水通道蛋白-5特异性重链VDJ敲入（A5H）小鼠揭示了分子模拟驱动的自身反应性B细胞反应的启动和多样化
Aquaporin-5-specific heavy chain VDJ knock-in (A5H) mice reveal molecular mimicry-driven initiation and diversification of autoreactive B-cell responses.
摘要(中文译文)
分子模拟是指微生物抗原与自身抗原相似，被认为参与触发自身免疫反应，但导致自身抗体产生的早期B细胞事件仍不清楚。在此，我们构建了A5H小鼠，这是一种敲入模型，其中与水通道蛋白-5（AQP5）“E”表位（AQP5E）结合的重链优先产生识别微生物模拟肽（PmE-L）的B细胞。A5H小鼠表现出正常的B细胞发育，但伴有失能相关B细胞区室的表型性减少以及模拟肽反应性B细胞池的扩增。在稳态下，A5H小鼠产生抗PmE-L抗体，而ELISA检测不到抗AQP5E自身抗体。用PmE-L免疫后，模拟肽反应性B细胞被招募进入生发中心反应，导致大量产生与同源AQP（AQP4和AQP1）交叉反应的抗AQP5E自身抗体。此外，用链霉亲和素复合的PmE-L免疫后，A5H小鼠产生了抗AQP5E自身抗体，表明A5H来源的模拟肽反应性B细胞能够克服与免疫优势载体抗原链霉亲和素的竞争。然而，未观察到向天然AQP5分子内表位扩展的证据。一致地，自身抗体的组织沉积和唾液腺病理改变仍然轻微。值得注意的是，杂合子（+/A5H）小鼠的自身抗体反应强于纯合子（A5H/A5H）小鼠，表明等位基因包容增强了自身反应性B细胞的活化。这些发现确立了A5H小鼠作为解析分子模拟如何启动和多样化自身反应性B细胞反应的有价值模型，推进了对自身免疫疾病起始机制的理解。
Abstract
Molecular mimicry, where microbial antigens resemble self-antigens, is implicated in triggering autoimmune responses, yet the early B-cell events leading to autoantibody production remain unclear. Here, we generated A5H mice, a knock-in model in which a heavy chain binding to the aquaporin-5 (AQP5) "E" epitope (AQP5E) preferentially generates B cells recognizing a microbial mimic peptide (PmE-L). A5H mice exhibited normal B-cell development with a phenotypic reduction in the anergy-associated B-cell compartment and an expanded pool of mimic-reactive B cells. At steady state, A5H mice produced anti-PmE-L antibodies, whereas anti-AQP5E autoantibodies were not detectable by ELISA. Upon immunization with PmE-L, mimic-reactive B cells were recruited into germinal center responses, leading to robust production of anti-AQP5E autoantibodies that cross-reacted with homologous AQPs (AQP4 and AQP1). Furthermore, A5H mice generated anti-AQP5E autoantibodies upon immunization with streptavidin-complexed PmE-L, indicating that A5H-derived mimic-reactive B cells can overcome competition with the immunodominant carrier antigen streptavidin. However, evidence of intramolecular epitope spreading to native AQP5 was not observed. Consistently, tissue deposition of autoantibodies and salivary gland pathology remained minimal. Notably, autoantibody responses were stronger in heterozygous (+/A5H) than homozygous (A5H/A5H) mice, indicating that allelic inclusion enhances autoreactive B-cell activation. These findings establish A5H mice as a valuable model to dissect how molecular mimicry initiates and diversifies autoreactive B-cell responses, advancing understanding of autoimmune disease initiation.
如何引用
AMA
Hyunjin Kim, Nayoon Lee, Sabin Acharya, Sungmin Kim, Youngnim Choi. Aquaporin-5-specific heavy chain VDJ knock-in (A5H) mice reveal molecular mimicry-driven initiation and diversification of autoreactive B-cell responses.. Frontiers in immunology. 2026; doi:10.3389/fimmu.2026.1866158.
APA
Hyunjin Kim, Nayoon Lee, Sabin Acharya, Sungmin Kim, Youngnim Choi (2026). Aquaporin-5-specific heavy chain VDJ knock-in (A5H) mice reveal molecular mimicry-driven initiation and diversification of autoreactive B-cell responses.. Frontiers in immunology. https://doi.org/10.3389/fimmu.2026.1866158
GB/T 7714
Hyunjin Kim, Nayoon Lee, Sabin Acharya, Sungmin Kim, Youngnim Choi. Aquaporin-5-specific heavy chain VDJ knock-in (A5H) mice reveal molecular mimicry-driven initiation and diversification of autoreactive B-cell responses.[J]. Frontiers in immunology, 2026 doi:10.3389/fimmu.2026.1866158.
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