轻度甲型血友病患者中携带精氨酸593突变为半胱氨酸突变的HLA II类基因型与凝血因子VIII抑制剂

HLA class II genotype and factor VIII inhibitors in mild haemophilia A patients with an Arg593 to Cys mutation.

作者信息

Bril W S, MacLean P E, Kaijen P H P, van den Brink E N, Lardy N M, Fijnvandraat K, Peters M, Voorberg J

机构信息

Department of Plasma Proteins, Sanquin Research at CLB, Amsterdam, The Netherlands.

出版信息

Haemophilia. 2004 Sep;10(5):509-14. doi: 10.1111/j.1365-2516.2004.01011.x.

DOI:10.1111/j.1365-2516.2004.01011.x

PMID:15357778

Abstract

We evaluated inhibitor formation in a group of patients with mild haemophilia A caused by an Arg593 to Cys mutation. A remarkably high cumulative inhibitor incidence of 14% over 22 years was observed. Three of 49 patients developed transient, low-titre inhibitors, which remained below 2.0 BU mL(-1). Four patients with an Arg593 to Cys mutation developed high-titre inhibitors (>5.0 BU mL(-1)). Three of these patients have been described previously. In this study, we characterized inhibitory antibodies in a fourth patient with high-titre inhibitors. Epitope mapping studies revealed that antibodies were predominantly directed to the A2 domain of factor VIII. We addressed the role of human leucocyte antigen (HLA) class II alleles in inhibitor development in patients with an Arg593 to Cys mutation by HLA genotyping. In the group of inhibitor patients raised frequencies of HLA-DRB101 and HLA-DQB105 were observed that did not reached statistical significance. Our data suggest that inhibitor development in mild haemophilia A patients with an Arg593 to Cys mutation is not linked to HLA class II profile.

摘要

我们评估了一组由精氨酸593突变为半胱氨酸导致的轻度甲型血友病患者中抑制物的形成情况。观察到在22年期间累积抑制物发生率显著高达14%。49名患者中有3名产生了短暂的低滴度抑制物，其滴度一直低于2.0 BU mL⁻¹。4名精氨酸593突变为半胱氨酸的患者产生了高滴度抑制物（>5.0 BU mL⁻¹）。其中3名患者此前已有描述。在本研究中，我们对第四名产生高滴度抑制物的患者体内的抑制性抗体进行了表征。表位作图研究表明，抗体主要针对凝血因子VIII的A2结构域。我们通过HLA基因分型探讨了人类白细胞抗原（HLA）II类等位基因在精氨酸593突变为半胱氨酸的患者中抑制物形成过程中的作用。在产生抑制物的患者组中，观察到HLA - DRB101和HLA - DQB105的频率升高，但未达到统计学意义。我们的数据表明，精氨酸593突变为半胱氨酸的轻度甲型血友病患者中抑制物的形成与HLA II类图谱无关。