Lin Erica V, Krier-Burris Rebecca A, Sokol Kristina A, Arce Betania, Vilela Natalia M, Hamilton Robert G, Bochner Bruce S, Dispenza Melanie C
Division of Allergy and Clinical Immunology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
Division of Allergy and Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States.
Front Immunol. 2025 Aug 25;16:1628194. doi: 10.3389/fimmu.2025.1628194. eCollection 2025.
NSG-SGM3 humanized mouse models are well-suited for studying human immune physiology but are technically challenging and expensive. We previously characterized a simplified NSG-SGM3 mouse, engrafted with human donor CD34 hematopoietic stem cells without receiving prior bone marrow ablation or human secondary lymphoid tissue implantation, that still retains human mast cell- and basophil-dependent passive anaphylaxis responses. Its capacities for human antibody production and human B cell maturation, however, remain unknown. Here, we show that NSG-SGM3 mice engrafted without prior marrow ablation spontaneously produce all human antibodies, including IgE, without deliberate sensitization. These human IgE antibodies are polyclonal with unexpected specificities to diverse allergens, such as millet, egg, and wasp venom, that are otherwise absent from the mouse diet or housing environments. Furthermore, human CD138 CD27 plasma cell and CD20 CD27 memory B cell populations can be expanded from naïve engrafted NSG-SGM3 splenocytes in response to human CD40L and IL-4 cytokine stimulation . Engrafted NSG-SGM3 mice, but not non-engrafted controls, also exhibit dose-dependent passive systemic anaphylaxis responses when challenged with goat anti-human IgE. In contrast, no anaphylaxis responses were observed in humanized NSG-SGM3 mice challenged with select food allergens. Together, our results demonstrate that engrafted NSG-SGM3 mice without prior ablation spontaneously produce abundant functional human antibodies, including polyclonal IgE that can facilitate anaphylaxis. These mice also unexpectedly possess the upstream capacity to support human B cell maturation into antibody-producing plasma cells and memory B cells. Our simpler humanized NSG-SGM3 model therefore reveals novel insights into dynamics of human B cell maturation, homing, and differentiation that facilitate the generation of a basal, functional, polyclonal IgE repertoire without deliberate sensitization.
NSG-SGM3人源化小鼠模型非常适合用于研究人类免疫生理学，但在技术上具有挑战性且成本高昂。我们之前鉴定了一种简化的NSG-SGM3小鼠，其植入了人类供体CD34造血干细胞，无需事先进行骨髓消融或植入人类二级淋巴组织，仍保留了人类肥大细胞和嗜碱性粒细胞依赖性被动过敏反应。然而，其产生人类抗体和人类B细胞成熟的能力仍不清楚。在此，我们表明未经事先骨髓消融植入的NSG-SGM3小鼠在没有故意致敏的情况下自发产生所有人类抗体，包括IgE。这些人类IgE抗体是多克隆的，对多种过敏原具有意想不到的特异性，如小米、鸡蛋和黄蜂毒液，而这些过敏原在小鼠饮食或饲养环境中原本是不存在的。此外，人类CD138 CD27浆细胞和CD20 CD27记忆B细胞群体可从初次植入的NSG-SGM3脾细胞中通过人类CD40L和IL-4细胞因子刺激而扩增。植入的NSG-SGM3小鼠而非未植入的对照小鼠在用山羊抗人IgE攻击时也表现出剂量依赖性被动全身过敏反应。相比之下，在用选定的食物过敏原攻击的人源化NSG-SGM3小鼠中未观察到过敏反应。总之，我们的结果表明未经事先消融植入的NSG-SGM3小鼠自发产生大量功能性人类抗体，包括可促进过敏反应的多克隆IgE。这些小鼠还意外地具备支持人类B细胞成熟为产生抗体的浆细胞和记忆B细胞的上游能力。因此，我们更简单的人源化NSG-SGM3模型揭示了人类B细胞成熟、归巢和分化动态的新见解，这些见解有助于在没有故意致敏的情况下产生基础的、功能性的、多克隆IgE库。
