Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
Int Immunol. 2019 May 21;31(6):397-406. doi: 10.1093/intimm/dxz017.
AbstractImmune homeostasis is critically regulated by the balance between activating and inhibitory receptors expressed on various immune cells such as T and B lymphocytes, and myeloid cells. The inhibitory receptors play a fundamental role in the immune checkpoint pathway, thus maintaining peripheral tolerance. We recently found that expression of leukocyte immunoglobulin-like receptor (LILR)B4, an inhibitory member of the human LILR family, is augmented in auto-antibody-producing plasmablasts/plasma cells of systemic lupus erythematosus (SLE) patients. However, the mechanism behind the 'paradoxical' up-regulation of this inhibitory receptor upon pathogenic antibody-secreting cells is yet to be known. To this end, in this study, we examined if glycoprotein 49B (gp49B), the murine counterpart of human LILRB4, is also elevated in auto-antibody-producing cells in several SLE mouse models, and tried to clarify the underlying mechanism. We found that gp49B is expressed on plasma cells of lupus-prone models but not of healthy C57BL/6 mice, and the level was positively correlated to the anti-double-stranded DNA IgG titer in serum. Gp49B genetic deletion, however, did not abolish the serum auto-antibodies or fully ameliorate the lethal glomerulonephritis, indicating that gp49B is not the sole regulator of lupus but a pathogenic element in the disease. We conclude that the elevated expression of this inhibitory receptor on pathogenic plasma cells was also relevant upon the murine SLE model. The mechanism of gp49B underlying the disease progression in lupus-prone mice has been discussed.
摘要 免疫稳态是由 T 和 B 淋巴细胞以及髓样细胞等各种免疫细胞上表达的激活和抑制受体之间的平衡来严格调控的。抑制性受体在免疫检查点途径中起着至关重要的作用，从而维持外周耐受。我们最近发现，白细胞免疫球蛋白样受体 (LILR)B4 的表达在系统性红斑狼疮 (SLE) 患者产生自身抗体的浆母细胞/浆细胞中增加，LILR 是人类 LILR 家族的抑制成员。然而，致病性抗体分泌细胞中这种抑制性受体“反常”上调的机制尚不清楚。为此，在这项研究中，我们检查了 gp49B（人类 LILRB4 的鼠类对应物）是否也在几种 SLE 小鼠模型中的产生自身抗体的细胞中升高，并试图阐明其潜在机制。我们发现 gp49B 在狼疮易感模型的浆细胞中表达，但在健康的 C57BL/6 小鼠中不表达，其水平与血清中抗双链 DNA IgG 滴度呈正相关。然而，gp49B 基因缺失并没有消除血清自身抗体或完全改善致命性肾小球肾炎，表明 gp49B 不是狼疮的唯一调节因子，而是疾病的致病因素之一。我们得出结论，这种抑制性受体在致病性浆细胞上的表达升高也与小鼠 SLE 模型有关。已经讨论了 gp49B 在狼疮易感小鼠中导致疾病进展的机制。
