigen called the ‘α‐gal epitope’ with the structure G alα1‐3 G alβ1‐4 G lc NA c‐ R . The α‐gal epitope is present as a major carbohydrate antigen in non‐primate mammals, prosimians and N ew W orld monkeys. Anti‐ G al can contributes to several immunological pathogeneses. Anti‐ G al I g E produced in some individuals causes allergies to meat and to the therapeutic monoclonal antibody cetuximab, all presenting α‐gal epitopes. Aberrant expression of the α‐gal epitope or of antigens mimicking it in humans may result in autoimmune processes, as in G raves' disease. α‐ G al epitopes produced by T rypanosoma cruzi interact with anti‐ G al and induce ‘autoimmune like’ inflammatory reactions in C hagas' disease. Anti‐ G al I g M and I g G further mediate rejection of xenografts expressing α‐gal epitopes. Because of its abundance, anti‐ G al may be exploited for various clinical uses. It increases immunogenicity of microbial vaccines (e.g. influenza vaccine) presenting α‐gal epitopes by targeting them for effective uptake by antigen‐presenting cells. Tumour lesions are converted into vaccines against autologous tumour‐associated antigens by intra‐tumoral injection of α‐gal glycolipids, which insert into tumour cell membranes. Anti‐ G al binding to α‐gal epitopes on tumour cells targets them for uptake by antigen‐presenting cells. Accelerated wound healing is achieved by application of α‐gal nanoparticles, which bind anti‐ G al, activate complement, and recruit and activate macrophages that induce tissue regeneration. This therapy may be of further significance in regeneration of internally injured tissues such as ischaemic myocardium and injured nerves.