Department of Dermatology, French Reference Center for Auto Immune Blistering Diseases, Rouen University Hospital, Normandie University, Rouen, France.
Normandie University, UNIROUEN, Inserm, U1234, FOCIS Center of Excellence PAn'THER, Rouen University Hospital, Department of Immunology and Biotherapy, Rouen, France.
Br J Dermatol. 2024 Sep 18;191(4):605-615. doi: 10.1093/bjd/ljae220.
Pemphigus vulgaris (PV) is characterized by autoantibodies targeting keratinocyte adhesion proteins desmoglein (Dsg) 1 and 3, and by the human leukocyte antigen (HLA) predisposition allele HLA-DRB1*0402. Treatment using rituximab (RTX) combined with short-term corticosteroids (CS) allows disease control and long-lasting remission.
The principal aim of this study was to evaluate the impact of RTX on the circulating subpopulations of Dsg3-specific T lymphocytes that specifically regulate B-cell responses: follicular helper T (Tfh) and follicular regulatory T (Tfr) lymphocytes.
Using the HLA-DRB1*0402 tetramer loaded with the Dsg3 immunodominant peptide, we used flow cytometry to analyse the frequency, polarization and activation status of blood Dsg3-specific follicular T-cell populations at baseline, month (M) 6 and long-term follow-up (M60-90) from patients with PV.
At baseline, we observed a predominance of Tfh1* and Tfh17 subsets and an underrepresentation of the Tfh2 subset among autoreactive Dsg3-specific Tfh cells compared with nonautoreactive Tfh cells. RTX treatment induced a decrease of autoreactive Tfh cells with no effect on their polarization during follow-up. In parallel, we observed the emergence of a Dsg3-specific Tfr subpopulation with a significant overexpression of the surface activation markers PD1, ICOS and CD25 that was not observed at the surface of autoreactive Tfh and nonautoreactive Tfr cells of the same patients with PV. In contrast, very few Dsg3-specific Tfr cells were observed in patients with PV who were treated with CS alone.
Here we show that the emergence of circulating autoreactive Dsg3-specific Tfr cells is associated with the long-term efficacy of RTX in patients with PV.
寻常型天疱疮（PV）的特征是自身抗体针对角质形成细胞黏附蛋白桥粒芯糖蛋白 1（Dsg）1 和 3，以及人类白细胞抗原（HLA）易感性等位基因 HLA-DRB1*0402。利妥昔单抗（RTX）联合短期皮质类固醇（CS）的治疗可控制疾病并实现长期缓解。
本研究的主要目的是评估 RTX 对调节 B 细胞反应的 Dsg3 特异性 T 淋巴细胞循环亚群的影响：滤泡辅助 T（Tfh）和滤泡调节 T（Tfr）淋巴细胞。
使用负载 Dsg3 免疫优势肽的 HLA-DRB1*0402 四聚体，我们使用流式细胞术分析了 PV 患者基线、第 6 个月（M）和第 60-90 个月（M60-90）时血液中 Dsg3 特异性滤泡 T 细胞群体的频率、极化和激活状态。
在基线时，与非自身反应性 Tfh 细胞相比，我们观察到自身反应性 Dsg3 特异性 Tfh 细胞中 Tfh1*和 Tfh17 亚群占优势，而 Tfh2 亚群占劣势。RTX 治疗诱导自身反应性 Tfh 细胞减少，但在随访过程中对其极化没有影响。与此同时，我们观察到 Dsg3 特异性 Tfr 亚群的出现，其表面激活标志物 PD1、ICOS 和 CD25 的表达显著上调，而在同一 PV 患者的自身反应性 Tfh 和非自身反应性 Tfr 细胞表面则观察不到。相比之下，单独接受 CS 治疗的 PV 患者中观察到的 Dsg3 特异性 Tfr 细胞很少。
在这里，我们表明循环自身反应性 Dsg3 特异性 Tfr 细胞的出现与 RTX 在 PV 患者中的长期疗效相关。
