Jacquemin Marc, Saint-Remy Jean-Marie
University of Leuven, Center for Molecular and Vascular Biology, Herestraat 49 Bus 913, B3000 Leuven, Belgium.
University of Leuven, Center for Molecular and Vascular Biology, Herestraat 49 Bus 913, B3000 Leuven, Belgium; ImCyse s.a.-n.v., Bioincubator II, Gaston Geenslaan 1, B-3001 Leuven, Belgium.
Cell Immunol. 2016 Mar;301:8-11. doi: 10.1016/j.cellimm.2015.09.007. Epub 2015 Sep 26.
Several lines of evidence indicate that the immune response to Factor VIII (FVIII) in patients with hemophilia A is T cell-dependent. This review highlights the link between the epitope specificity of FVIII-specific T cells and their potential roles in different categories of patients. FVIII-specific T cells able to recognize wild-type (i.e. therapeutic) FVIII but not the mutated self FVIII of hemophilia patients have been identified in patients with mild/moderate hemophilia carrying some point mutations. Such T cells likely contribute to the higher frequency of neutralizing anti-FVIII antibodies (inhibitors) development in these patients. In contrast, as yet no T cells have been identified that can differentiate between FVIII molecules with non-hemophilia-causing single amino acid variants encoded by non-synonymous single-nucleotide polymorphisms in the F8 gene. Other mechanisms are therefore still to be identified that will explain the clinically noted differences in the incidence of inhibitor development between patients of different races who are known to have differences at these sites. Beside information about the mechanism of inhibitor development, the analysis of FVIII-specific T cells has provided tools to develop novel diagnostic and therapeutic approaches, such as the generation of FVIII-specific regulatory T cells that may be useful in preventing or suppressing the immune response to FVIII.
多条证据表明，甲型血友病患者对凝血因子VIII（FVIII）的免疫反应是T细胞依赖性的。本综述强调了FVIII特异性T细胞的表位特异性与其在不同类别患者中的潜在作用之间的联系。在携带一些点突变的轻度/中度血友病患者中，已鉴定出能够识别野生型（即治疗性）FVIII但不能识别血友病患者突变的自身FVIII的FVIII特异性T细胞。此类T细胞可能导致这些患者中产生中和性抗FVIII抗体（抑制剂）的频率更高。相比之下，尚未鉴定出能够区分由F8基因中的非同义单核苷酸多态性编码的具有非血友病致病单氨基酸变体的FVIII分子的T细胞。因此，仍有待确定其他机制，以解释在这些位点存在差异的不同种族患者中临床上观察到的抑制剂产生发生率的差异。除了有关抑制剂产生机制的信息外，对FVIII特异性T细胞的分析还提供了开发新型诊断和治疗方法的工具，例如生成可能有助于预防或抑制对FVIII的免疫反应的FVIII特异性调节性T细胞。
