記述言語：英語   出版者・発行元：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

Web of Science

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PubMed

記述言語：英語   出版者・発行元：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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PubMed

記述言語：英語   出版者・発行元：Modern Rheumatology Case Reports  

A 25-year-old woman was admitted to our hospital with severe pulmonary arterial hypertension associated with systemic lupus erythematosus (SLE-PAH). Her mean pulmonary arterial pressure was 56 mmHg, and her SLE Disease Activity Index-2 K score was 14 on admission. In addition to a strong immunosuppressive regimen, which included steroid pulse therapy followed by high-dose oral prednisolone (1 mg/kg) and intravenous cyclophosphamide, an upfront combination of vasodilator therapy, including oral tadalafil, macitentan, and intravenous epoprostenol, was administered in the early phase. Two months later, her mean pulmonary arterial pressure was 29 mmHg, and her other haemodynamic markers showed significant improvement. She refused to start life-long intravenous epoprostenol therapy and so was switched to oral selexipag and inhaled iloprost. The transition was successful, and she has experienced no exacerbations of SLE-PAH during the 10 months since the onset of pulmonary arterial hypertension. To the best of our knowledge, this is the first report of intravenous epoprostenol being switched to alternative oral and inhaled therapy in a patient with SLE-PAH. In combination with adequate immunosuppressive therapy, it is probably easier to make this transition in patients with SLE-PAH than in those with pulmonary arterial hypertension of a different aetiology. Continuous infusion of epoprostenol can have potentially life-threatening complications and a detrimental effect on the quality of life. Our alternative treatment strategy was successful, and we hope that it will prove beneficial in other cases.

DOI： 10.1093/mrcr/rxac009

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PubMed

担当区分：筆頭著者  

DOI： 10.1016/j.jneuroim.2021.577631

担当区分：筆頭著者  

DOI： 10.1080/24725625.2021.1904607

記述言語：英語  

記述言語：英語  

記述言語：英語  

記述言語：日本語   出版者・発行元：(株)羊土社  

B細胞は抗体産生,免疫記憶,サイトカインの分泌を介して生体防御免疫を担うが,機能によるB細胞サブセットの多様性が自己免疫疾患との関連において注目されている.自己免疫反応を抑制するB細胞のサブセットとしてregulatory B cells(制御性B細胞)が同定され,一方,自己免疫反応を促進するB細胞のサブセットとしてage-associated B cells(加齢性B細胞,ABCs)が同定され,脚光を浴びている.これらのB細胞の分化や維持のメカニズム,そして疾患への関与を理解することは,自己免疫疾患の病態の理解や治療開発に必須である.本稿では,免疫応答を正負に制御するB細胞サブセットについて概説する.(著者抄録)

記述言語：日本語   出版者・発行元：(有)科学評論社