PDF(Pubmed)
Abstract：
BACKGROUND: Elevated systemic antibody responses against gut microbiota flagellins are observed in both Crohn\'s disease (CD) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), suggesting potential serological biomarkers for diagnosis. However, flagellin-specific antibody repertoires and functional roles in the diseases remain incompletely understood. Bacterial flagellins can be categorized into three types depending on their interaction with toll-like receptor 5 (TLR5): (1) \"stimulator\" and (2) \"silent\" flagellins, which bind TLR5 through a conserved N-terminal motif, with only stimulators activating TLR5 (involving a C-terminal domain); (3) \"evader\" flagellins of pathogens, which entirely circumvent TLR5 activation via mutations in the N-terminal TLR5 binding motif.
RESULTS: Here, we show that both CD and ME/CFS patients exhibit elevated antibody responses against distinct regions of flagellins compared to healthy individuals. N-terminal binding to Lachnospiraceae flagellins was comparable in both diseases, while C-terminal binding was more prevalent in CD. N-terminal antibody-bound flagellin sequences were similar across CD and ME/CFS, resembling \"stimulator\" and \"silent\" flagellins more than evaders. However, C-terminal antibody-bound flagellins showed a higher resemblance to the stimulator than to silent flagellins in CD, which was not observed in ME/CFS.
CONCLUSIONS: These findings suggest that antibody binding to the N-terminal domain of stimulator and silent flagellins may impact TLR5 activation in both CD and ME/CFS patients. Blocking this interaction could lead commensal bacteria to be recognized as pathogenic evaders, potentially contributing to dysregulation in both diseases. Furthermore, elevated antibody binding to the C-terminal domain of stimulator flagellins in CD may explain pathophysiological differences between the diseases. Overall, these results highlight the diagnostic potential of these antibody responses and lay a foundation for deeper mechanistic studies of flagellin/TLR5 interactions and their impact on innate/adaptive immunity balance.
RESULTS: Here, we show that both CD and ME/CFS patients exhibit elevated antibody responses against distinct regions of flagellins compared to healthy individuals. N-terminal binding to Lachnospiraceae flagellins was comparable in both diseases, while C-terminal binding was more prevalent in CD. N-terminal antibody-bound flagellin sequences were similar across CD and ME/CFS, resembling \"stimulator\" and \"silent\" flagellins more than evaders. However, C-terminal antibody-bound flagellins showed a higher resemblance to the stimulator than to silent flagellins in CD, which was not observed in ME/CFS.
CONCLUSIONS: These findings suggest that antibody binding to the N-terminal domain of stimulator and silent flagellins may impact TLR5 activation in both CD and ME/CFS patients. Blocking this interaction could lead commensal bacteria to be recognized as pathogenic evaders, potentially contributing to dysregulation in both diseases. Furthermore, elevated antibody binding to the C-terminal domain of stimulator flagellins in CD may explain pathophysiological differences between the diseases. Overall, these results highlight the diagnostic potential of these antibody responses and lay a foundation for deeper mechanistic studies of flagellin/TLR5 interactions and their impact on innate/adaptive immunity balance.
摘要：
背景：在克罗恩病（CD）和肌能性脑脊髓炎/慢性疲劳综合征（ME/CFS）中均观察到针对肠道微生物鞭毛蛋白的系统性抗体反应升高，提示潜在的血清学生物标志物用于诊断。然而,鞭毛蛋白特异性抗体库和在疾病中的功能作用仍未完全了解。细菌鞭毛蛋白可根据其与Toll样受体5（TLR5）的相互作用分为三种类型：（1）“刺激物”和（2）“沉默”鞭毛蛋白，通过保守的N端基序结合TLR5，只有刺激物激活TLR5（涉及C末端结构域）；（3）病原体的“逃避”鞭毛蛋白，通过N端TLR5结合基序中的突变完全规避了TLR5的激活。
结果：这里，我们显示,与健康个体相比,CD和ME/CFS患者对鞭毛蛋白不同区域的抗体应答均升高.在两种疾病中，N端与Lachnospirosaceae鞭毛蛋白的结合具有可比性，而C端结合在CD中更为普遍。N末端抗体结合的鞭毛蛋白序列在CD和ME/CFS中相似，比逃避者更像“刺激器”和“沉默”鞭毛蛋白。然而,C端抗体结合的鞭毛蛋白与刺激因子的相似性高于CD中的沉默鞭毛蛋白，这在ME/CFS中未观察到。
结论：这些研究结果表明，在CD和ME/CFS患者中，抗体与刺激因子和沉默鞭毛蛋白的N末端结构域结合可能会影响TLR5的激活。阻断这种相互作用可能导致共生细菌被认为是致病逃避者，可能导致这两种疾病的失调。此外，CD中与刺激鞭毛蛋白C末端结构域结合的抗体升高可能解释了疾病之间的病理生理差异。总的来说,这些结果突出了这些抗体应答的诊断潜力,并为更深层次的鞭毛蛋白/TLR5相互作用机制研究及其对先天/适应性免疫平衡的影响奠定了基础.
结果：这里，我们显示,与健康个体相比,CD和ME/CFS患者对鞭毛蛋白不同区域的抗体应答均升高.在两种疾病中，N端与Lachnospirosaceae鞭毛蛋白的结合具有可比性，而C端结合在CD中更为普遍。N末端抗体结合的鞭毛蛋白序列在CD和ME/CFS中相似，比逃避者更像“刺激器”和“沉默”鞭毛蛋白。然而,C端抗体结合的鞭毛蛋白与刺激因子的相似性高于CD中的沉默鞭毛蛋白，这在ME/CFS中未观察到。
结论：这些研究结果表明，在CD和ME/CFS患者中，抗体与刺激因子和沉默鞭毛蛋白的N末端结构域结合可能会影响TLR5的激活。阻断这种相互作用可能导致共生细菌被认为是致病逃避者，可能导致这两种疾病的失调。此外，CD中与刺激鞭毛蛋白C末端结构域结合的抗体升高可能解释了疾病之间的病理生理差异。总的来说,这些结果突出了这些抗体应答的诊断潜力,并为更深层次的鞭毛蛋白/TLR5相互作用机制研究及其对先天/适应性免疫平衡的影响奠定了基础.
