Do proteolytic antibodies complete the panoply of the autoimmune response in acquired haemophilia A?

Abstract

Acquired haemophilia A (AHA) is a rare bleeding disorder characterized by the sudden generation of autoantibodies against factor VIII (FVIII) in individuals with no previous history of abnormal haemostasis. Understanding the pathogenesis of this disease has been hampered by the rarity of the patients and the difficulty in obtaining biological material from untreated patients. Still, progress has been made recently in understanding the pathogenesis of AHA. In particular, the importance of CD4(+) T cells in AHA development has been documented and the epitopes targeted by T cells on FVIII have been delineated. Accordingly, a polymorphism in the cytotoxic T-lymphocyte-associated protein 4 gene (CTLA4), known to participate in the regulation of CD4(+) T-cell responses, and a preferential usage of certain human leukocyte antigen class II haplotypes, have been associated with the disease. Recent findings have documented the presence of immunoglobulin G (IgG) with proteolytic activity against FVIII and factor IX (FIX) in patients with AHA. While FVIII-hydrolysing IgG has been shown to inactivate FVIII, FIX-hydrolysing IgG from AHA patients activate FIX in vitro. Here, we describe the latest findings on the immuno-pathogenesis of AHA, with a special focus on the potential role played by antibodies endowed with proteolytic properties.