Matta Bharati, Battaglia Jenna, Lapan Margaret, Sharma Vinay, Barnes Betsy J
Center for Autoimmune Musculoskeletal and Hematopoietic Disease, The Feinstein Institutes for Medical Research, Manhasset, New York, USA.
Amity Institute of Biotechnology, Amity University Rajasthan, Jaipur, India.
Immunology. 2025 Feb;174(2):226-238. doi: 10.1111/imm.13879. Epub 2024 Nov 21.
Elevated levels of serum autoantibodies are a hallmark of systemic lupus erythematosus (SLE) and are produced by plasma cells in response to a variety of antigenic triggers. In SLE, the triggers are complex and may include both T cell-dependent/-independent and TLR-dependent/-independent mechanisms of immune activation, which ultimately contributes to the significant immune dysregulation seen in patients at the level of cytokine production and cellular activation (B cells, T cells, dendritic cells, neutrophils and macrophages). Interferon regulatory factor 5 (IRF5) has been identified as an autoimmune susceptibility gene and polymorphisms in IRF5 associate with altered expression and hyper-activation in distinct SLE immune cell subsets. To gain further insight into the mechanisms that drive IRF5-mediated SLE immune activation, we characterised wild-type (WT) and Irf5 Balb/c mice in response to immunisation. WT and Irf5 Balb/c mice were immunised to activate various signalling pathways in vivo followed by systemic immunophenotyping and detection of antibody production by multi-colour flow cytometry and ELISPOT. We identified two pathways, TLR9-dependent and T cell-dependent that resulted in IRF5 cell type-specific function. Immunisation with either CpG-B + Alum or NP-KLH + Alum but not with R848 + Alum, NP-LPS + Alum or NP-Ficoll+Alum resulted in decreased plasma cell generation and reduced antibody production in Irf5 mice. Notably, the mechanism(s) leading to this downstream phenotype was distinct. In CpG-B + Alum immunised mice, we found reduced activation of plasmacytoid dendritic cells, resulting in reduced IFNα and IL6 production in Irf5 mice. Conversely, mice immunised with NP-KLH + Alum had reduced numbers of T follicular helper cells and germinal centre B cells with reduced expression of Bcl6 in Irf5 mice. Moreover, T follicular helper cells from Irf5 mice were functionally defective. Even though the downstream phenotype of reduced antibody production in Irf5 mice was conserved between T cell-dependent and TLR9-dependent immunisation, the mechanisms leading to this phenotype were antigen- and cell type-specific.
血清自身抗体水平升高是系统性红斑狼疮（SLE）的一个标志，由浆细胞针对多种抗原触发因素产生。在SLE中，触发因素很复杂，可能包括T细胞依赖性/非依赖性和Toll样受体（TLR）依赖性/非依赖性免疫激活机制，这最终导致患者在细胞因子产生和细胞激活（B细胞、T细胞、树突状细胞、中性粒细胞和巨噬细胞）水平出现显著的免疫失调。干扰素调节因子5（IRF5）已被确定为一种自身免疫易感性基因，IRF5中的多态性与不同SLE免疫细胞亚群中表达改变和过度激活相关。为了进一步深入了解驱动IRF5介导的SLE免疫激活的机制，我们对野生型（WT）和Irf5基因敲除的Balb/c小鼠进行免疫接种后的情况进行了表征。WT和Irf5基因敲除的Balb/c小鼠经免疫接种以在体内激活各种信号通路，随后通过多色流式细胞术和酶联免疫斑点法进行全身免疫表型分析和抗体产生检测。我们确定了两条通路，即TLR9依赖性和T细胞依赖性通路，它们导致了IRF5细胞类型特异性功能。用CpG-B+明矾或NP-KLH+明矾免疫，但不用R848+明矾、NP-LPS+明矾或NP-Ficoll+明矾免疫，会导致Irf5基因敲除小鼠的浆细胞生成减少和抗体产生降低。值得注意的是，导致这种下游表型的机制是不同的。在经CpG-B+明矾免疫的小鼠中，我们发现浆细胞样树突状细胞的激活减少，导致Irf5基因敲除小鼠中IFNα和IL6的产生减少。相反，用NP-KLH+明矾免疫的小鼠中，T滤泡辅助细胞和生发中心B细胞数量减少，Irf5基因敲除小鼠中Bcl6的表达降低。此外，Irf5基因敲除小鼠的T滤泡辅助细胞功能有缺陷。尽管在T细胞依赖性和TLR9依赖性免疫接种中，Irf5基因敲除小鼠中抗体产生减少的下游表型是一致的，但导致这种表型的机制是抗原和细胞类型特异性的。
