TY - JOUR
T1 - IFN-I promotes T-cell–independent immunity and RBC autoantibodies via modulation of B-1 cell subsets in murine SCD
AU - Su, Shan
AU - Bao, Weili
AU - Liu, Yunfeng
AU - Shi, Patricia A.
AU - Manwani, Deepa
AU - Murakhovskaya, Irina
AU - Campbell-Lee, Sally
AU - Lobo, Cheryl A.
AU - Mendelson, Avital
AU - An, Xiuli
AU - Zhong, Hui
AU - Yi, Woelsung
AU - Yazdanbakhsh, Karina
N1 - Publisher Copyright:
© 2025 American Society of Hematology
PY - 2025/1/16
Y1 - 2025/1/16
N2 - 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.
AB - 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.
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U2 - 10.1182/blood.2024025175
DO - 10.1182/blood.2024025175
M3 - Article
C2 - 39656114
AN - SCOPUS:85214285773
SN - 0006-4971
VL - 145
SP - 334
EP - 347
JO - Blood
JF - Blood
IS - 3
ER -