The pathophysiology of sickle cell disease (SCD) is characterized by hemolytic anemia and vaso-occlusion, although its impact on the adaptive immune responses remains incompletely understood. To comprehensibly profile the humoral immune responses, we immunized SCD mice with T cell-independent (TI) and T cell-dependent (TD) antigens. Our study showed that SCD mice have significantly enhanced type 2 TI (TI-2) immune responses in a manner dependent on the level of type I IFN (IFN-I), while maintaining similar or decreased TD immune responses depending on the route of antigen administration. Consistent with the enhanced TI-2 immune responses in SCD mice, the frequencies of B-1b cells (B-1 cells in humans), a major cell type responding to TI-2 antigens, were significantly increased in both the peritoneal cavity and spleens of SCD mice and in blood of patients with SCD. In support of expanded B-1 cells, elevated levels of anti-red blood cell (RBC) autoantibodies were detected in both SCD mice and patients. Both the levels of TI-2 immune responses and anti-RBC autoantibodies were significantly reduced following IFNAR antibody blockades and in IFNAR-1 deficient SCD mice. Moreover, the alteration of B-1 cell subsets were reversed in IFNAR-1 deficient SCD mice, uncovering a critical role for IFN-I in the enhanced TI-2 immune responses and the increased production of anti-RBC autoantibodies by modulating the innate B-1 cell subsets in SCD. Overall, our study provides experimental evidence that the modulation of B-1 cells and IFN-I can regulate TI immune responses and the levels of anti-RBC autoantibodies in SCD.

中文翻译：

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IFN-I 通过调节小鼠 SCD 中的 B-1 细胞亚群来促进 T 细胞非依赖性免疫和 RBC 自身抗体。


镰状细胞病 （SCD） 的病理生理学特征是溶血性贫血和血管闭塞，但其对适应性免疫反应的影响仍不完全清楚。为了更清楚地了解体液免疫反应，我们用 T 细胞非依赖性 （TI） 和 T 细胞依赖性 （TD） 抗原对 SCD 小鼠进行了免疫接种。我们的研究表明，SCD 小鼠以取决于 I 型 IFN （IFN-I） 水平的方式显着增强 2 型 TI （TI-2） 免疫反应，同时根据抗原给药途径保持相似或降低的 TD 免疫反应。与 SCD 小鼠增强的 TI-2 免疫反应一致，B-1b 细胞（人类 B-1 细胞）的频率（一种响应 TI-2 抗原的主要细胞类型）在 SCD 小鼠的腹膜腔和脾脏以及 SCD 患者的血液中均显著增加。为了支持扩增的 B-1 细胞，在 SCD 小鼠和患者中检测到抗红细胞 （RBC） 自身抗体水平升高。IFNAR 抗体阻断后和 IFNAR-1 缺陷型 SCD 小鼠的 TI-2 免疫反应和抗 RBC 自身抗体水平均显著降低。此外，在 IFNAR-1 缺陷型 SCD 小鼠中，B-1 细胞亚群的改变被逆转，揭示了 IFN-I 通过调节 SCD 中的先天性 B-1 细胞亚群，在增强 TI-2 免疫反应和增加抗 RBC 自身抗体产生中的关键作用。总体而言，我们的研究提供了实验证据，表明 B-1 细胞和 IFN-I 的调节可以调节 TI 免疫反应和 SCD 中抗 RBC 自身抗体的水平。