title: Distinct characteristics of antibody responses against factor VIII in healthy individuals and in different cohorts of hemophilia A patients.
abstract: Neutralizing antibodies against factor VIII (FVIII) remain the major complication in the replacement therapy of hemophilia A patients. To better understand the evolution of these antibodies it is important to generate comprehensive datasets which include both neutralizing and nonneutralizing antibodies, their isotypes, and IgG subclasses. We developed sensitive ELISAs to analyze FVIII-binding antibodies in different cohorts of hemophilia A patients and in healthy individuals. Our data reveal the prevalence of FVIII-binding antibodies among healthy individuals (n = 600) to be as high as 19%, with a prevalence of antibody titers > or =1:80 of 2%. The prevalence of FVIII-binding antibodies was 34% (5% for titers > or =1:80) in patients without FVIII inhibitors (n = 77), 39% (4% for titers > 1:80) in patients after successful immune tolerance induction therapy (n = 23), and 100% (n = 20, all titers > or =1:80) in patients with FVIII inhibitors. We found significant differences for IgG subclasses of FVIII-binding antibodies between the different study cohorts. IgG4 and IgG1 were the most abundant IgG subclasses in patients with FVIII inhibitors. Strikingly, IgG4 was completely absent in patients without FVIII inhibitors and in healthy subjects. These findings point toward a distinct immune regulatory pathway responsible for the development of FVIII-specific IgG4 associated with FVIII inhibitors.
authors.affiliation: Baxter Innovation GmbH, Vienna, Austria.
authors.forename: Shawn F J
authors.initials: SF
authors.lastname: Whelan
authors.forename: Christoph J
authors.initials: CJ
authors.lastname: Hofbauer
authors.forename: Frank M
authors.initials: FM
authors.lastname: Horling
authors.forename: Peter
authors.initials: P
authors.lastname: Allacher
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Wolfsegger
authors.forename: Johannes
authors.initials: J
authors.lastname: Oldenburg
authors.forename: Christoph
authors.initials: C
authors.lastname: Male
authors.forename: Jerzy
authors.initials: J
authors.lastname: Windyga
authors.forename: Andreas
authors.initials: A
authors.lastname: Tiede
authors.forename: Hans Peter
authors.initials: HP
authors.lastname: Schwarz
authors.forename: Friedrich
authors.initials: F
authors.lastname: Scheiflinger
authors.forename: Birgit M
authors.initials: BM
authors.lastname: Reipert
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D057134:Antibodies, Neutralizing / Q000097:blood / Q000276:immunology; D000917:Antibody Formation / Q000276:immunology*; D019774:Blood Coagulation Factor Inhibitors / Q000627:therapeutic use; D015331:Cohort Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005169:Factor VIII / Q000037:antagonists & inhibitors / Q000276:immunology*; D005260:Female; D006467:Hemophilia A / Q000097:blood / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood / Q000145:classification / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D055815:Young Adult
chemical_list: D057134:Antibodies, Neutralizing; D019774:Blood Coagulation Factor Inhibitors; D007074:Immunoglobulin G; D005169:Factor VIII