Department of Pulmonary Medicine, Erasmus MC, Rotterdam, The Netherlands.
Department of Pulmonary Medicine, Erasmus MC, Rotterdam, The Netherlands; Department of Rheumatology, Erasmus MC, Rotterdam, The Netherlands.
J Autoimmun. 2015 Feb;57:30-41. doi: 10.1016/j.jaut.2014.11.008. Epub 2014 Dec 16.
While surrogate light chain (SLC) expression is normally terminated in differentiating pre-B cells, co-expression of SLC and conventional light chains has been reported in a small population of autoreactive peripheral human B cells that accumulate in arthritic joints. Despite this association with autoimmunity the contribution of SLC expressing mature B cells to disease development is still unknown. We studied the pathogenicity of SLC(+) B cells in a panel of mice that transgenically express the SLC components VpreB and λ5 throughout B cell development. Here we report that although VpreB or λ5 expression mildly activated mature B cells, only moderate VpreB expression levels - in the absence of λ5 - enhanced IgG plasma cell formation. However, no autoantibody production was detectable in VpreB or λ5 transgenic mice and VpreB expression could not accelerate autoimmunity. Instead, moderate VpreB expression partially protected mice from induced autoimmune arthritis. In support of a tolerogenic role of SLC-transgenic B cells, we observed that in a dose-dependent manner SLC expression beyond the pre-B cell stage enhanced clonal deletion among immature and transitional B cells and rendered mature B cells anergic. These findings suggest that SLC expression does not propagate autoimmunity, but instead may impose tolerance.
虽然替代轻链 (SLC) 的表达通常在分化前 B 细胞中终止，但在关节炎关节中积累的一小部分自身反应性外周人类 B 细胞中已经报道了 SLC 和常规轻链的共表达。尽管与自身免疫有关，但 SLC 表达成熟 B 细胞对疾病发展的贡献仍然未知。我们在一组转基因小鼠中研究了 SLC(+)B 细胞的致病性，这些小鼠在 B 细胞发育过程中表达 SLC 成分 VpreB 和 λ5。在这里，我们报告尽管 VpreB 或 λ5 的表达轻度激活了成熟 B 细胞，但只有适度的 VpreB 表达水平 - 在没有 λ5 的情况下 - 增强了 IgG 浆细胞的形成。然而，在 VpreB 或 λ5 转基因小鼠中未检测到自身抗体产生，并且 VpreB 表达不能加速自身免疫。相反，适度的 VpreB 表达部分保护了小鼠免受诱导性自身免疫性关节炎的影响。为了支持 SLC 转基因 B 细胞的耐受作用，我们观察到 SLC 表达在超过前 B 细胞阶段以剂量依赖的方式增强了未成熟和过渡 B 细胞中的克隆删除，并使成熟 B 细胞失能。这些发现表明 SLC 表达不会传播自身免疫，但可能会施加耐受。
