背景:NR1-IgG在N-甲基-D-天冬氨酸受体(NMDAR)抗体脑炎中的致病性是已知的,但其产生的免疫生物学机制尚不清楚。
方法:第一次,我们探索NR1-IgG的来源,并评估B细胞对血清NR1-IgG水平的贡献。从患者和健康对照(HC)获得外周血单核细胞(PBMC)。天真,未交换存储器(USM),开关存储器B单元(SM),抗体分泌细胞(ASC),通过荧光激活细胞分选获得去除ASC的PBMC并体外培养。
结果:对于一些患者,PBMC自发产生NR1-IgG。与PBMC阴性组患者相比,阳性组的脑脊液NR1-IgG滴度和改良Rankin量表评分较高.PBMC培养物中NR1-IgG阳性孔的比例与血清和CSF中的NR1-IgG滴度相关。纯化的ASC,SM,USMB细胞在体外产生NR1-IgG。与ASCs阴性组患者相比,阳性组在3个月随访时对二线IT的反应较差.初始B细胞也产生NR1-IgG,暗示NR1-IgG起源于初始B细胞和一些患者的B细胞耐受检查点的生发前中心缺陷。对于HC,未观察到来自培养物的NR1-IgG。耗尽ASC的PBMC几乎消除了NR1-IgG的产生。
结论:这些共同发现表明,ASC可能主要有助于急性期NMDAR抗体脑炎患者外周NR1-IgG的产生。我们的研究揭示了发病机理,并有助于开发量身定制的治疗方法(例如,抗CD38)用于NMDAR抗体脑炎。
BACKGROUND: The pathogenicity of NR1-IgGs in N-methyl-D-aspartate receptor (NMDAR)-antibody encephalitis is known, but the immunobiological mechanisms underlying their production remain unclear.
METHODS: For the first time, we explore the origin of NR1-IgGs and evaluate the contribution of B-cells to serum NR1-IgGs levels. Peripheral blood mononuclear cells (PBMCs) were obtained from patients and healthy controls (HCs). Naïve, unswitched memory (USM), switched memory B cells (SM), antibody-secreting cells (ASCs), and PBMC depleted of ASCs were obtained by fluorescence-activated cell sorting and cultured in vitro.
RESULTS: For some patients, PBMCs spontaneously produced NR1-IgGs. Compared to the patients in PBMC negative group, the positive group had higher NR1-IgG titers in cerebrospinal fluid and Modified Rankin scale scores. The proportions of NR1-IgG positive wells in PBMCs cultures were correlated with NR1-IgGs titers in serum and CSF. The purified ASCs, SM, USM B cells produced NR1-IgGs in vitro. Compared to the patients in ASCs negative group, the positive group exhibited a worse response to second-line IT at 3-month follow-up. Naïve B cells also produce NR1-IgGs, implicating that NR1-IgGs originate from naïve B cells and a pre-germinal centres defect in B cell tolerance checkpoint in some patients. For HCs, no NR1-IgG from cultures was observed. PBMC depleted of ASCs almost eliminated the production of NR1-IgGs.
CONCLUSIONS: These collective findings suggested that ASCs might mainly contribute to the production of peripheral NR1-IgG in patients with NMDAR-antibody encephalitis in the acute phase. Our study reveals the pathogenesis and helps develop tailored treatments (eg, anti-CD38) for NMDAR-antibody encephalitis.