Department of Pediatrics, Faculty of Medicine, Dalhousie Unversity, Halifax, NS, Canada.
IWK Health Centre, Halifax, NS, Canada.
Front Immunol. 2024 May 22;15:1352251. doi: 10.3389/fimmu.2024.1352251. eCollection 2024.
Antigen-presenting dendritic cells (DCs) and monocytes play an essential role in rheumatoid arthritis (RA) pathogenesis, however, their tolerogenic potential remains unclear. Herein, the tolerogenic profiles of DCs are characterized in treatment-naïve RA patients to determine their role to inflammatory arthritis management.
Thirty-six treatment-naïve RA patients were enrolled, of which 62% were non-responders to methotrexate (MTX) monotherapy based on disease activity score (DAS) after 6-months of therapy. DC and monocyte subset frequencies, activation (CD40, CD86, CD209 expression), and tolerogenic profile (intracellular indoleamine-2,3-dioxygenase [IDO1] and cytotoxic T lymphocyte antigen 4 [CTLA-4] expression) were examined in the baseline peripheral blood by multicolor flow-cytometry. Soluble CTLA-4 (sCTLA-4) levels in plasma were measured.
DC subsets were decreased in RA compared to healthy controls (HC), and the frequency of conventional DCs (cDC) inversely correlated with inflammatory markers and improvement in disease activity. CD141 cDC1s were the major IDO1-expressing cells. IDO1cDC1s were reduced in RA patients compared to HC. The baseline frequency of IDO1cDC1s inversely correlated with improvement in disease activity. CTLA-4 expression in CD1c cDC2s and monocytes was lower in RA patients compared to HC. Moreover, MTX-responders had a significantly lower frequency of IDO1cDC1 cells and higher level of sCTLA-4 in the plasma compared to MTX non-responders. There was a strong predictive association of low IDO1cDC1 cells, low sCTLA-4 and non-response to MTX.
Our findings reveal altered DC and monocytes immunophenotypes that are associated with RA pathology and treatment response. The frequencies of tolerogenic IDO1cDC1s and the low level of sCTLA-4 are strongly associated with MTX non-responsiveness and therapeutic outcome. These results suggest that investigation of the association IDO1cDC1 and sCTLA-4 with response to treatment may be more generalizable to other autoimmune diseases.
抗原呈递树突状细胞（DC）和单核细胞在类风湿关节炎（RA）发病机制中起着至关重要的作用，但它们的耐受性潜力尚不清楚。在此，我们对未经治疗的 RA 患者的 DC 耐受性特征进行了表征，以确定其在炎症性关节炎管理中的作用。
纳入 36 名未经治疗的 RA 患者，其中 62%的患者在接受 6 个月的治疗后根据疾病活动评分（DAS）判断为甲氨蝶呤（MTX）单药治疗无应答者。通过多色流式细胞术检测外周血中 DC 和单核细胞亚群频率、活化（CD40、CD86、CD209 表达）和耐受性特征（细胞内色氨酸 2,3-双加氧酶 [IDO1]和细胞毒性 T 淋巴细胞抗原 4 [CTLA-4]表达）。检测血浆中可溶性 CTLA-4（sCTLA-4）水平。
与健康对照组（HC）相比，RA 患者的 DC 亚群减少，常规 DC（cDC）的频率与炎症标志物和疾病活动改善呈负相关。CD141 cDC1s 是主要的 IDO1 表达细胞。与 HC 相比，RA 患者的 IDO1cDC1s 减少。IDO1cDC1s 的基线频率与疾病活动的改善呈负相关。与 HC 相比，RA 患者 CD1c cDC2s 和单核细胞中 CTLA-4 的表达较低。此外，与 MTX 无应答者相比，MTX 应答者的 IDO1cDC1 细胞频率显著降低，血浆中 sCTLA-4 水平更高。低 IDO1cDC1 细胞、低 sCTLA-4 和 MTX 无应答与治疗反应之间存在很强的预测关联。
我们的发现揭示了改变的 DC 和单核细胞免疫表型与 RA 病理学和治疗反应相关。具有耐受性的 IDO1cDC1 细胞的频率和 sCTLA-4 的低水平与 MTX 无应答和治疗结果密切相关。这些结果表明，对 IDO1cDC1 和 sCTLA-4 与治疗反应之间的关联进行研究可能更适用于其他自身免疫性疾病。
