Su Shan, Bao Weili, Liu Yunfeng, Shi Patricia A, Manwani Deepa, Murakhovskaya Irina, Campbell-Lee Sally, Lobo Cheryl A, Mendelson Avital, An Xiuli, Zhong Hui, Yi Woelsung, Yazdanbakhsh Karina
Laboratory of Complement Biology, Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY.
Clinical Research in Sickle Cell Disease, Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY.
Blood. 2025 Jan 16;145(3):334-347. doi: 10.1182/blood.2024025175.
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 (Ags). 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 interferons (IFN-I), while maintaining similar or decreased TD immune responses depending on the route of Ag 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 Ags, were significantly increased in both the peritoneal cavity and spleens of SCD mice and in the blood of patients with SCD. In support of expanded B-1 cells, elevated levels of anti-red blood cell (anti-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 after IFN-I receptor (IFNAR) antibody blockades and in IFNAR1-deficient SCD mice. Moreover, the alterations of B-1 cell subsets were reversed in IFNAR1-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.
镰状细胞病（SCD）的病理生理学特征为溶血性贫血和血管阻塞，尽管其对适应性免疫反应的影响仍未完全了解。为了全面描绘体液免疫反应，我们用非T细胞依赖性（TI）和T细胞依赖性（TD）抗原（Ag）免疫SCD小鼠。我们的研究表明，SCD小鼠以依赖于I型干扰素（IFN-I）水平的方式显著增强了2型TI（TI-2）免疫反应，而根据Ag给药途径的不同，TD免疫反应则保持相似或降低。与SCD小鼠中增强的TI-2免疫反应一致，B-1b细胞（人类中的B-1细胞）的频率在SCD小鼠的腹腔和脾脏以及SCD患者的血液中均显著增加，B-1b细胞是对TI-2 Ag作出反应的主要细胞类型。为支持B-1细胞的扩增，在SCD小鼠和患者中均检测到抗红细胞（anti-RBC）自身抗体水平升高。在IFN-I受体（IFNAR）抗体阻断后以及在IFNAR1缺陷的SCD小鼠中，TI-2免疫反应水平和抗RBC自身抗体均显著降低。此外，IFNAR1缺陷的SCD小鼠中B-1细胞亚群的改变得到逆转，揭示了IFN-I在增强的TI-2免疫反应以及通过调节SCD中先天性B-1细胞亚群增加抗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的调节可调节SCD中的TI免疫反应和抗RBC自身抗体水平。
