Abnormalities of T cells in systemic lupus erythematosus: new insights in pathogenesis and therapeutic strategies
Abnormalities of T cells in systemic lupus erythematosus: new insights in pathogenesis and therapeutic strategies
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DOI：
10.1016/j.jaut.2022.102870
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发表时间：
2022-10-01
影响因子：
12.8
通讯作者：
Tsokos, George C.
中科院分区：
文献类型：
--
作者：
Li, Hao;Boulougoura, Afroditi;Tsokos, George C.
系统性红斑狼疮（SLE）是一种自身免疫性疾病，其特征是免疫耐受丧失和持续产生自身抗体。SLE中多种和严重的T细胞异常与疾病表达交织在一起。在主要的CD 4 + T辅助细胞亚群中，包括Th 1、Th 2、Th 17、调节性和滤泡辅助细胞，已经报道了数量和功能障碍。已知SLE CD 4 + T细胞为B细胞提供帮助，产生过量的IL-17但产生不足的IL-2，并浸润组织。在缺乏足够量的IL-2的情况下，调节性T细胞不能正常发挥作用以抑制炎症。一系列复杂的早期信号缺陷和激酶和磷酸酶的异常激活通过改变代谢谱和表观遗传景观导致复杂的细胞表型。所有主要的代谢途径，包括糖酵解，氨解和氧化磷酸化改变的T细胞从狼疮易感小鼠和SLE患者。SLE CD 8+细胞毒性T细胞表现出降低的细胞溶解活性，这是导致感染率较高和维持自身免疫的原因。此外，在风湿性疾病的情况下，CD 8 + T细胞失去CD 8的表达，获得IL-17+ CD 4-CD 8-双阴性T（DNT）细胞表型并浸润组织。在此，我们提出了这些T细胞异常的更新沿着与潜在的机制，并讨论如何利用这些进展治疗。纠正T细胞中这些畸变的新策略显示出SLE治疗的前景。
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by loss of immune tolerance and sustained production of autoantibodies. Multiple and profound T cell abnormalities in SLE are intertwined with disease expression. Both numerical and functional disturbances have been reported in main CD4+ T helper cell subsets including Th1, Th2, Th17, regulatory, and follicular helper cells. SLE CD4+ T cells are known to provide help to B cells, produce excessive IL-17 but insufficient IL-2, and infiltrate tissues. In the absence of sufficient amounts of IL-2, regulatory T cells, do not function properly to constrain inflammation. A complicated series of early signaling defects and aberrant activation of kinases and phosphatases result in complex cell phenotypes by altering the metabolic profile and the epigenetic landscape. All main metabolic pathways including glycolysis, glutaminolysis and oxidative phosphorylation are altered in T cells from lupus prone mice and patients with SLE. SLE CD8+ cytotoxic T cells display reduced cytolytic activity which accounts for higher rates of infection and the sustenance of autoimmunity. Further, CD8+ T cells in the context of rheumatic diseases lose the expression of CD8, acquire IL-17+CD4-CD8- double negative T (DNT) cell phenotype and infiltrate tissues. Herein we present an update on these T cell abnormalities along with underlying mechanisms and discuss how these advances can be exploited therapeutically. Novel strategies to correct these aberrations in T cells show promise for SLE treatment.