Department of Histology and Cytology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt.
Laboratory of Anatomy, Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
Front Immunol. 2021 Jul 21;12:665100. doi: 10.3389/fimmu.2021.665100. eCollection 2021.
Mediastinal fat-associated lymphoid clusters (MFALCs) are novel immune clusters that function in the pathogenesis of bleomycin (BLM)-induced pneumonitis in a C57BL/6 mouse model. However, we lack literature on the effects of BLM in an autoimmune disease mouse model (AIDM). In the present study, BLM sulfate (BLM group) or phosphate-buffered saline (PBS group) were intranasally administered in BXSB/MpJ-Yaa (Yaa) AIDM and its wild-type strains (BXSB/MpJ "BXSB") and the histopathology of MFALCs and lungs were examined on days 7 and 21 days. Immunohistochemical analysis was performed to detect lymphatic vessels (LVs), high endothelial venules (HEVs), proliferating, and immune cells. Furthermore, the mRNA expression of Yaa locus genes (, , , , and ) was detected in the lung tissues. Here, we show a dual effect of BLM on intra-thoracic immune hemostasis among Yaa AIDM and its corresponding wild-type strain (BXSB mice). The BLM group of BXSB mice displayed significantly higher values of lung injury scores (LIS) and size of MFALCs as compared with the corresponding PBS group. However, an opposite effect was detected in Yaa mice. Furthermore, Yaa mice displayed decreased serum autoantibody titers and downregulated expression of , , , and in the lungs following BLM administration, especially on day 21. Interestingly, significant positive correlations were detected in both strains between the LIS and the size of MFALCs, LVs, HEVs, and proliferating cells. Conclusively, our findings revealed a crucial function of HEVs on the extent of lung injury and the development of MFALCs in BLM-administered Yaa AIDM and control BXSB mice with dual effects. Moreover, our data suggest that down regulation of Yaa locus genes could contribute as an important attributing factor leading to decrease in the degree of autoimmunity and lung injury in AIDM. Therefore, we suggest that genetic background contributes to BLM diversity among AIDM and the wild-type strain. Targeting some genes or venules could provide novel therapeutic approaches for some autoimmune-associated respiratory diseases controlling the MFALCs development.
纵隔脂肪相关淋巴簇 (MFALCs) 是一种新型免疫簇，在 C57BL/6 小鼠模型的博来霉素 (BLM) 诱导性肺炎发病机制中发挥作用。然而，我们缺乏 BLM 在自身免疫性疾病小鼠模型 (AIDM) 中作用的文献。在本研究中，BLM 硫酸盐 (BLM 组) 或磷酸盐缓冲盐水 (PBS 组) 通过鼻腔内给药于 BXSB/MpJ-Yaa (Yaa) AIDM 及其野生型菌株 (BXSB/MpJ "BXSB")，并在第 7 天和 21 天检查 MFALCs 和肺的组织病理学。进行免疫组织化学分析以检测淋巴管 (LVs)、高内皮静脉 (HEVs)、增殖和免疫细胞。此外，还检测了肺组织中 Yaa 基因座基因 (、、、和 ) 的 mRNA 表达。在这里，我们展示了 BLM 对 Yaa AIDM 及其相应野生型菌株 (BXSB 小鼠) 胸内免疫止血的双重作用。与相应的 PBS 组相比，BLM 组 BXSB 小鼠的肺损伤评分 (LIS) 和 MFALCs 大小显著升高。然而，在 Yaa 小鼠中检测到相反的效果。此外，BLM 给药后，Yaa 小鼠的血清自身抗体滴度降低，并且肺中 、 、 、 和 的表达下调，尤其是在第 21 天。有趣的是，在两种菌株中，LIS 与 MFALCs、LVs、HEVs 和增殖细胞的大小之间均存在显著的正相关。总之，我们的研究结果揭示了 HEVs 在 BLM 给药的 Yaa AIDM 和对照 BXSB 小鼠的肺损伤程度和 MFALCs 发展中的关键作用，具有双重作用。此外，我们的数据表明，Yaa 基因座基因的下调可能是导致 AIDM 中自身免疫和肺损伤程度降低的一个重要归因因素。因此，我们认为遗传背景导致 AIDM 和野生型菌株之间 BLM 的多样性。针对某些基因或静脉可能为控制 MFALCs 发展的某些自身免疫性相关呼吸系统疾病提供新的治疗方法。
