Wu Yin, Deshpande Aditee, Geraci Nicholas, Budde Petra, Sellers Vera, Velisetty Phanindra, Sun Chia-Chi, Strand Fatima, Bhavsar Carmina, Niewold Timothy B, Jensen Mark A, Kalatskaya Irina, Sarin Kavita Y, Fiorentino David, Bender Andrew T
EMD Serono, Billerica, Massachusetts.
Oncimmune Germany GmbH, Dortmund, Germany.
Arthritis Rheumatol. 2025 Feb;77(2):190-201. doi: 10.1002/art.42989. Epub 2024 Nov 4.
Activation of endosomal toll-like receptors (TLRs) is one possible driver of inflammation in idiopathic inflammatory myopathies (IIM). We investigated the potential contribution of TLR7 and TLR8 to IIM pathogenesis.
Activation of TLR7/8 in healthy donor peripheral blood mononuclear cells (PBMCs) by immune complexes from patients with IIMs and lupus was tested. Autoantibody profiling of patient IgG samples was performed using a 1581 antigen array. TLR7 and/or TLR8 activation by RNA molecules associated with autoantibodies was assessed. Gene expression in human myoblasts and satellite cells following treatment with supernatants from TLR7/8-activated PBMCs was evaluated by NanoString. C57BL/6 mice were dosed intramuscularly with the TLR7/8 agonist R848 and single-cell RNA-sequencing was performed on the muscle to ascertain the cell types responding to TLR7/8 activation and the downstream effects.
Overall, 69 patients with IIMs were included with representation of dermatomyositis, polymyositis, and inclusion body myositis subsets. Immune complexes from patients with IIMs, as well as autoantibody-associated RNAs histidyl-transfer RNA, Y1, Y4, and U1, activated PBMCs to produce interferon-α and IL-6 via TLR7/8. Several canonical (Ro60, Ro52, and HIST1H4A) and novel (IL-36RN) autoreactivities correlated highly with TLR7/8 activation. Supernatants from TLR7/8-activated PBMCs had a negative impact on human myoblasts and satellite cells. Endothelial cells were activated by R848 in mouse muscle in vivo in addition to immune cells such as monocytes and macrophages.
Our results suggest that patients with IIMs have autoantibodies in their blood causing TLR7/8 activation, which leads to inflammation in muscles with potential deleterious effects.
内体 toll 样受体（TLR）的激活是特发性炎性肌病（IIM）炎症的一个可能驱动因素。我们研究了 TLR7 和 TLR8 对 IIM 发病机制的潜在作用。
测试了 IIM 患者和狼疮患者的免疫复合物对健康供体外周血单个核细胞（PBMC）中 TLR7/8 的激活作用。使用 1581 抗原阵列对患者 IgG 样本进行自身抗体谱分析。评估了与自身抗体相关的 RNA 分子对 TLR7 和/或 TLR8 的激活作用。通过 NanoString 评估用 TLR7/8 激活的 PBMC 上清液处理后人成肌细胞和卫星细胞中的基因表达。对 C57BL/6 小鼠进行肌肉内注射 TLR7/8 激动剂 R848，并对肌肉进行单细胞 RNA 测序，以确定对 TLR7/8 激活作出反应的细胞类型及其下游效应。
总体而言，纳入了 69 例 IIM 患者，包括皮肌炎、多发性肌炎和包涵体肌炎亚组。IIM 患者的免疫复合物以及自身抗体相关的 RNA（组氨酰 - 转运 RNA、Y1、Y4 和 U1）通过 TLR7/8 激活 PBMC 产生干扰素 -α和白细胞介素 -6。几种典型的（Ro60、Ro52 和 HIST1H4A）和新发现的（IL - 36RN）自身反应性与 TLR7/8 激活高度相关。TLR7/8 激活的 PBMC 上清液对人成肌细胞和卫星细胞有负面影响。除了单核细胞和巨噬细胞等免疫细胞外，R848 在体内还激活了小鼠肌肉中的内皮细胞。
我们的结果表明，IIM 患者血液中的自身抗体导致 TLR7/8 激活，进而导致肌肉炎症并可能产生有害影响。
