title: Hypogalactosylation of serum IgG in patients with ANCA-associated systemic vasculitis.
abstract: The triad of small vessel vasculitides (SVV) comprise Wegener's granulomatosis (WG), microscopic polyangiitis (MPA) and Churg-Strauss syndrome (CS). All three are associated with presence of circulating IgG antineutrophil cytoplasm antibodies (ANCA) which target autoantigens contained, primarily, within neutrophil azurophilic granules. The widely accepted model of pathogenesis suggests that ANCA activate cytokine-primed neutrophils within the microvasculature, leading to by-stander damage to endothelial cells, and rapid escalation of inflammation with recruitment of mononuclear cells. Activation may be initiated, in vitro, by the coligation of the PR3 or MPO antigen, translocated to the cell surface, and FcgammaRIIa/FcgammaRIIIb receptors. This suggests that the IgG subclass profile of ANCA and, possibly, its glycosylation status could influence the inflammatory mechanisms activated. The glycosylation status of total IgG isolated from the sera of patients with WG (13), MPA (6) and CSS (1) was determined by analysis of the released oligosaccharides. A deficit in IgG galactosylation is demonstrated for all patient samples, compared to controls. The mean percentage values for the agalactosylated (G0) oligosaccharides were 57% (SD +/- 9.71), 47% (SD +/- 4.25) and 28% (SD +/- 4.09) for WG, MPO and control samples, respectively. The G0 levels for polyclonal IgG isolated from the sera of both WG and MPA patients were significantly increased compared to controls (P < 0.0001). The major glycoform present therefore is agalactosylated (G0) IgG. In previous studies the G0 glycoform of IgG has been shown to bind and activate mannan binding lectin, and hence to activate the complement cascade, and to facilitate mannose receptor binding and the uptake of IgG complexes by macrophages and dendritic cells. Both of these activities could impact on the processing and presentation of self-antigens in autoimmune disease.
authors.affiliation: MRC centre for Immune regulation, The Medical School, University of Birmingham, UK.
authors.forename: M
authors.initials: M
authors.lastname: Holland
authors.forename: K
authors.initials: K
authors.lastname: Takada
authors.forename: T
authors.initials: T
authors.lastname: Okumoto
authors.forename: N
authors.initials: N
authors.lastname: Takahashi
authors.forename: K
authors.initials: K
authors.lastname: Kato
authors.forename: D
authors.initials: D
authors.lastname: Adu
authors.forename: A
authors.initials: A
authors.lastname: Ben-Smith
authors.forename: L
authors.initials: L
authors.lastname: Harper
authors.forename: C O S
authors.initials: CO
authors.lastname: Savage
authors.forename: R
authors.initials: R
authors.lastname: Jefferis
mesh_terms: D000293:Adolescent; D000368:Aged; D000369:Aged, 80 and over; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000097:blood* / Q000276:immunology; D000918:Antibody Specificity; D017951:Antigen Presentation; D001323:Autoantibodies / Q000097:blood* / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D001327:Autoimmune Diseases / Q000097:blood* / Q000276:immunology; D015267:Churg-Strauss Syndrome / Q000097:blood / Q000276:immunology; D005260:Female; D005690:Galactose / Q000097:blood*; D006031:Glycosylation; D014890:Granulomatosis with Polyangiitis / Q000097:blood / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000737:chemistry*; D008297:Male; D008875:Middle Aged; D053146:Myeloblastin; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology; D009195:Peroxidase / Q000276:immunology; D011134:Polysaccharides / Q000097:blood; D011499:Protein Processing, Post-Translational; D012697:Serine Endopeptidases / Q000276:immunology; D014657:Vasculitis / Q000097:blood / Q000276:immunology*
chemical_list: D019268:Antibodies, Antineutrophil Cytoplasmic; D001323:Autoantibodies; D001324:Autoantigens; D007074:Immunoglobulin G; D011134:Polysaccharides; D009195:Peroxidase; D012697:Serine Endopeptidases; D053146:Myeloblastin; D005690:Galactose