Anti-factor H autoantibodies in C3 glomerulopathies and in atypical hemolytic uremic syndrome: one target, two diseases.

Abstract

Autoantibodies targeting factor H (FH), which is a main alternative complement pathway regulatory protein, have been well characterized in atypical hemolytic uremic syndrome (aHUS) but have been less well described in association with alternative pathway-mediated glomerulopathies (GP). In this study, we studied 17 patients presenting with GP who were positive for anti-FH IgG. Clinical data were collected and biological characteristics were compared with those of patients presenting with anti-FH Ab-associated aHUS. In contrast to the aHUS patients, the GP patients had no circulating FH-containing immune complexes, and their anti-FH IgG had a weaker affinity for FH. Functional studies demonstrated that these Abs induced no perturbations in FH cell surface protection or the binding of FH to its ligand. However, anti-FH IgG samples isolated from three patients were able to affect the factor I cofactor activity of FH. Epitope mapping identified the N-terminal domain of FH as the major binding site for GP patient IgG. No homozygous deletions of the CFHR1 and CFHR3 genes, which are frequently associated with the anti-FH Ab in aHUS patients, were found in the GP patients. Finally, anti-FH Abs were frequently associated with the presence of C3 nephritic factor in child GP patients and with monoclonal gammopathy in adult GP patients, who frequently showed Ig Lchain restriction during reactivity against factor H. These data provide deeper insights into the pathophysiological differences between aHUS and GP, demonstrating heterogeneity of anti-FH IgG.

• Authors: Caroline Blanc, Shambhuprasad Kotresh Togarsimalemath, Sophie Chauvet, Moglie Le Quintrec, Bruno Moulin, Matthias Buchler, T Sakari Jokiranta, Lubka T Roumenina, Véronique Fremeaux-Bacchi, Marie-Agnès Dragon-Durey
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 194 Issue 11 Pg. 5129-38 (Jun 01 2015) ISSN: 1550-6606 [Electronic] United States
• PMID: 25917093 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 by The American Association of Immunologists, Inc.

Chemical References

• Autoantibodies
• Blood Proteins
• CFHR1 protein, human
• CFHR3 protein, human
• Complement C3b Inactivator Proteins
• Immunoglobulin G
• Complement Factor H
• Complement Factor I

Topics

• Adolescent
• Adult
• Aged
• Atypical Hemolytic Uremic Syndrome (immunology)
• Autoantibodies (immunology)
• Binding Sites
• Blood Proteins (genetics)
• Child
• Complement C3b Inactivator Proteins (genetics)
• Complement Factor H (antagonists & inhibitors, immunology)
• Complement Factor I (immunology)
• Epitope Mapping
• Female
• Glomerulonephritis, Membranoproliferative (immunology)
• Humans
• Immunoglobulin G (immunology)
• Kidney Diseases (immunology)
• Male
• Middle Aged
• Young Adult