当前位置: X-MOL 学术J. Immunol. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
The Role of Autoimmunity-Related Gene CLEC16A in the B Cell Receptor–Mediated HLA Class II Pathway
The Journal of Immunology ( IF 4.4 ) Pub Date : 2020-07-08 , DOI: 10.4049/jimmunol.1901409
Liza Rijvers 1, 2 , Marie-José Melief 1, 2 , Jamie van Langelaar 1, 2 , Roos M van der Vuurst de Vries 2, 3 , Annet F Wierenga-Wolf 1, 2 , Steven C Koetzier 1, 2 , John J Priatel 4, 5 , Tineke Jorritsma 6 , S Marieke van Ham 6 , Rogier Q Hintzen 1, 2, 3 , Marvin M van Luijn 2, 7
Affiliation  

Key Points CLEC16A correlates to surface CLIP expression in human B-LCLs and primary B cells. CLEC16A knockdown impairs BCR-mediated uptake of Ag into MIICs. CLIP is abundant and not coregulated with CLEC16A in blood B cells of MS patients. Visual Abstract C-type lectin CLEC16A is located next to CIITA, the master transcription factor of HLA class II (HLA-II), at a susceptibility locus for several autoimmune diseases, including multiple sclerosis (MS). We previously found that CLEC16A promotes the biogenesis of HLA-II peptide-loading compartments (MIICs) in myeloid cells. Given the emerging role of B cells as APCs in these diseases, in this study, we addressed whether and how CLEC16A is involved in the BCR-dependent HLA-II pathway. CLEC16A was coexpressed with surface class II–associated invariant chain peptides (CLIP) in human EBV-positive and not EBV-negative B cell lines. Stable knockdown of CLEC16A in EBV-positive Raji B cells resulted in an upregulation of surface HLA-DR and CD74 (invariant chain), whereas CLIP was slightly but significantly reduced. In addition, IgM-mediated Salmonella uptake was decreased, and MIICs were less clustered in CLEC16A-silenced Raji cells, implying that CLEC16A controls both HLA-DR/CD74 and BCR/Ag processing in MIICs. In primary B cells, CLEC16A was only induced under CLIP-stimulating conditions in vitro and was predominantly expressed in CLIPhigh naive populations. Finally, CLIP-loaded HLA-DR molecules were abnormally enriched, and coregulation with CLEC16A was abolished in blood B cells of patients who rapidly develop MS. These findings demonstrate that CLEC16A participates in the BCR-dependent HLA-II pathway in human B cells and that this regulation is impaired during MS disease onset. The abundance of CLIP already on naive B cells of MS patients may point to a chronically induced stage and a new mechanism underlying B cell–mediated autoimmune diseases such as MS.

中文翻译:

自身免疫相关基因 CLEC16A 在 B 细胞受体介导的 HLA II 类通路中的作用

关键点 CLEC16A 与人 B-LCL 和原代 B 细胞中的表面 CLIP 表达相关。CLEC16A 敲低会损害 BCR 介导的 Ag 摄取到 MIIC 中。在 MS 患者的血 B 细胞中,CLIP 很丰富,并且不与 CLEC16A 共调节。Visual Abstract C 型凝集素 CLEC16A 位于 II 类 HLA (HLA-II) 的主要转录因子 CIITA 旁边,位于多种自身免疫性疾病的易感位点,包括多发性硬化症 (MS)。我们以前发现 CLEC16A 促进骨髓细胞中 HLA-II 肽加载区室 (MIIC) 的生物发生。鉴于 B 细胞作为 APC 在这些疾病中的新兴作用,在本研究中,我们讨论了 CLEC16A 是否以及如何参与 BCR 依赖性 HLA-II 通路。CLEC16A 在人类 EBV 阳性和非 EBV 阴性 B 细胞系中与表面 II 类相关不变链肽 (CLIP) 共表达。EBV 阳性 Raji B 细胞中 CLEC16A 的稳定敲低导致表面 HLA-DR 和 CD74(不变链)的上调,而 CLIP 略微但显着降低。此外,IgM 介导的沙门氏菌摄取减少,并且 MIIC 在 CLEC16A 沉默的 Raji 细胞中较少聚集,这意味着 CLEC16A 控制 MIIC 中的 HLA-DR/CD74 和 BCR/Ag 处理。在原代 B 细胞中,CLEC16A 仅在体外 CLIP 刺激条件下被诱导,并且主要在 CLIPhigh 幼稚群体中表达。最后,加载 CLIP 的 HLA-DR 分子异常富集,并且与 CLEC16A 的协同调节在快速发展为 MS 的患者的血 B 细胞中被消除。这些发现表明 CLEC16A 参与人 B 细胞中 BCR 依赖性 HLA-II 途径,并且这种调节在 MS 疾病发作期间受损。MS 患者幼稚 B 细胞上已经存在的大量 CLIP 可能指向慢性诱导阶段和 B 细胞介导的自身免疫性疾病(如 MS)的新机制。
更新日期:2020-07-08
down
wechat
bug