Distinct characteristics of antibody responses against factor VIII in healthy individuals and in different cohorts of hemophilia A patients
Distinct characteristics of antibody responses against factor VIII in healthy individuals and in different cohorts of hemophilia A patients
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DOI：
10.1182/blood-2012-07-444877
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发表时间：
2013-02-07
期刊：
影响因子：
20.3
通讯作者：
Reipert, Birgit M.
中科院分区：
文献类型：
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作者：
Whelan, Shawn F. J.;Hofbauer, Christoph J.;Reipert, Birgit M.
抗凝血因子VIII（FVIII）中和抗体仍然是血友病A患者替代治疗的主要并发症。为了更好地了解这些抗体的演变，重要的是要生成全面的数据集，其中包括中和和非中和抗体，其同种型和IgG亚类。我们开发了灵敏的ELISA来分析不同队列的血友病A患者和健康个体中的FVIII结合抗体。我们的数据显示，健康个体（n = 600）中FVIII结合抗体的流行率高达19%，抗体滴度≥ 1：80的流行率为2%。在未使用FVIII抑制剂的患者（n = 77）中，FVIII结合抗体的患病率为34%（滴度≥ 1：80为5%），在成功免疫耐受诱导治疗后的患者（n = 23）中为39%（滴度≥ 1：80为4%），在使用FVIII抑制剂的患者中为100%（n = 20，所有滴度均≥ 1：80）。我们发现不同研究队列之间FVIII结合抗体的IgG亚类存在显著差异。IgG 4和IgG 1是FVIII抑制剂患者中最丰富的IgG亚类。引人注目的是，在没有FVIII抑制剂的患者和健康受试者中完全不存在IgG 4。这些发现指向一种独特的免疫调节途径，该途径负责与FVIII抑制剂相关的FVIII特异性IgG 4的形成。（血。2013;121（6）：1039-1048）
Neutralizing antibodies against factor VIII (FVIII) remain the major complication in the replacement therapy of hemophilia A patients. To better understand the evolution of these antibodies it is important to generate comprehensive datasets which include both neutralizing and nonneutralizing antibodies, their isotypes, and IgG subclasses. We developed sensitive ELISAs to analyze FVIII-binding antibodies in different cohorts of hemophilia A patients and in healthy individuals. Our data reveal the prevalence of FVIII-binding antibodies among healthy individuals (n = 600) to be as high as 19%, with a prevalence of antibody titers >= 1:80 of 2%. The prevalence of FVIII-binding antibodies was 34% (5% for titers >= 1:80) in patients without FVIII inhibitors (n = 77), 39% (4% for titers >= 1:80) in patients after successful immune tolerance induction therapy (n = 23), and 100% (n = 20, all titers >= 1:80) in patients with FVIII inhibitors. We found significant differences for IgG subclasses of FVIII-binding antibodies between the different study cohorts. IgG4 and IgG1 were the most abundant IgG subclasses in patients with FVIII inhibitors. Strikingly, IgG4 was completely absent in patients without FVIII inhibitors and in healthy subjects. These findings point toward a distinct immune regulatory pathway responsible for the development of FVIII-specific IgG4 associated with FVIII inhibitors. (Blood. 2013;121(6):1039-1048)