Differential glycosylation of polymeric and monomeric IgA: a possible role in glomerular inflammation in IgA nephropathy.
IgA nephropathy (IgAN) is characterized by mesangial deposition of polymeric IgA1 (pIgA1) and complement. Complement activation via mannose-binding lectin and the lectin pathway is associated with disease progression. Furthermore, recent studies have indicated a possible role for secretory IgA. IgAN is associated with abnormalities in circulating IgA, including aberrant O-linked glycosylation. This study characterized and compared functional properties and N-linked glycosylation of highly purified monomeric IgA (mIgA) and pIgA from patients with IgAN and control subjects. Total serum IgA was affinity-purified from patients (n = 11) and control subjects (n = 11) followed by size separation. pIgA but not mIgA contained secretory IgA, and its concentration was significantly higher in patients with IgAN than in control subjects. Both in patients with IgAN and in control subjects, IgA binding to the GalNAc-specific lectin Helix Aspersa and to mannose-binding lectin was much stronger for pIgA than for mIgA. Furthermore, binding of IgA to mesangial cells largely was restricted to polymeric IgA. Binding of pIgA to mesangial cells resulted in increased production of IL-8, predominantly with IgA from patients with IgAN. Quantitative analysis of N-linked glycosylation of IgA heavy chains showed significant differences in glycan composition between mIgA and pIgA, including the presence of oligomannose exclusively on pIgA. In conclusion, binding and activation of mesangial cells, as well as lectin pathway activation, is a predominant characteristic of pIgA as opposed to mIgA. Furthermore, pIgA has different N-glycans, which may recruit lectins of the inflammatory pathway. These results underscore the role of pIgA in glomerular inflammation in IgAN.
Oortwijn
Beatrijs D
BD
Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands.
Roos
Anja
A
Royle
Louise
L
van Gijlswijk-Janssen
Daniëlle J
DJ
Faber-Krol
Maria C
MC
Eijgenraam
Jan-Willem
JW
Dwek
Raymond A
RA
Daha
Mohamed R
MR
Rudd
Pauline M
PM
van Kooten
Cees
C
D000328:Adult; D000818:Animals; D018932:Chemokine CCL2 / Q000378:metabolism; D005260:Female; D005922:Glomerulonephritis, IGA / Q000276:immunology* / Q000378:metabolism; D006031:Glycosylation; D006372:Helix, Snails; D006801:Humans; D007070:Immunoglobulin A / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D007678:Kidney Glomerulus / Q000473:pathology; D037102:Lectins / Q000378:metabolism*; D008297:Male; D037601:Mannose-Binding Lectin / Q000378:metabolism; D050527:Mesangial Cells / Q000378:metabolism*; D008875:Middle Aged; D009439:Neuraminidase / Q000494:pharmacology
D018932:Chemokine CCL2; D007070:Immunoglobulin A; D016209:Interleukin-8; D037102:Lectins; D037601:Mannose-Binding Lectin; D009439:Neuraminidase