title: Novel mechanism for the generation of human xeno-autoantibodies against the nonhuman sialic acid N-glycolylneuraminic acid.
abstract: The nonhuman sialic acid N-glycolylneuraminic acid (Neu5Gc) is metabolically incorporated into human tissues from certain mammalian-derived foods, and this occurs in the face of an anti-Neu5Gc "xeno-autoantibody" response. Given evidence that this process contributes to chronic inflammation in some diseases, it is important to understand when and how these antibodies are generated in humans. We show here that human anti-Neu5Gc antibodies appear during infancy and correlate with weaning and exposure to dietary Neu5Gc. However, dietary Neu5Gc alone cannot elicit anti-Neu5Gc antibodies in mice with a humanlike Neu5Gc deficiency. Other postnatally appearing anti-carbohydrate antibodies are likely induced by bacteria expressing these epitopes; however, no microbe is known to synthesize Neu5Gc. Here, we show that trace exogenous Neu5Gc can be incorporated into cell surface lipooligosaccharides (LOS) of nontypeable Haemophilus influenzae (NTHi), a human-specific commensal/pathogen. Indeed, infant anti-Neu5Gc antibodies appear coincident with antibodies against NTHi. Furthermore, NTHi that express Neu5Gc-containing LOS induce anti-Neu5Gc antibodies in Neu5Gc-deficient mice, without added adjuvant. Finally, Neu5Gc from baby food is taken up and expressed by NTHi. As the flora residing in the nasopharynx of infants can be in contact with ingested food, we propose a novel model for how NTHi and dietary Neu5Gc cooperate to generate anti-Neu5Gc antibodies in humans.
authors.affiliation: Department of Medicine, Skaggs School of Pharmacy and PharmaceuticalSciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Taylor
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Gregg
authors.forename: Vered
authors.initials: V
authors.lastname: Padler-Karavani
authors.forename: Darius
authors.initials: D
authors.lastname: Ghaderi
authors.forename: Hai
authors.initials: H
authors.lastname: Yu
authors.forename: Shengshu
authors.initials: S
authors.lastname: Huang
authors.forename: Ricardo U
authors.initials: RU
authors.lastname: Sorensen
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.forename: Jaime
authors.initials: J
authors.lastname: Inostroza
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
authors.forename: Ajit
authors.initials: A
authors.lastname: Varki
mesh_terms: D000328:Adult; D000818:Animals; D000910:Antibodies, Heterophile / Q000097:blood / Q000276:immunology*; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D004040:Dietary Carbohydrates / Q000008:administration & dosage / Q000276:immunology; D005260:Female; D005690:Galactose / Q000276:immunology; D006193:Haemophilus influenzae / Q000276:immunology / Q000378:metabolism; D006801:Humans; D056724:Immunity, Humoral / Q000276:immunology*; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D007075:Immunoglobulin M / Q000097:blood / Q000276:immunology; D007223:Infant; D007225:Infant Food / Q000382:microbiology; D007231:Infant, Newborn; D008070:Lipopolysaccharides / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D006899:Mixed Function Oxygenases / Q000235:genetics; D009438:Neuraminic Acids / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D014611:Vaccination
chemical_list: D000910:Antibodies, Heterophile; D001323:Autoantibodies; D004040:Dietary Carbohydrates; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D008070:Lipopolysaccharides; D009438:Neuraminic Acids; C023023:lipid-linked oligosaccharides; C032592:N-glycolylneuraminic acid; D006899:Mixed Function Oxygenases; C074383:CMPacetylneuraminate monooxygenase; D005690:Galactose