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Protective and Nonprotective Human Immunoglobulin M Monoclonal Antibodies to Cryptococcus neoformans Glucuronoxylomannan Manifest Different Specificities and Gene Use Profiles

机译:新型隐球菌葡糖醛酸甘露聚糖的保护性和非保护性人类免疫球蛋白M单克隆抗体表现出不同的特异性和基因使用特征

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摘要

The features of protective murine antibodies to the Cryptococcus neoformans capsular polysaccharide glucuronoxylomannan (GXM) have been rigorously investigated; however, the characteristics of protective human antibodies to GXM have not been defined. We produced monoclonal antibodies (MAbs) from XenoMouse mice (transgenic mice that express human immunoglobulin M [IgM], IgG2, and κ) which were immunized with a C. neoformans serotype D strain 24067 GXM-diphtheria toxoid conjugate. This study reports the specificity and efficacy of three human IgM MAbs, G14, G15, and G19, generated from these mice. Each MAb was specific for GXM, but G14 and G19 had different specificity based on their binding to serotype A strain H99 and SB4 GXMs, to which G15 did not bind. Nucleic acid sequence analysis revealed that G15 uses VH3-64 in the germ line configuration. G14 and G19 use VH6-1, which has somatic mutations. All of the MAbs use Vκ DPK22/A27. Studies of MAb efficacy in BALB/c mice showed that administration of 0.1 mg, but not 1 or 0.01 mg, of G15 prolonged survival against lethal C. neoformans strain 24067 challenge, whereas G14 and G19 were not protective at any dose. This panel of MAbs illustrates that serotype D GXM has epitopes that elicit human antibodies that can be either protective or nonprotective. Our findings suggest that VH gene use may influence GXM specificity and efficacy, and they provide insights into the possible contribution that VH gene use may have in resistance and susceptibility to cryptococcosis.
机译:严格研究了新型隐球菌荚膜多糖葡糖醛酸羟甘露聚糖(GXM)的保护性鼠抗体的功能;但是,尚未定义针对GXM的保护性人类抗体的特征。我们从XenoMouse小鼠(表达人免疫球蛋白M [IgM],IgG2和κ的转基因小鼠)中生产了单克隆抗体(MAb),这些单克隆抗体已用新孢子虫血清型D株24067 GXM-白喉类毒素结合物免疫。这项研究报告了从这些小鼠中产生的三种人IgM MAb G14,G15和G19的特异性和功效。每个MAb对GXM都是特异性的,但是G14和G19基于它们与血清型A株H99和SB4 GXM的结合而具有不同的特异性,而G15不与之结合。核酸序列分析显示,G15在种系构型中使用VH3-64。 G14和G19使用具有体细胞突变的VH6-1。所有的单克隆抗体都使用VκDPK22 / A27。在BALB / c小鼠中对MAb功效的研究表明,施用0.1 mg(而非1或0.01 mg)的G15可以延长其对致死性新孢梭菌菌株24067攻击的存活率,而G14和G19在任何剂量下均无保护性。该组MAb说明血清型D GXM具有表位,该表位引发可以是保护性或非保护性的人抗体。我们的发现表明,VH基因的使用可能会影响GXM的特异性和功效,并且它们为VH基因的使用可能对隐球菌病的耐药性和易感性提供了可能的见解。

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