Language：English   Publishing type：Research paper (scientific journal)   Publisher：Science Advances  

Age-associated B cells (ABCs) with autoreactive properties accumulate with age and expand prematurely in autoimmune diseases. However, the mechanisms behind ABC generation and maintenance remain poorly understood. We show that continuous B cell receptor (BCR) signaling is essential for ABC development from anergic B cells in aged and autoimmune mice. ABCs exhibit constitutive BCR activation, with surface BCRs being internalized. Notably, anergic B cells, but not nonautoreactive B cells, contributed to ABC formation in these models. Anergic B cells also showed a greater propensity for in vitro differentiation into ABCs, which was inhibited by the expression of the transcription factor Nr4a1. Bruton’s tyrosine kinase (Btk), a key BCR signaling component, was constitutively activated in ABCs from aged and autoimmune mice as well as patients with lupus. Inhibiting Btk reduced ABC numbers and ameliorated the pathogenicity of lupus mice. Our findings reveal critical mechanisms underlying ABC development and offer previously unrecognized therapeutic insights for autoimmune diseases.

DOI： 10.1126/sciadv.adt8199

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Frontiers in Immunology  

Sepsis is a systemic inflammatory response to a severe, life-threatening infection with organ dysfunction. Although there is no effective treatment for this fatal illness, a deeper understanding of the pathophysiological basis of sepsis and its underlying mechanisms could lead to the development of new treatment approaches. Here, we demonstrate that the selective Bruton’s tyrosine kinase (Btk) inhibitor acalabrutinib augments survival rates in a lipopolysaccharide (LPS)-induced septic model. Our in vitro and in vivo findings both indicate that acalabrutinib reduces IL-6 production specifically in marginal zone B (MZ B) cells rather than in macrophages. Furthermore, Btk-deficient MZ B cells exhibited suppressed LPS-induced IL-6 production in vitro. Nuclear factor-kappa B (NF-κB) signaling, which is the downstream signaling cascade of Toll-like receptor 4 (TLR4), was also severely attenuated in Btk-deficient MZ B cells. These findings suggest that Btk blockade may prevent sepsis by inhibiting IL-6 production in MZ B cells. In addition, although Btk inhibition may adversely affect B cell maturation and humoral immunity, antibody responses were not impaired when acalabrutinib was administered for a short period after immunization with T-cell-independent (TI) and T-cell-dependent (TD) antigens. In contrast, long-term administration of acalabrutinib slightly impaired humoral immunity. Therefore, these findings suggest that Btk inhibitors may be a potential option for alleviating endotoxic shock without compromising humoral immunity and emphasize the importance of maintaining a delicate balance between immunomodulation and inflammation suppression.

DOI： 10.3389/fimmu.2024.1388947

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Language：English   Presentation type：Poster presentation  

Language：English   Presentation type：Oral presentation (general)  

Language：English   Presentation type：Poster presentation  

Language：English   Presentation type：Oral presentation (general)