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Antibody Repertoires in Humanized NOD-scid-IL2Rγnull Mice and Human B Cells Reveals Human-Like Diversification and Tolerance Checkpoints in the Mouse

机译:人源化NOD-scid-IL2Rγnull小鼠和人类B细胞中的抗体库揭示了小鼠中类似人类的多样化和耐受性检查点

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摘要

Immunodeficient mice reconstituted with human hematopoietic stem cells enable the in vivo study of human hematopoiesis. In particular, NOD-scid-IL2Rγnull engrafted mice have been shown to have reasonable levels of T and B cell repopulation and can mount T-cell dependent responses; however, antigen-specific B-cell responses in this model are generally poor. We explored whether developmental defects in the immunoglobulin gene repertoire might be partly responsible for the low level of antibody responses in this model. Roche 454 sequencing was used to obtain over 685,000 reads from cDNA encoding immunoglobulin heavy (IGH) and light (IGK and IGL) genes isolated from immature, naïve, or total splenic B cells in engrafted NOD-scid-IL2Rγnull mice, and compared with over 940,000 reads from peripheral B cells of two healthy volunteers. We find that while naïve B-cell repertoires in humanized mice are chiefly indistinguishable from those in human blood B cells, and display highly correlated patterns of immunoglobulin gene segment use, the complementarity-determining region H3 (CDR-H3) repertoires are nevertheless extremely diverse and are specific for each individual. Despite this diversity, preferential DH-JH pairings repeatedly occur within the CDR-H3 interval that are strikingly similar across all repertoires examined, implying a genetic constraint imposed on repertoire generation. Moreover, CDR-H3 length, charged amino-acid content, and hydropathy are indistinguishable between humans and humanized mice, with no evidence of global autoimmune signatures. Importantly, however, a statistically greater usage of the inherently autoreactive IGHV4-34 and IGKV4-1 genes was observed in the newly formed immature B cells relative to naïve B or total splenic B cells in the humanized mice, a finding consistent with the deletion of autoreactive B cells in humans. Overall, our results provide evidence that key features of the primary repertoire are shaped by genetic factors intrinsic to human B cells and are principally unaltered by differences between mouse and human stromal microenvironments.
机译:用人类造血干细胞重建的免疫缺陷小鼠能够进行体内人类造血研究。尤其是,已植入NOD-scid-IL2Rγnull的小鼠具有合理水平的T细胞和B细胞种群,并且可以引发T细胞依赖性反应。但是,该模型中的抗原特异性B细胞反应通常较差。我们探索了免疫球蛋白基因库中的发育缺陷是否可能部分归因于该模型中抗体应答的低水平。使用Roche 454测序从植入的NOD-scid-IL2Rγnull小鼠的未成熟,幼稚或总脾B细胞中分离的免疫球蛋白重(IGH)和轻(IGK和IGL)基因编码的cDNA中获得超过685,000个读数,并与从两名健康志愿者的外周血B细胞读取940,000条信息。我们发现,虽然人源化小鼠中的初次B细胞谱与人类血液B细胞中的朴素主要区别不大,并且显示出高度相关的免疫球蛋白基因片段使用模式,但互补决定区H3(CDR-H3)谱却极为不同并针对每个人。尽管有这种多样性,但优先DH-JH配对在CDR-H3区间内反复出现,在所有检查的谱库中都极为相似,这意味着对谱库生成施加了遗传限制。此外,在人与人源化的小鼠之间,CDR-H3的长度,带电荷的氨基酸含量和亲水性是无法区分的,没有证据表明存在整体自身免疫特征。然而重要的是,在新形成的未成熟B细胞中,与人源化小鼠的幼稚B细胞或总脾脏B细胞相比,在统计学上更多地使用了固有的自身反应性IGHV4-34和IGKV4-1基因,这一发现与删除了人体中的自身反应性B细胞。总体而言,我们的结果提供了证据,表明主要库的关键特征受人类B细胞固有的遗传因素影响,并且基本上不受小鼠和人类基质微环境之间差异的影响。

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