Wiedemann Annika, Lettau Marie, Wirries Ina, Jungmann Annemarie, Salhab Abdulrahman, Gasparoni Gilles, Mei Henrik E, Perka Carsten, Walter Jörn, Radbruch Andreas, Lino Andreia C, Dörner Thomas
Department of Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany.
German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany.
Front Immunol. 2021 Feb 12;11:628923. doi: 10.3389/fimmu.2020.628923. eCollection 2020.
The functions of bone marrow plasma cells (BMPC) beyond antibody production are not fully elucidated and distinct subsets of BMPC suggest potential different functions. Phenotypic differences were identified for human BMPC depending on CD19 expression. Since CD19 is a co-stimulatory molecule of the B-cell-receptor (BCR), and IgA and IgM BMPC express the BCR on their surface, we here studied whether CD19 expression affects cellular responses, such as BCR signaling and the expression of checkpoint molecules. We analyzed 132 BM samples from individuals undergoing routine total hip arthroplasty. We found that both CD19 and CD19 BMPC expressed BCR signaling molecules. Notably, the BCR-associated kinase spleen tyrosine kinase (SYK) including pSYK was higher expressed in CD19 BMPC compared to CD19 BMPC. BCR stimulation also resulted in increased kinase phosphorylation downstream of the BCR while expression of CD19 remained stable afterwards. Interestingly, the BCR response was restricted to IgA BMPC independently of CD19 expression. With regard to the expression of checkpoint molecules, CD19 BMPC expressed higher levels of co-inhibitory molecule programmed cell death protein-1 (PD-1) than CD19 BMPC. IgA BMPC characteristically upregulated PD-1 upon BCR stimulation in contrast to other PC subsets and inhibition of the kinase SYK abrogated PD-1 upregulation. In contrast, expression of PD-1 ligand, B and T lymphocyte attenuator (BTLA) and CD28 did not change upon BCR activation of IgA BMPC. Here, we identify a distinct characteristic of IgA BMPC that is independent of the phenotypic heterogeneity of the subsets according to their CD19 expression. The data suggest that IgA BMPC underlie different regulatory principles and/or exert distinct regulatory functions.
骨髓浆细胞（BMPC）在抗体产生之外的功能尚未完全阐明，且BMPC的不同亚群提示可能存在不同功能。根据CD19表达情况，已确定人类BMPC存在表型差异。由于CD19是B细胞受体（BCR）的共刺激分子，且IgA和IgM BMPC在其表面表达BCR，因此我们在此研究CD19表达是否影响细胞反应，如BCR信号传导和检查点分子的表达。我们分析了132例接受常规全髋关节置换术患者的骨髓样本。我们发现CD19+和CD19− BMPC均表达BCR信号分子。值得注意的是，与CD19− BMPC相比，包括pSYK在内的BCR相关激酶脾酪氨酸激酶（SYK）在CD19+ BMPC中表达更高。BCR刺激还导致BCR下游激酶磷酸化增加，而CD19表达随后保持稳定。有趣的是，BCR反应仅限于IgA BMPC，与CD19表达无关。关于检查点分子的表达，CD19+ BMPC比CD19− BMPC表达更高水平的共抑制分子程序性细胞死亡蛋白1（PD-1）。与其他浆细胞亚群相比，IgA BMPC在BCR刺激后特征性地上调PD-1，并且激酶SYK的抑制消除了PD-1的上调。相反，IgA BMPC的BCR激活后，PD-1配体、B和T淋巴细胞衰减器（BTLA）和CD28的表达没有变化。在此，我们确定了IgA BMPC的一个独特特征，该特征独立于根据其CD19表达划分的亚群的表型异质性。数据表明，IgA BMPC遵循不同的调节原则和/或发挥不同的调节功能。
