Glycosylation and Size of IgA1 Are Essential for Interaction with Mesangial Transferrin Receptor in IgA Nephropathy
| Autor: | François Vrtovsnik, Valérie Leroy, Marc Benhamou, Ivan C. Moura, Renato C. Monteiro, Koteswara R Chintalacharuvu, Elie Haddad, Jan Novak, Michelle Arcos-Fajardo, Charlotte Sadaka |
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| Rok vydání: | 2004 |
| Předmět: |
medicine.medical_specialty
Glycosylation media_common.quotation_subject chemical and pharmacologic phenomena Transferrin receptor Immune complex formation chemistry.chemical_compound fluids and secretions stomatognathic system Internal medicine Receptors Transferrin medicine Humans Internalization Receptor Cells Cultured media_common chemistry.chemical_classification Mesangial cell Chemistry Glomerulonephritis IGA General Medicine Molecular biology Immune complex Glomerular Mesangium Immunoglobulin A Endocrinology Nephrology Transferrin |
| Zdroj: | Journal of the American Society of Nephrology. 15:622-634 |
| ISSN: | 1046-6673 |
| DOI: | 10.1097/01.asn.0000115401.07980.0c |
| Popis: | Transferrin receptor (TfR) has been identified as a candidate IgA1 receptor expressed on human mesangial cells (HMC). TfR binds IgA1 but not IgA2, co-localizes with mesangial IgA1 deposits, and is overexpressed in patients with IgA nephropathy (IgAN). Here, structural requirements of IgA1 for its interaction with mesangial TfR were analyzed. Polymeric but not monomeric IgA1 interacted with TfR on cultured HMC and mediates internalization. IgA1 binding was significantly inhibited (>50%) by soluble forms of both TfR1 and TfR2, confirming that TfR serves as mesangial IgA1 receptor. Hypogalactosylated serum IgA1 from patients with IgAN bound TfR more efficiently than IgA1 from healthy individuals. Serum IgA immune complexes from patients with IgAN containing aberrantly glycosylated IgA1 bound more avidly to TfR than those from normal individuals. This binding was significantly inhibited by soluble TfR, highlighting the role of TfR in mesangial IgA1 deposition. For addressing the potential role of glycosylation sites in IgA1-TfR interaction, a variety of recombinant dimeric IgA1 molecules were used in binding studies on TfR with Daudi cells that express only TfR as IgA receptor. Deletion of either N- or O-linked glycosylation sites abrogated IgA1 binding to TfR, suggesting that sugars are essential for IgA1 binding. However, sialidase and beta-galactosidase treatment of IgA1 significantly enhanced IgA1/TfR interaction. These results indicate that aberrant glycosylation of IgA1 as well as immune complex formation constitute essential factors favoring mesangial TfR-IgA1 interaction as initial steps in IgAN pathogenesis. |
| Databáze: | OpenAIRE |
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