Division of Rheumatology, Department of Medicine, University of Washington, Seattle, Washington, United States of America.
PLoS One. 2018 Oct 4;13(10):e0205172. doi: 10.1371/journal.pone.0205172. eCollection 2018.
Defective clearance of apoptotic cells in MFG-E8 deficient mice results in lupus-like disease in the mixed B6x129, but not pure B6 background. The lack of overt autoimmunity in MFG-E8-/- B6 mice suggests that accumulation of apoptotic cells is not sufficient to break central tolerance. However, the delayed clearance of apoptotic cells in the follicles of MFG-E8-/- B6 mice provides an excellent opportunity to investigate how B cells respond to excessive apoptotic cells in the periphery under relatively non-inflammatory conditions. In MFG-E8-/- B6 mice, we found increased IgG2c production against apoptotic cells and oxidized LDL. Apoptotic cell induced antibody responses depended on MyD88 signal and T cell help. In addition, MFG-E8-/- B6 mice had enlarged MZ B cell compartments as well as an enhanced antibody response to NP-Ficoll. Moreover, a significant percentage of MZ B cells in aged MFG-E8-/- B6 mice migrated into follicles. Injecting apoptotic cells or oxidized LDL into wild type mice as well as physiological accumulation of LDL in ApoE-/- mice recapitulated the translocation of MZ B cells. To determine how MFG-E8 deficiency affects the functions of autoreactive B cells specific for nucleic acids in the periphery under non-inflammatory conditions, we utilized BCR transgenic mice to bypass central selection and compared the differentiation of TLR9 dependent anti-dsDNA 56R B cells and TLR7 dependent anti-ssRNA H564 B cells in MFG-E8-/- mice. In MFG-E8-/- 56R mice, anti-dsDNA specific 56R/Vκ38c B cells differentiated into MZ B cells but not AFCs. On the contrary, in MFG-E8-/-H564 mice, anti-ssRNA specific H564 B cells further differentiated into GC B cells and AFCs. Adoptive transfer of activated autoreactive B cells confirmed that H564 B cells were more sensitive to apoptotic cell antigens than 56R B cells. Our observations provide new insights about the MZ B cell translocation in lupus patients as well as the dichotomy of TLR9 and TLR7 signals in the pathogenesis of lupus.
在混合 B6x129 而非纯 B6 背景中，MFG-E8 缺陷小鼠清除凋亡细胞的功能缺陷导致狼疮样疾病。MFG-E8-/-B6 小鼠中未出现明显的自身免疫表明，凋亡细胞的堆积不足以打破中枢耐受。然而，MFG-E8-/-B6 小鼠滤泡中凋亡细胞的清除延迟为研究在相对非炎症条件下，B 细胞如何对外周过多的凋亡细胞作出反应提供了极好的机会。在 MFG-E8-/-B6 小鼠中，我们发现针对凋亡细胞和氧化型 LDL 的 IgG2c 产生增加。凋亡细胞诱导的抗体反应依赖于 MyD88 信号和 T 细胞辅助。此外，MFG-E8-/-B6 小鼠的边缘区（MZ）B 细胞区室增大，对 NP-Ficoll 的抗体反应增强。而且，衰老的 MFG-E8-/-B6 小鼠中有相当大比例的 MZ B 细胞迁移到滤泡中。向野生型小鼠注射凋亡细胞或氧化型 LDL 以及 ApoE-/-小鼠中 LDL 的生理性堆积可再现 MZ B 细胞的易位。为了确定在非炎症条件下，MFG-E8 缺陷如何影响外周自身反应性 B 细胞针对核酸的功能，我们利用 BCR 转基因小鼠绕过中枢选择，并比较了 TLR9 依赖性抗 dsDNA 56R B 细胞和 TLR7 依赖性抗 ssRNA H564 B 细胞在 MFG-E8-/-小鼠中的分化。在 MFG-E8-/-56R 小鼠中，抗 dsDNA 特异性 56R/Vκ38c B 细胞分化为 MZ B 细胞而非 AFC。相反，在 MFG-E8-/-H564 小鼠中，抗 ssRNA 特异性 H564 B 细胞进一步分化为 GC B 细胞和 AFC。活化的自身反应性 B 细胞的过继转移证实，H564 B 细胞对凋亡细胞抗原比 56R B 细胞更敏感。我们的观察结果为狼疮患者的 MZ B 细胞易位以及狼疮发病机制中 TLR9 和 TLR7 信号的二分法提供了新的见解。
