类风湿关节炎相关间质性肺病患者外周血髓系细胞亚群的扩增。
Expansion of distinct peripheral blood myeloid cell subpopulations in patients with rheumatoid arthritis-associated interstitial lung disease.
机构信息
Department of Internal Medicine, USA.
Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA.
出版信息
Int Immunopharmacol. 2024 Jan 25;127:111330. doi: 10.1016/j.intimp.2023.111330. Epub 2023 Dec 11.
OBJECTIVES
Interstitial lung disease (ILD) is associated with significant mortality in rheumatoid arthritis (RA) patients with key cellular players remaining largely unknown. This study aimed to characterize inflammatory and myeloid derived suppressor cell (MDSC) subpopulations in RA-ILD as compared to RA, idiopathic pulmonary fibrosis (IPF) without autoimmunity, and controls.
METHODS
Peripheral blood was collected from patients with RA, RA-ILD, IPF, and controls (N = 60, 15/cohort). Myeloid cell subpopulations were identified phenotypically by flow cytometry using the following markers:CD45,CD3,CD19,CD56,CD11b,HLA-DR,CD14,CD16,CD15,CD125,CD33. Functionality of subsets were identified with intracellular arginase-1 (Arg-1) and inducible nitric oxide synthase (iNOS) expression.
RESULTS
There was increased intermediate (CD14CD16) and nonclassical (CD14CD16) and decreased classical (CD14CD16) monocytes in RA, RA-ILD, and IPF vs. control. Intermediate monocytes were higher and classical monocytes were lower in RA-ILD vs. RA but not IPF. Monocytic (m)MDSCs were higher in RA-ILD vs. control and RA but not IPF. Granulocytic (g)MDSCs did not significantly differ. In contrast, neutrophils were increased in IPF and RA-ILD patients with elevated expression of Arg-1 sharing similar dimensional clustering pattern. Eosinophils were increased in RA-ILD vs. controls, RA and IPF. Across cohorts, iNOS was decreased in intermediate/nonclassical monocytes but increased in mMDSCs vs. classical monocytes. In RA-ILD, iNOS positive mMDSCs were increased versus classic monocytes.
CONCLUSIONS
Myeloid cell subpopulations are significantly modulated in RA-ILD patients with expansion of CD16 monocytes, mMDSCs, and neutrophils, a phenotypic profile more aligned with IPF than other RA patients. Eosinophil expansion was unique to RA-ILD, potentially facilitating disease pathogenesis and providing a future therapeutic target.
目的
间质性肺病（ILD）与类风湿关节炎（RA）患者的死亡率显著相关，但其关键细胞因子仍知之甚少。本研究旨在比较 RA-ILD、无自身免疫性特发性肺纤维化（IPF）和对照组患者的炎症和髓系来源抑制细胞（MDSC）亚群。
方法
收集 RA、RA-ILD、IPF 和对照组患者（N=60，每组 15 例）的外周血。使用以下标记物通过流式细胞术对髓样细胞亚群进行表型鉴定：CD45、CD3、CD19、CD56、CD11b、HLA-DR、CD14、CD16、CD15、CD125、CD33。通过细胞内精氨酸酶-1（Arg-1）和诱导型一氧化氮合酶（iNOS）表达鉴定亚群的功能。
结果
RA、RA-ILD 和 IPF 患者的中间（CD14CD16）和非经典（CD14CD16）单核细胞增多，经典（CD14CD16）单核细胞减少，与对照组相比。RA-ILD 患者的中间单核细胞更高，经典单核细胞更低，但与 IPF 患者相比则不然。RA-ILD 患者的单核细胞来源 MDSC（m）MDSC 高于对照组和 RA 患者，但与 IPF 患者相比则不然。粒细胞来源 MDSC（g）MDSC 无显著差异。相反，在 IPF 和 RA-ILD 患者中，中性粒细胞增加，Arg-1 表达升高，具有相似的维度聚类模式。与对照组、RA 和 IPF 患者相比，RA-ILD 患者的嗜酸性粒细胞增加。在所有队列中，中间/非经典单核细胞中的 iNOS 降低，但与经典单核细胞相比，m MDSC 中的 iNOS 增加。在 RA-ILD 患者中，iNOS 阳性 m MDSC 与经典单核细胞相比增加。
结论
RA-ILD 患者的髓样细胞亚群发生了显著的调节，表现为 CD16 单核细胞、m MDSC 和中性粒细胞的扩增，其表型谱与 IPF 比其他 RA 患者更相似。嗜酸性粒细胞的扩增是 RA-ILD 所特有的，可能有助于疾病的发病机制，并为未来的治疗靶点提供了依据。
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