Falconar Andrew K I
Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, UK.
Clin Vaccine Immunol. 2007 May;14(5):493-504. doi: 10.1128/CVI.00371-06. Epub 2007 Feb 28.
Antibodies generated to the purified dengue type 2 virus (D-2V) nonstructural-1 (NS1) protein in mice and rabbits were compared with those generated to this protein in congeneic (H-2 class II) mouse strains and humans after D-2V infections. Unlike the profiles observed with the rabbits, similar antibody reaction profiles were generated by mice and humans with severe D-2V disease (dengue hemorrhagic fever [DHF]/dengue shock syndrome [DSS]). Many of these epitopes contained the core acidic-hydrophobic-basic (tri-amino-acid; ELK-type) motifs present in the positive or negative orientations. Antibody responses generated to these ELK/KLE-type motifs and the epitope LX1 on this protein were influenced by class II molecules in mice during D-2V infections; but these antibodies cross-reacted with human fibrinogen and platelets, as implicated in DHF/DSS pathogenesis. The core LX1 epitope (113YSWKTWG119), identified by the dengue virus complex-specific monoclonal antibody (MAb) 3D1.4, was prepared so that it contained natural I-Ad-binding and ELK-type motifs. This AFLX1 peptide, which appropriately displayed the ELK-type and LX1 epitopes in solid-phase immunoassays, generated a similar, but lower, immunodominant anti-ELK-motif antibody reaction in I-Ad-positive mice, as generated in mice and humans during D-2V infections. These antibody responses were much stronger in the high-responding mouse strains and each of the DHF/DSS patients tested and may therefore account for the association of DHF/DSS resistance or susceptibility with particular class II molecules and autoantibodies, antibody-stimulating cytokines (e.g., interleukin-6), and complement product C3a being implicated in DHF/DSS pathogenesis. These results are likely to be important for the design of a safe vaccine against this viral disease and showed the AFLX1 peptide and MAb 3D1.4 to be valuable diagnostic reagents.
将在小鼠和兔子体内针对纯化的登革2型病毒（D - 2V）非结构蛋白1（NS1）产生的抗体，与在同基因（H - 2 II类）小鼠品系和人类感染D - 2V后针对该蛋白产生的抗体进行了比较。与在兔子中观察到的情况不同，患有严重D - 2V疾病（登革出血热[DHF]/登革休克综合征[DSS]）的小鼠和人类产生了相似的抗体反应谱。这些表位中有许多含有以正向或负向存在的核心酸性 - 疏水 - 碱性（三氨基酸；ELK型）基序。在D - 2V感染期间，小鼠体内针对这些ELK/KLE型基序和该蛋白上的表位LX1产生的抗体反应受II类分子影响；但这些抗体与人类纤维蛋白原和血小板发生交叉反应，这与DHF/DSS的发病机制有关。由登革病毒复合物特异性单克隆抗体（MAb）3D1.4鉴定的核心LX1表位（113YSWKTWG119），其制备使其包含天然的I - Ad结合基序和ELK型基序。这种AFLX1肽在固相免疫测定中能恰当地展示ELK型和LX1表位，在I - Ad阳性小鼠中产生了与小鼠和人类在D - 2V感染期间产生的类似但较弱的免疫显性抗ELK基序抗体反应。在高反应性小鼠品系以及所检测的每例DHF/DSS患者中，这些抗体反应要强得多，因此可能解释了DHF/DSS抗性或易感性与特定II类分子、自身抗体、抗体刺激细胞因子（如白细胞介素 - 6）以及参与DHF/DSS发病机制的补体产物C3a之间的关联。这些结果可能对设计针对这种病毒性疾病的安全疫苗很重要，并表明AFLX1肽和MAb 3D1.4是有价值的诊断试剂。
