期刊
THROMBOSIS AND HAEMOSTASIS
卷 112, 期 1, 页码 53-64出版社
SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN
DOI: 10.1160/TH13-08-0634
关键词
Heparin-induced thrombocytopenia; platelet factor 4; GAGs; CD spectroscopy; antigenicity
资金
- Zentrum fur Innovationskompetenz Humorale Immunreaktionen bei Kardiovaskularen Erkrankungen (ZIK HIKE, Federal Ministry of Education and Research-BMBF) [FKZ 03Z2CN11, FKZ 03Z2CN12]
- European Social Fund [UG 10 022]
- Vetenskapsradet [K2013-65X-21462-04-5]
- ERC [StG-2012-311575]
Heparin-induced thrombocytopenia (HIT) is the most frequent drug-induced immune reaction affecting blood cells. Its antigen is formed when the chemokine platelet factor 4 (PF4) complexes with polyanions. By assessing polyanions of varying length and degree of sulfation using immunoassay and circular dichroism (CD)-spectroscopy, we show that PF4 structural changes resulting in antiparallel beta-sheet content >30% make PF4/polyanion complexes antigenic. Further, we found that polyphosphates (polyP-55) induce antigenic changes on PF4, whereas fondaparinux does not. We provide a model suggesting that conformational changes exposing antigens on PF4/polyanion complexes occur in the hairpin involving AA 32-38, which form together with C-terminal AA (66-70) of the adjacent PF4 monomer a continuous patch on the PF4 tetramer surface, explaining why only tetrameric PF4 molecules express HIT antigens. The correlation of antibody binding in immunoassays with PF4 structural changes provides the intriguing possibility that CD-spectroscopy could become the first antibody-independent, in vitro method to predict potential immunogenicity of drugs. CD-spectroscopy could identify compounds during preclinical drug development that induce PF4 structural changes correlated with antigenicity. The clinical relevance can then be specifically addressed during clinical trials. Whether these findings can be transferred to other endogenous proteins requires further studies.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据