Anti-factor H autoantibodies in C3 glomerulopathies and in atypical hemolytic uremic syndrome: one target, two diseases.
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.
INSERM Unité Mixte de Recherche S1138, "Complément et Maladies" Équipe 10, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, 75006 Paris, France; Université Paris Diderot, 75013 Paris, France;
Caroline
C
Blanc
INSERM Unité Mixte de Recherche S1138, "Complément et Maladies" Équipe 10, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, 75006 Paris, France; Service de Néphrologie, Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, 75970 Paris Cedex 20, France;
Shambhuprasad Kotresh
SK
Togarsimalemath
INSERM Unité Mixte de Recherche S1138, "Complément et Maladies" Équipe 10, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, 75006 Paris, France; Université Paris Descartes, 75006 Paris, France;
Sophie
S
Chauvet
INSERM Unité Mixte de Recherche S1138, "Complément et Maladies" Équipe 10, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, 75006 Paris, France; Service de Néphrologie, Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, 75970 Paris Cedex 20, France;
Moglie
M
Le Quintrec
Service de Néphrologie et Transplantation Rénale, Centre Hospitalier Universitaire Hautepierre, 67098 Strasbourg, France;
Bruno
B
Moulin
Service de Néphrologie, Immunologie Clinique, Hôpital Bretonneau, 37044 Tours, France;
Matthias
M
Buchler
Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, 00014 Helsinki, Finland; and.
T Sakari
TS
Jokiranta
INSERM Unité Mixte de Recherche S1138, "Complément et Maladies" Équipe 10, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, 75006 Paris, France;
Lubka T
LT
Roumenina
INSERM Unité Mixte de Recherche S1138, "Complément et Maladies" Équipe 10, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, 75006 Paris, France; Service d'Immunologie Biologique, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, 75908 Paris, France.
Véronique
V
Fremeaux-Bacchi
INSERM Unité Mixte de Recherche S1138, "Complément et Maladies" Équipe 10, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, 75006 Paris, France; Service de Néphrologie, Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, 75970 Paris Cedex 20, France; Service d'Immunologie Biologique, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, 75908 Paris, France marie-agnes.durey@egp.aphp.fr.
Marie-Agnès
MA
Dragon-Durey
D000293:Adolescent; D000328:Adult; D000368:Aged; D065766:Atypical Hemolytic Uremic Syndrome / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology*; D001665:Binding Sites; D001798:Blood Proteins / Q000235:genetics; D002648:Child; D003180:Complement C3b Inactivator Proteins / Q000235:genetics; D017242:Complement Factor H / Q000037:antagonists & inhibitors* / Q000276:immunology; D017244:Complement Factor I / Q000276:immunology; D018604:Epitope Mapping; D005260:Female; D015432:Glomerulonephritis, Membranoproliferative / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007674:Kidney Diseases / Q000276:immunology; D008297:Male; D008875:Middle Aged; D055815:Young Adult
D001323:Autoantibodies; D001798:Blood Proteins; C517621:CFHR1 protein, human; C105970:CFHR3 protein, human; D003180:Complement C3b Inactivator Proteins; D007074:Immunoglobulin G; D017242:Complement Factor H; D017244:Complement Factor I