Those studies are expected to have a significant impact on the optimization of treatments for patients with inhibitor as well as for patients with thrombophilia. Replacement therapy with factor VIII (FVIII) concentrates prepared from plasma or with recombinant FVIII (rFVIII) can elicit the production of specific antibodies neutralizing FVIII function, also called inhibitors

[1]. Different types of anti-FVIII antibodies have been distinguished. Type I and type II inhibitors have been defined as antibodies inhibiting FVIII activity completely or partially, respectively Z-VAD-FMK manufacturer [2]. The mechanisms of action of type II inhibitor are still only partially understood and are still intensively studied. Competition with von Willebrand factor (VWF) has been demonstrated as one such mechanism [2]. Conversely, some inhibitors rely on the presence of VWF to inhibit FVIII activity [3,4]. A detailed analysis of the specificity of FVIII inhibitors has proven to be difficult because of the large diversity of the humoral response, including antibodies which do not interfere with FVIII activity [5]. Moreover, anti-idiotypic antibodies have been described that can neutralize FVIII inhibitors PD0325901 [6,7]. To circumvent difficulties inherent to the use

of polyclonal antibodies, we produced human monoclonal antibodies directed towards FVIII and representative of patients’ pathogenic antibodies by immortalizing memory B cells from haemophilia A patients with inhibitor [8]. We have applied that strategy to characterize at the clonal level the relation between alteration of FVIII B cell epitopes and humoral response of a mild haemophilia A patient (LE) with inhibitor, who maintained significant endogenous FVIII activity RAS p21 protein activator 1 despite the presence of a high level of FVIII inhibitor [9]. The FVIII gene

mutation carried by patient LE was located in the C1 domain. When we started those experiments, mutations in that FVIII region were known to be associated with a high incidence of inhibitors in mild/moderate haemophilia A patients [10], although the reason for such an association was unclear. Moreover, inhibitor antibodies recognizing the C1 domain had never been demonstrated and no role of the latter domain in FVIII function and/or stability had been determined [11,12]. Clonal characterization of patient LE antibodies offered therefore the potential of determining whether epitopes recognized by inhibitor antibodies were located in the C1 domain, but also provided an opportunity to analyse the structure/function relationship of a FVIII domain whose function was still completely unknown. In this review, the properties of a type II human monoclonal antibody derived from patient LE will be examined in details. The importance of an unusual glycosylation in the antigen binding site of the antibody will be highlighted. This review will also emphasize how that study unexpectedly improved understanding of FVIII structure/function relation.