TNF is important in immune-mediated inflammatory diseases, including spondyloarthritis (SpA). Transgenic (tg) mice overexpressing transmembrane TNF (tmTNF) develop features resembling human SpA. Furthermore, both tmTNF tg mice and SpA patients develop ectopic lymphoid aggregates, but it is unclear whether these contribute to pathology. Therefore, we characterized the lymphoid aggregates in detail and studied potential alterations in the B and T cell lineage in tmTNF tg mice. Lymphoid aggregates developed in bone marrow (BM) of vertebrae and near the ankle joints prior to the first SpA features and displayed characteristics of ectopic lymphoid structures (ELS) including presence of B cells, T cells, germinal centers, and high endothelial venules. Detailed flow cytometric analyses demonstrated more germinal center B cells with increased CD80 and CD86 expression, along with significantly more T follicular helper, T follicular regulatory, and T regulatory cells in tmTNF tg BM compared with non-tg controls. Furthermore, tmTNF tg mice exhibited increased IgA serum levels and significantly more IgA⁺ plasma cells in the BM, whereas IgA⁺ plasma cells in the gut were not significantly increased. In tmTNF tg × TNF-RI^−/− mice, ELS were absent, consistent with reduced disease symptoms, whereas in tmTNF tg × TNF-RII^−/− mice, ELS and clinical symptoms were still present. Collectively, these data show that tmTNF overexpression in mice results in osteitis and ELS formation in BM, which may account for the increased serum IgA levels that are also observed in human SpA. These effects are mainly dependent on TNF-RI signaling and may underlie important aspects of SpA pathology.

TNF 在免疫介导的炎症性疾病中很重要，包括脊柱关节炎 (SpA)。过表达跨膜 TNF (tmTNF) 的转基因 (tg) 小鼠发展出类似于人类 SpA 的特征。此外，tmTNF tg 小鼠和 SpA 患者都会出现异位淋巴聚集，但尚不清楚这些是否有助于病理学。因此，我们详细表征了淋巴聚集体，并研究了 tmTNF tg 小鼠中 B 和 T 细胞谱系的潜在改变。在首次出现 SpA 特征之前，在椎骨的骨髓 (BM) 和踝关节附近形成淋巴聚集物，并显示出异位淋巴结构 (ELS) 的特征，包括存在 B 细胞、T 细胞、生发中心和高内皮小静脉。详细的流式细胞术分析表明，与非 tg 对照相比，tmTNF tg BM 中更多的生发中心 B 细胞具有增加的 CD80 和 CD86 表达，以及显着更多的 T 滤泡辅助细胞、T 滤泡调节细胞和 T 调节细胞。此外，tmTNF tg 小鼠表现出增加的 IgA 血清水平和显着更多的 IgA⁺ BM 中的浆细胞，而肠道中的IgA ⁺浆细胞没有显着增加。在 tmTNF tg × TNF-RI ^-/-小鼠中，ELS 不存在，与疾病症状减轻一致，而在 tmTNF tg × TNF-RII ^-/-小鼠中，ELS 和临床症状仍然存在。总的来说，这些数据表明小鼠中 tmTNF 的过度表达导致 BM 中的骨炎和 ELS 形成，这可能是在人 SpA 中也观察到的血清 IgA 水平升高的原因。这些影响主要取决于 TNF-RI 信号传导，并且可能是 SpA 病理学的重要方面的基础。