Ding Liang, Dong Guanjun, Zhang Dongya, Ni Yanhong, Hou Yayi
The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology and Hospital of Stomatology, Medical School, Nanjing University, Nanjing, China.
The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology and Hospital of Stomatology, Medical School, Nanjing University, Nanjing, China.
Med Hypotheses. 2015 Dec;85(6):846-9. doi: 10.1016/j.mehy.2015.09.026. Epub 2015 Sep 28.
The systemic dysregulation of adaptive and innate immunity have been identified as major hallmark of systemic lupus erythematosus (SLE) pathogenesis that predominantly affects women. Patients with SLE develop heterogeneous clinical manifestations which involve of multiple organ damage including renal, spleen, nervous system, joints and hematopoietic organs. A high rate of cell death, e.g., NETosis, and clearance deficiencies by myeloid cells led to increased cell debris and accumulation of endogenous nucleic acids, and the presence of anti-nuclear antibodies (ANAs) derived from immune response can break of self-tolerance and exacerbate SLE pathology. Currently, the nucleic acid receptors, such as Toll-like receptors, RIG-I-like receptors, AIM2-like receptors and IFI 200-family have been uncovered to be potential predisposing causes for SLE via triggering interferon (IFN) response and maturation of IL-1β. Notably, as the newly found DNA sensor, cyclic GMP-AMP synthase (cGAS) can activate the stimulator of interferon genes (STING), which plays a pivotal role in DNA/RNA sensing pathway, for type I IFN and other inflammatory cytokines induction including IL-6 and attributes to STING-associated inflammatory disorders. Interestingly, the elevated levels of IFN-α/β and IFN-stimulated genes were found in SLE patients than healthy individuals. Given this, we propose a hypothesis that the cGAS-STING pathway in multiple organs function versatile and can facilitate overall disease progression of SLE though impertinent cytosolic self-DNA sensing.
适应性免疫和先天性免疫的系统性失调已被确定为系统性红斑狼疮（SLE）发病机制的主要标志，该病主要影响女性。SLE患者会出现异质性临床表现，涉及包括肾脏、脾脏、神经系统、关节和造血器官在内的多个器官损伤。细胞死亡率高，例如中性粒细胞胞外诱捕网形成，以及髓样细胞的清除缺陷导致细胞碎片增加和内源性核酸积累，并且免疫反应产生的抗核抗体（ANA）的存在会破坏自身耐受性并加剧SLE病理。目前，已发现核酸受体，如Toll样受体、RIG-I样受体、AIM2样受体和IFI 200家族，是通过触发干扰素（IFN）反应和IL-1β成熟而导致SLE的潜在易感因素。值得注意的是，作为新发现的DNA传感器，环状GMP-AMP合酶（cGAS）可以激活干扰素基因刺激因子（STING），其在DNA/RNA传感途径中起关键作用，用于诱导I型干扰素和其他炎症细胞因子，包括IL-6，并导致与STING相关的炎症性疾病。有趣的是，与健康个体相比，SLE患者中IFN-α/β和IFN刺激基因的水平升高。鉴于此，我们提出一个假设，即多个器官中的cGAS-STING途径功能多样，并且可以通过不适当的胞质自身DNA传感促进SLE的整体疾病进展。
