The human natural anti-αGal antibody targets common pathogens by broad-spectrum polyreactivity

Naturally occurring antibodies are abundant in human plasma, but their importance in the defence against bacterial pathogens is unclear. We studied the role of the most abundant of such antibodies, the antibody against terminal galactose-alpha-1,3-galactose (anti-alpha Gal), in the protection against pneumococcal infections (Streptococcus pneumonia). All known pneumococcal capsular polysaccharides lack terminal galactose-alpha-1,3-galactose, yet highly purified human anti-alpha Gal antibody of the IgG class reacted with 48 of 91 pneumococcal serotypes. Anti-alpha Gal was found to contain multiple antibody subsets that possess distinct specificities beyond their general reactivity with terminal galactose-alpha-1,3-galactose. These subsets in concert targeted a wide range of microbial polysaccharides. We found that anti-alpha Gal constituted up to 40% of the total antibody reactivity to pneumococci in normal human plasma, that anti-alpha Gal drives phagocytosis of pneumococci by human neutrophils and that the anti-alpha Gal level was twofold lower in patients prone to pneumococcal infections compared with controls. Moreover, during a 48-year period in Denmark, the 48 anti-alpha Gal-reactive serotypes caused fewer invasive pneumococcal infections (n = 10 927) than the 43 non-reactive serotypes (n = 18 107), supporting protection on the population level. Our findings explain the broad-spectrum pathogen reactivity of anti-alpha Gal and support that these naturally occurring polyreactive antibodies contribute significantly to human protective immunity.

Automated summary

Research shows that naturally occurring antibodies against terminal galactose-alpha-1,3-galactose play a significant role in protecting against pneumococcal infections by targeting a wide range of microbial polysaccharides. These antibodies constitute a substantial portion of total antibody reactivity in normal human plasma, driving phagocytosis of pneumococci and contributing to human protective immunity on a population level.