Department of Plasma Proteins, Sanquin Research, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands.
Department of Pediatric Hematology, Immunology and Infectious Diseases, Emma Children's Hospital, Academic Medical Center, Amsterdam, The Netherlands.
Blood Rev. 2017 Sep;31(5):339-347. doi: 10.1016/j.blre.2017.07.001. Epub 2017 Jul 4.
Hemophilia A is a bleeding disorder characterized by the absence or dysfunction of blood coagulation factor VIII (FVIII). Patients are treated with regular infusions of FVIII concentrate. In response to treatment, approximately 30% of patients with severe hemophilia A develop inhibitory antibodies targeting FVIII. Both patient and treatment related risk factors for inhibitor development have been described. Multiple studies comparing the immunogenicity of recombinant and plasma-derived FVIII have yielded conflicting results. The randomized controlled SIPPET (Survey of Inhibitors in Plasma-Product Exposed Toddlers) trial demonstrated an increased risk of inhibitor development of recombinant FVIII when compared to von Willebrand factor (VWF)-containing plasma-derived FVIII. Presently, it is unclear which mechanism underlies the reduced immunogenicity of plasma-derived FVIII. In this review we address the potential role of VWF on FVIII immunogenicity and we discuss how VWF affects the immune recognition, processing and presentation of FVIII. We also briefly discuss the potential impact of glycan-composition on FVIII immunogenicity. It is well established that VWF shields the uptake of FVIII by antigen presenting cells. We have recently shown that VWF binds to the surface of dendritic cells. Here, we present a novel model in which surface bound FVIII-VWF complexes regulate the internalization of FVIII. Binding of FVIII to VWF is critically dependent on sulfation of Tyr1699 (HVGS numbering) in the light chain of FVIII. Incomplete sulfation of Tyr1699 has been suggested to occur in several recombinant FVIII products resulting in a loss of VWF binding. We hypothesize that this results in alternative pathways of FVIII internalization by antigen presenting cells which are not regulated by VWF. This hypothetical mechanism may explain the reduced immunogenicity of VWF containing plasma-derived FVIII concentrates as found in the SIPPET study.
血友病 A 是一种出血性疾病，其特征是缺乏或功能失调的凝血因子 VIII（FVIII）。患者接受 FVIII 浓缩物的常规输注治疗。在接受治疗后，约 30%的重度血友病 A 患者会产生针对 FVIII 的抑制性抗体。已描述了患者和治疗相关的抑制物发展风险因素。多项比较重组和血浆源性 FVIII 免疫原性的研究得出了相互矛盾的结果。随机对照 SIPPET（暴露于血浆产品的婴儿抑制剂调查）试验表明，与含有血管性血友病因子（VWF）的血浆源性 FVIII 相比，重组 FVIII 发展抑制剂的风险增加。目前，尚不清楚哪种机制导致血浆源性 FVIII 的免疫原性降低。在这篇综述中，我们探讨了 VWF 对 FVIII 免疫原性的潜在作用，并讨论了 VWF 如何影响 FVIII 的免疫识别、加工和呈递。我们还简要讨论了聚糖组成对 FVIII 免疫原性的潜在影响。众所周知，VWF 可阻止 FVIII 被抗原呈递细胞摄取。我们最近表明，VWF 与树突状细胞的表面结合。在这里，我们提出了一个新的模型，其中表面结合的 FVIII-VWF 复合物调节 FVIII 的内化。FVIII 与 VWF 的结合严重依赖于 FVIII 轻链中 Tyr1699（HVGS 编号）的硫酸化。据报道，几种重组 FVIII 产品中的 Tyr1699 硫酸化不完全，导致 VWF 结合丧失。我们假设这导致抗原呈递细胞内化 FVIII 的替代途径，而这些途径不受 VWF 调节。这个假设的机制可能解释了 SIPPET 研究中发现的含有 VWF 的血浆源性 FVIII 浓缩物的免疫原性降低。
