Extracellular vesicles are involved in the intercellular communication of the immune system. In rheumatoid arthritis (RA), these structures are considered a source of autoantigens that drive proinflammatory responses of innate immune cells. A high concentration of circulating medium/large size extracellular vesicles (m/lEVs) and m/lEVs forming immune complexes (m/lEV-ICs) have been associated with disease activity and systemic inflammation in patients with RA. B cells are central components of RA immunopathology because of their involvement in the production of autoantibodies, antigen presentation, and cytokine production. However, the effect of m/lEVs on B cell function in the context of RA and other autoimmune diseases remains unknown. We evaluated the effect of m/lEVs obtained from healthy donors (HD) and patients with RA on B cell responses in vitro. In addition, we evaluated the effect of pre-exposition of monocyte-derived macrophages (MDM) to m/lEVs on activation of autologous B cells from HD and patients. The presence of m/lEVs reduced the frequency of CD69+ and CD86+ B cells from HD activated by an agonist of antigen receptor. This regulation of the B cell activation markers by m/lEVs was partially dependent on phosphatidylserine binging. These m/lEVs also reduced the proliferation, calcium mobilization, and global phosphorylation of tyrosine. Similar responses were observed in B cells from patients with RA. However, the presence of m/lEVs promoted high antibody levels in B cells cultured with T cell-dependent stimuli by 7 days. In addition, despite the direct inhibitory effect of m/lEVs on early B cell responses, when B cells were cocultured with autologous MDM previously exposed to m/lEVs or m/lEV-ICs, an increased frequency of CD69+ B cells from patients with RA was observed, albeit not with cells from HD. These data together suggest that m/lEVs have a direct modulatory effect in early responses of B cells through B cell receptor that can potentially fail in patients with RA because of the impact of these vesicles over cells of the innate immune system. This phenomenon can potentially contribute to the loss of tolerance and disease activity in patients with RA.

中文翻译：

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类风湿性关节炎患者细胞外囊泡对 B 细胞活化的调节和该途径的潜在改变

细胞外囊泡参与免疫系统的细胞间通讯。在类风湿性关节炎 (RA) 中，这些结构被认为是驱动先天免疫细胞促炎反应的自身抗原的来源。高浓度的循环中/大型细胞外囊泡 (m/lEVs) 和形成免疫复合物的 m/lEVs (m/lEV-ICs) 与 RA 患者的疾病活动和全身炎症有关。B 细胞是 RA 免疫病理学的核心成分，因为它们参与自身抗体的产生、抗原呈递和细胞因子的产生。然而，在 RA 和其他自身免疫性疾病的背景下，m/lEVs 对 B 细胞功能的影响仍然未知。我们评估了从健康供体 (HD) 和 RA 患者获得的 m/lEVs 对体外 B 细胞反应的影响。此外，我们评估了单核细胞衍生巨噬细胞 (MDM) 预先暴露于 m/lEVs 对 HD 和患者自体 B 细胞活化的影响。m/lEVs 的存在降低了由抗原受体激动剂激活的 HD 中 CD69+ 和 CD86+ B 细胞的频率。m/lEVs 对 B 细胞活化标志物的这种调节部分依赖于磷脂酰丝氨酸结合。这些 m/lEVs 还减少了酪氨酸的增殖、钙动员和整体磷酸化。在来自 RA 患者的 B 细胞中观察到类似的反应。然而，m/lEVs 的存在促进了用 T 细胞依赖性刺激培养的 B 细胞中的高抗体水平 7 天。此外，尽管 m/lEVs 对早期 B 细胞反应有直接抑制作用，但当 B 细胞与先前暴露于 m/lEVs 或 m/lEV-ICs 的自体 MDM 共培养时，观察到来自 RA 患者的 CD69+ B 细胞频率增加，尽管不是来自 HD 的细胞。这些数据共同表明，m/lEVs 在 B 细胞通过 B 细胞受体的早期反应中具有直接调节作用，由于这些囊泡对先天免疫系统细胞的影响，可能在 RA 患者中失败。这种现象可能会导致 RA 患者耐受性和疾病活动性的丧失。尽管不是来自 HD 的细胞。这些数据共同表明，m/lEVs 在 B 细胞通过 B 细胞受体的早期反应中具有直接调节作用，由于这些囊泡对先天免疫系统细胞的影响，可能在 RA 患者中失败。这种现象可能会导致 RA 患者耐受性和疾病活动性的丧失。尽管不是来自 HD 的细胞。这些数据共同表明，m/lEVs 在 B 细胞通过 B 细胞受体的早期反应中具有直接调节作用，由于这些囊泡对先天免疫系统细胞的影响，可能在 RA 患者中失败。这种现象可能会导致 RA 患者耐受性和疾病活动性的丧失。