系统性红斑狼疮（SLE）B细胞对TLR9刺激的反应性降低，表现为增殖和细胞因子产生异常，并可能影响T和B细胞互动。研究发现SLE B细胞在CpG刺激后PD-L1和CD86的上调显著减少，与B细胞增殖减少相关。同时，PD-L1表达与B细胞增殖正相关，而与干扰素标志物Siglec-1呈负相关。临床活动度较低的SLE患者中，PD-L1表达也较低。这些发现强调了评估创新治疗干预措施在SLE中的潜力。
摘要：
Background Prior studies on systemic lupus erythematosus (SLE) B cells reported an altered responsiveness to TLR9 stimulation, such as proliferation, cytokine production as well as indications for impaired T and B cell interaction [1]. The role of co-inhibitory and co-stimulatory (check-point) molecules in this setting has not been delineated in detail so far. Objectives Assess the expression of co-inhibitory (PD-1, PD-L1 and PD-L2) and co-stimulatory molecules (CD86 and CD40) by SLE B cells after in vitro stimulation and their potential contribution for B cell hyporesponsiveness in SLE. Methods PBMCs from 10 SLE patients and 10 healthy donors (HD) were stimulated with IL-2/IL-10, anti (α) - B cell receptor (BCR), CpG and CD40L alone or in combination. Expression of PD-1, PD-L1, PD-L2 as well as CD86, CD40 on CD19+CD20+ B cell subsets after 48h stimulation was analyzed by FACS. CD71 was employed to measure proliferation of CD19CD20 B cells after 48h stimulation. Results SLE B cells exhibited a substantially decreased upregulation of PD-L1 (p = 0,0006) and CD86 (p = 0,0188, Fig.1) associated with significantly reduced B cell proliferation (p = 0,0039) after 48h stimulation with CpG alone and in combination compared with HD. While TLR9 engagement in SLE B cells appeared to be abnormal, activation of CD40 resulted into a consistent upregulation of both, inhibitory and stimulatory molecules. PD-L1 was positively correlated with B cell proliferation (p = 0.003). Notably, the expression of PD-L1 and CD86 correlated inversely with Siglec-1, as surrogate marker for interferon signature (p < 0,0001 and p = 0.0021 respectively). PD-L1 expression correlated inversely with cSLEDAI (p = 0.0087). Download figure Open in new tab Download powerpoint Conclusion Hyporesponsive/anergic lupus B cells are characterized by a functionally diminished PD-L1 and CD86 upregulation associated with reduced proliferation and clinical activity. The data mandate evaluations of innovative therapeutic interventions in SLE. Reference [1] Schrezenmeier, E., et al., Postactivated B cells in systemic lupus erythematosus: update on translational aspects and therapeutic considerations. Curr Opin Rheumatol, 2018. Disclosure of Interests Ana-Luisa Stefanski: None declared, Annika Wiedemann: None declared, Karin Reiter: None declared, Andreia Lino: None declared, Thomas Drner Grant/research support from: Eli Lilly, Janssen, Roche, UCB Pharma, Consultant for: Eli Lilly, Janssen, Roche, UCB Pharma, Speakers bureau: Eli Lilly, Janssen
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