Prevalence and immunogenicity of HNA-3a and -3b antibodies and antigens

HNA-3a 和 -3b 抗体和抗原的流行率和免疫原性

• 批准号: 8207902
• 负责人: Richard Herbert Aster
• 金额: $ 20.81万
• 依托单位: VERSITI WISCONSIN, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8207902
• 关键词: Acute Lung Injury; Address; Alleles; Alloantigen; Amino Acid Substitution; Antibodies; Antigens; Biological Assay; Biological Response Modifiers; Blood; Blood Transfusion; Blood donor; Blood donor screening; Cells; Complication; Detection; Donor Selection; Exposure to; FDA approved; Female; Genetic Polymorphism; Grant; HLA Antigens; Immunoassay; Incidence; Individual; Insecta; Isoantibodies; Laboratories; Length; Leukocytes; Membrane; Molecular; Mutate; Patients; Peptides; Phase; Phenotype; Population; Pregnancy; Prevalence; Property; Proteins; Reaction; Recombinants; Research; Research Personnel; Safety; Sampling; Serological; Serum; Solid; System; Testing; Time; Transfusion; Work; abstracting; base; blood product; choline transporter; extracellular; immunogenicity; improved; male; mortality; neutrophil; prototype; theories

Summary/Abstract Transfusion-associated acute lung injury (TRALI), currently the leading cause of transfusion- associated fatality, is triggered by transfusion of blood products containing leukocyte antibodies and/or biological response modifiers to susceptible patients. Although many different leukocyte antibodies have been shown to induce TRALI, those specific for the leukocyte antigen HNA-3a are especially prone to cause very severe, and often fatal reactions. Unfortunately, it has not been possible to screen blood donors routinely for anti-HNA-3a because its molecular properties have for many years eluded investigators and because HNA-3a was thought to be neutrophil-specific, a cell difficult to use in serologic studies. Thus, very little is known about the prevalence of anti-HNA-3a in blood donors and the immunogenicity of this antigen is poorly understood. Even less is known about antibodies that recognize HNA-3b, the allele of HNA-3a, although they should, in theory, be as likely to cause TRALI as anti-HNA-3a. We recently showed that HNA-3a is carried on choline transporter- like protein 2 (CTL2) and that the HNA-3a/b polymorphism is almost certainly determined by an R>Q154 (R=HNA-3a, Q = HNA-3b) amino acid substitution in the first extracellular loop of the 10- membrane-spanning CTL2 protein. These findings suggest ways to develop a practical assay for detection of anti-HNA-3a and anti-3b suitable for routine donor screening. In this application, we propose to generate recombinant and synthetic CTL2 and CTL2 fragments containing R154 and Q154 and characterize their reactions against a panel of HNA-3-specific antibodies. Constructs found to be most sensitive and specific for anti-CTL2 detection will be produced in quantity, formatted into a prototype solid phase immunoassay, and used to screen 7,000 serum samples from transfused, non-transfused and parous males and females to determine the prevalence of anti-HNA-3a in these populations. The Q154 version of these constructs should provide comparable information about anti-HNA-3b. Findings made are expected to 1) define, for the first time, the prevalence of anti-HNA-3a and anti- HNA-3b in blood donor populations; 2) characterize the immunogenicity of HNA-3 and HNA-3b (likelihood of an antibody being induced upon exposure to antigen through transfusion or during pregnancy) and 3) establish a basis for determining whether routine screening of blood donors for anti-HNA-3a and anti-HNA-3b is warranted.

摘要/摘要 输血相关急性肺损伤（TRALI），目前是输血的主要原因 相关的死亡是由含白细胞抗体的血液产物输血引发的 和/或对易感患者的生物反应修饰剂。虽然许多不同的白细胞 已显示抗体诱导TRALI，那些针对白细胞抗原HNA-3A的抗体是 特别容易引起非常严重的反应。不幸的是，它不是 可以常规筛选抗HNA-3A的献血者，因为其分子特性具有 多年来，研究人员被认为是中性粒细胞特异性的，所以一个细胞 在血清学研究中很难使用。因此，关于抗HNA-3A的患病率很少 鲜血和这种抗原的免疫原性知之甚少。关于 识别HNA-3B的抗体，HNA-3a的等位基因，尽管从理论上讲应该有可能 引起Trali为抗HNA-3A。我们最近表明，HNA-3A在胆碱转运蛋白上携带 像蛋白质2（CTL2）一样，HNA-3A/B多态性几乎可以肯定取决于 R> Q154（r = HNA-3A，Q = HNA-3B）在10-的第一个细胞外环中的氨基酸取代 跨膜CTL2蛋白。 这些发现提出了开发用于检测抗HNA-3A和抗3b的实用测定法的方法 适合常规供体筛选。在此应用中，我们建议生成重组和 合成CTL2和CTL2片段包含R154和Q154，并表征其反应 针对一组HNA-3特异性抗体。发现最敏感和特异的结构 抗CTL2检测将以数量生产，格式化为原型固相 免疫测定法，并用于从输血，未转移和欺骗中筛选7,000种血清样品 男性和女性确定这些人群中抗HNA-3A的患病率。 Q154 这些结构的版本应提供有关抗HNA-3B的可比较信息。 预计提出的发现将是1）首次定义抗HNA-3A和抗 - 的患病率 献血者种群中的HNA-3B； 2）表征HNA-3和HNA-3B的免疫原性 （通过输血暴露于抗原或期间诱导抗体的可能性 怀孕）和3）建立一个基础来确定是否常规筛选献血者 抗HNA-3A和抗HNA-3B是有必要的。

项目成果

Acute thrombocytopenia in patients treated with amiodarone is caused by antibodies specific for platelet membrane glycoproteins.

• DOI: 10.1111/bjh.12521
• 发表时间: 2013-10
• 期刊: British journal of haematology
• 影响因子: 6.5
• 作者: Sahud MA;Caulfield M;Clarke N;Koch R;Bougie D;Aster R
• 通讯作者: Aster R

Transfusion-related acute lung injury-associated HNA-3a antibodies recognize complex determinants on choline transporter-like protein 2.

与输血相关的急性肺损伤相关的 HNA-3a 抗体可识别胆碱转运蛋白样蛋白 2 上的复杂决定因素。

• DOI: 10.1111/trf.12717
• 发表时间: 2014
• 期刊: Transfusion
• 影响因子: 2.9
• 作者: Bougie,DanielW;Peterson,JulieA;Kanack,AdamJ;Curtis,BrianR;Aster,RichardH
• 通讯作者: Aster,RichardH

Full-length recombinant choline transporter-like protein 2 containing arginine 154 reconstitutes the epitope recognized by HNA-3a antibodies.

含有精氨酸 154 的全长重组胆碱转运蛋白样蛋白 2 重建了 HNA-3a 抗体识别的表位。

• DOI: 10.1111/j.1537-2995.2011.03411.x
• 发表时间: 2012
• 期刊: Transfusion
• 影响因子: 2.9
• 作者: Kanack,AdamJ;Peterson,JulieA;Sullivan,MiaJ;Bougie,DanielW;Curtis,BrianR;Aster,RichardH
• 通讯作者: Aster,RichardH