Supplementary Materials Varthaman et al

Supplementary Materials Varthaman et al. where all hemophilia A patients develop anti-factor VIII immune responses during replacement therapy irrespective of associated danger signals. We further postulate that the onset of clinically relevant factor VIII inhibitors results from an inability to develop counteractive tolerogenic responses to exogenous factor VIII rather than from an exacerbated activation of the immune system at the time of factor VIII administration. A better understanding of the pathogenesis of neutralizing anti-factor VIII antibodies will have repercussions on the clinical management of patients and highlight new strategies to achieve active immune tolerance to therapeutic factor VIII. Introduction Hemophilia A is a rare X-linked hemorrhagic disorder that results from insufficient levels of pro-coagulant factor VIII (FVIII). Patients with hemophilia A constitute a heterogeneous group of individuals. Three severities of hemophilia A are distinguished depending on the levels of circulating endogenous FVIII. They reflect the diversity in the CCB02 mutations in the gene encoding for FVIII: patients with a severe form of the disease have undetectable FVIII activity in plasma, while patients with mild and moderate hemophilia A ADAM17 have more than 1% of the normal levels of FVIII activity. Patients with severe hemophilia A are further differentiated according to the presence or absence of a non-functional FVIII protein (FVIII:Ag). For instance, among patients with severe hemophilia A, those with the V634M missense mutation have normal levels of FVIII:Ag, although the protein is non-functional,1 while patients with large deletion/intron inversions have no circulating protein.2 Due to such differences in protein expression, patients are also heterogeneous as far as the education of their immune system against endogenous FVIII is concerned. To date, the prevention or treatment of bleeds in hemophilia A patients relies on the intravenous administration of therapeutic FVIII. Therapeutic FVIII is usually purified from pools of plasma from healthy blood donors or originates from recombinant technology. While differences exist between plasma-derived and recombinant FVIII products, as well as CCB02 among recombinant products, CCB02 in terms of structure, glycosylation pattern,3 ability to bind von Willebrand factor (VWF),4 the endogenous chaperone for FVIII, all the available products share the property of inducing neutralizing immunoglobulin G (IgG), termed FVIII inhibitors, in a substantial number of patients. The occurrence of FVIII inhibitors following replacement therapy is usually a serious clinical problem that complicates patients management and reduces their quality of life, as well as being a major society issue owing to the high costs associated with the treatment of bleeding when FVIII cannot be used.5 Several factors have been identified CCB02 as increasing the risk of a patient developing FVIII inhibitors, in particular genetic risk factors such as a family history of inhibitor development,6 the type of gene abnormality causing the hemophilia A and the ensuing severity of the disease,7,8 HLA-DR haplotypes9,10 and polymorphisms in a restricted set of immune genes.11C14 CCB02 Nevertheless, it is, to date, impossible to predict with certainty whether a given patient will develop FVIII inhibitors. Over the last 20 years, a large body of the research dedicated to deciphering the immunogenicity of FVIII has been based on the danger theory proposed by Polly Matzinger almost 25 years ago.15 Researchers have attempted to elucidate the nature of the danger signals that are adjuvants of the immune response to exogenous FVIII in 5-30% of patients with hemophilia A (including all severities of the disease) following replacement therapy. Here, we review the.