Department of Dermatology, Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, China.
Research Unit of Key Technologies of Diagnosis and Treatment for Immune-related Skin Diseases, Chinese Academy of Medical Sciences, Changsha, China.
J Clin Invest. 2022 May 2;132(9). doi: 10.1172/JCI152345.
The trace element iron affects immune responses and vaccination, but knowledge of its role in autoimmune diseases is limited. Expansion of pathogenic T cells, especially T follicular helper (Tfh) cells, has great significance to systemic lupus erythematosus (SLE) pathogenesis. Here, we show an important role of iron in regulation of pathogenic T cell differentiation in SLE. We found that iron overload promoted Tfh cell expansion, proinflammatory cytokine secretion, and autoantibody production in lupus-prone mice. Mice treated with a high-iron diet exhibited an increased proportion of Tfh cell and antigen-specific GC response. Iron supplementation contributed to Tfh cell differentiation. In contrast, iron chelation inhibited Tfh cell differentiation. We demonstrated that the miR-21/BDH2 axis drove iron accumulation during Tfh cell differentiation and further promoted Fe2+-dependent TET enzyme activity and BCL6 gene demethylation. Thus, maintaining iron homeostasis might be critical for eliminating pathogenic Th cells and might help improve the management of patients with SLE.
微量元素铁会影响免疫反应和疫苗接种，但人们对其在自身免疫性疾病中的作用知之甚少。致病性 T 细胞（尤其是滤泡辅助性 T 细胞[Tfh]细胞）的扩增对系统性红斑狼疮（SLE）的发病机制具有重要意义。在这里，我们发现铁在调节 SLE 中致病性 T 细胞分化方面起着重要作用。我们发现铁过载会促进狼疮易感小鼠中 Tfh 细胞的扩增、促炎细胞因子的分泌和自身抗体的产生。用高铁饮食处理的小鼠表现出 Tfh 细胞和抗原特异性 GC 反应的比例增加。铁补充剂有助于 Tfh 细胞分化。相比之下，铁螯合剂抑制 Tfh 细胞分化。我们证明，miR-21/BDH2 轴在 Tfh 细胞分化过程中驱动铁积累，并进一步促进 Fe2+-依赖性 TET 酶活性和 BCL6 基因去甲基化。因此，维持铁稳态对于消除致病性 Th 细胞可能至关重要，并可能有助于改善 SLE 患者的治疗。
