Generation of a novel CD30+ B cell subset producing GM-CSF and its possible link to the pathogenesis of systemic sclerosis.,Clinical & Experimental Immunology

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Generation of a novel CD30+ B cell subset producing GM-CSF and its possible link to the pathogenesis of systemic sclerosis.
Clinical & Experimental Immunology ( IF 3.4 ) Pub Date : 2020-06-15 , DOI: 10.1111/cei.13477
K Higashioka ₁ , Y Kikushige ₁ , M Ayano ₁ , Y Kimoto ₂ , H Mitoma ₁ , M Kikukawa ₃ , M Akahoshi ₁ , Y Arinobu ₁ , T Horiuchi ₂ , K Akashi ₁ , H Niiro ₃

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Systemic sclerosis (SSc) is a T helper type 2 (Th2)‐associated autoimmune disease characterized by vasculopathy and fibrosis. Efficacy of B cell depletion therapy underscores antibody‐independent functions of B cells in SSc. A recent study showed that the Th2 cytokine interleukin (IL)‐4 induces granulocyte–macrophage colony‐stimulating factor (GM‐CSF)‐producing effector B cells (GM‐B_effs) in humans. In this study, we sought to elucidate the generation mechanism of GM‐B_effs and also determine a role of this subset in SSc. Among Th‐associated cytokines, IL‐4 most significantly facilitated the generation of GM‐B_effs within memory B cells in healthy controls (HCs). In addition, the profibrotic cytokine transforming growth factor (TGF)‐β further potentiated IL‐4‐ and IL‐13‐induced GM‐B_effs. Of note, tofacitinib, a Janus kinase (JAK) inhibitor, inhibited the expression of GM‐CSF mRNA and protein in memory B cells induced by IL‐4, but not by TGF‐β. GM‐B_effs were enriched within CD20⁺CD30⁺CD38^−/low cells, a distinct population from plasmablasts, suggesting that GM‐B_effs exert antibody‐independent functions. GM‐B_effs were also enriched in a CD30⁺ fraction of freshly isolated B cells. GM‐B_effs generated under Th2 conditions facilitated the differentiation from CD14⁺ monocytes to DC‐SIGN⁺CD1a⁺CD14⁻CD86⁺ cells, which significantly promoted the proliferation of naive T cells. CD30⁺ GM‐B_effs were more pronounced in patients with SSc than in HCs. A subpopulation of SSc patients with the diffuse type and concomitant interstitial lung disease exhibited high numbers of GM‐B_effs. Together, these findings suggest that human GM‐B_effs are enriched in a CD30⁺ B cell subset and play a role in the pathogenesis of SSc.

中文翻译：

产生 GM-CSF 的新型 CD30+ B 细胞亚群的产生及其与系统性硬化症发病机制的可能联系。

系统性硬化症 (SSc) 是一种 2 型辅助 T (Th2) 相关的自身免疫性疾病，其特征是血管病变和纤维化。 B 细胞耗竭疗法的功效强调了 SSc 中 B 细胞的抗体独立功能。最近的一项研究表明，Th2 细胞因子白介素 (IL)-4 可诱导人类产生粒细胞-巨噬细胞集落刺激因子 (GM-CSF) 效应 B 细胞 (GM-B _effs )。在这项研究中，我们试图阐明 GM-B _effs的产生机制，并确定该子集在 SSc 中的作用。在 Th 相关细胞因子中，IL-4 最能显着促进健康对照 (HC) 记忆 B 细胞内 GM-B_效应的产生。此外，促纤维化细胞因子转化生长因子 (TGF)-β 进一步增强了 IL-4 和 IL-13 诱导的 GM-B_效应。值得注意的是，托法替尼是一种 Janus 激酶 (JAK) 抑制剂，可抑制 IL-4 诱导的记忆 B 细胞中 GM-CSF mRNA 和蛋白的表达，但不抑制 TGF-β 诱导的记忆 B 细胞的 GM-CSF mRNA 和蛋白表达。 GM-B _effs在 CD20 ⁺ CD30 ⁺ CD38 ^-/low细胞（与浆母细胞不同的群体）中富集，表明 GM-B _effs发挥不依赖于抗体的功能。 GM-B _effs也在新鲜分离的 B 细胞的 CD30 ⁺部分中富集。 Th2条件下产生的GM-B _effs促进CD14 ⁺单核细胞分化为DC-SIGN ⁺ CD1a ⁺ CD14 ^- CD86 ⁺细胞，显着促进初始T细胞的增殖。 SSc 患者中的 CD30 ⁺ GM-B_效应比 HC 患者更明显。患有弥漫型并伴有间质性肺疾病的 SSc 患者亚群表现出大量 GM-B _effs 。总之，这些发现表明人类 GM-B _effs在 CD30 ⁺ B 细胞亚群中富集，并在 SSc 的发病机制中发挥作用。

更新日期：2020-08-12

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