Rijvers Liza, Melief Marie-José, van Langelaar Jamie, van der Vuurst de Vries Roos M, Wierenga-Wolf Annet F, Koetzier Steven C, Priatel John J, Jorritsma Tineke, van Ham S Marieke, Hintzen Rogier Q, van Luijn Marvin M
Department of Immunology, Erasmus MC, 3015 CN Rotterdam, the Netherlands.
MS Center ErasMS, Erasmus MC, 3015 CN Rotterdam, the Netherlands.
J Immunol. 2020 Aug 15;205(4):945-956. doi: 10.4049/jimmunol.1901409. Epub 2020 Jul 8.
C-type lectin is located next to , 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 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 is involved in the BCR-dependent HLA-II pathway. 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 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 uptake was decreased, and MIICs were less clustered in -silenced Raji cells, implying that controls both HLA-DR/CD74 and BCR/Ag processing in MIICs. In primary B cells, was only induced under CLIP-stimulating conditions in vitro and was predominantly expressed in CLIP naive populations. Finally, CLIP-loaded HLA-DR molecules were abnormally enriched, and coregulation with 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.
C型凝集素位于HLA-II类（HLA-II）的主要转录因子旁边，处于包括多发性硬化症（MS）在内的多种自身免疫性疾病的易感位点。我们之前发现，它能促进髓系细胞中HLA-II肽装载区室（MIICs）的生物发生。鉴于B细胞作为抗原呈递细胞在这些疾病中日益重要的作用，在本研究中，我们探讨了它是否以及如何参与BCR依赖性HLA-II途径。在人EBV阳性而非EBV阴性B细胞系中，它与表面II类相关恒定链肽（CLIP）共表达。在EBV阳性的Raji B细胞中稳定敲低它会导致表面HLA-DR和CD74（恒定链）上调，而CLIP略有但显著减少。此外，IgM介导的摄取减少，并且在敲低它的Raji细胞中MIICs聚集减少，这意味着它控制MIICs中的HLA-DR/CD74和BCR/抗原加工。在原代B细胞中，它仅在体外CLIP刺激条件下被诱导，并且主要在CLIP未接触群体中表达。最后，在快速发展为MS的患者的血液B细胞中，装载CLIP的HLA-DR分子异常富集，并且与它的协同调节被消除。这些发现表明CLEC16A参与人B细胞中的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患者未接触B细胞上已经存在的CLIP丰度可能指向一个慢性诱导阶段以及B细胞介导的自身免疫性疾病如MS的新机制。
