Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
Center for Cancer and Blood Disorders, Children's National Medical Center, Washington DC, United States of America.
PLoS One. 2021 Mar 12;16(3):e0248343. doi: 10.1371/journal.pone.0248343. eCollection 2021.
Immune aplastic anemia (AA) results from T cell attack on hematopoietic cells, resulting in bone marrow hypocellularity and pancytopenia. Animal models have been successfully developed to study pathophysiological mechanisms in AA. While we have systemically defined the critical components of the adaptive immune response in the pathogenesis of immune marrow failure using this model, the role of innate immunity has not been fully investigated. Here, we demonstrate that lymph node (LN) cells from B6-based donor mice carrying IL-6, TLR2, or TLR4 gene deletions were fully functional in inducing severe pancytopenia and bone marrow failure (BMF) when infused into MHC-mismatched CByB6F1 recipients. Conversely, B6-based recipient mice with IL-6, TLR2, and TLR4 deletion backgrounds were all susceptible to immune-mediated BMF relative to wild-type B6 recipients following infusion of MHC-mismatched LN cells from FVB donors, but the disease appeared more severe in IL-6 deficient mice. We conclude that IL-6, TLR2, and TLR4, molecular elements important in maintenance of normal innate immunity, have limited roles in a murine model of immune-mediated BMF. Rather, adaptive immunity appears to be the major contributor to the animal disease.
免疫性再生障碍性贫血（AA）是由 T 细胞攻击造血细胞引起的，导致骨髓细胞减少和全血细胞减少。已经成功开发了动物模型来研究 AA 发病机制中的病理生理机制。虽然我们已经使用该模型系统地定义了适应性免疫反应在免疫性骨髓衰竭发病机制中的关键组成部分，但先天免疫的作用尚未得到充分研究。在这里，我们证明了携带 IL-6、TLR2 或 TLR4 基因缺失的基于 B6 的供体小鼠的淋巴结 (LN) 细胞在输注到 MHC 错配的 CByB6F1 受体中时完全能够诱导严重的全血细胞减少和骨髓衰竭 (BMF)。相反，与野生型 B6 受体相比，具有 IL-6、TLR2 和 TLR4 缺失背景的基于 B6 的受体小鼠在输注来自 FVB 供体的 MHC 错配 LN 细胞后均易发生免疫介导的 BMF，但在缺乏 IL-6 的小鼠中疾病似乎更严重。我们得出结论，在免疫介导的 BMF 小鼠模型中，维持正常先天免疫的重要分子元素 IL-6、TLR2 和 TLR4 的作用有限。相反，适应性免疫似乎是导致动物疾病的主要因素。
