IL-22 在HIV-1慢性感染肠粘膜损伤中的机制研究

It is important to elucidate the immune mechanisms underlying the disease progression of chronic HIV-1 infection. Recent studies have shown that HIV-1 infection mainly depleted intestinal CD4 T cells and increased the intestinal permeability, thus leading to the hyper-activation of immune system and immune exhaustion. Interleukin (IL)-22 is a kind of cytokines that is produced by immune cells but functions as antimicrobial defense and protection against tissue damage through inducing acute phase reactants and chemokines. IL-22 receptor is preferentially expressed by several tissue cells including epithelial cells, hepatocytes and intestinal epithelium cells. The function of IL-22 is also regulated by IL-22 binding protein (IL-22BP) which preferentially binds IL-22 than IL-22 receptor and largely reduces IL-22 activities. Our previous study had indicated that IL-22 expression by CD4 T cells significantly decreased in the peripheral blood in patients with chronic HIV-1 infection as compared to that of healthy subjects; this reduction of IL-22 expression was further found to be positively associated with peripheral CD4 T cell counts. In addition, we also found that IL-22 positive cells were enriched in the injuried mucosa of intestin in patients with chronic HIV-1 infection. Basing on these data, we hypotheze that the balance of IL-22-IL-22BP axis may be disturbed in chronic HIV-1-infected patients, which subsequently leads to the loss of intestinal epithelial cell barrier and the spreading of numerous bacterial products such as LPS into circulation and finally inducing the host immune hyper-activation. This study highlights the key role of IL-22-IL-22BP axis in the pathogenesis of chronic HIV-1 infection and will provide a novel therapeutic strategy targeting IL-22-IL-22BP axis in chronic HIV-1 infection.

阐明导致HIV-1慢性感染疾病进展的免疫学机制对于临床治疗具有重要意义。近期研究表明，HIV-1慢性感染主要删除肠道CD4 T细胞，导致免疫超活化和免疫功能耗竭。IL-22由免疫细胞产生具有促进组织修复和抵御病原体感染的作用，其受体主要表达在包括肠上皮细胞在内的多种组织细胞，其功能还受到IL-22结合蛋白（IL-22BP）的竞争性抑制。我们前期研究结果提示，HIV-1慢性感染者外周血IL-22表达降低，与CD4计数呈显著正相关。免疫组化显示，IL-22阳性细胞聚集在HIV-1慢性感染者肠粘膜损伤部位。据此我们假设，HIV-1慢性感染IL-22-IL-22BP平衡被打破，进而导致IL-22对肠上皮细胞的保护作用受损，最终加剧机体免疫超活化，推动疾病进展。该研究目的在于阐明IL-22-IL-22BP轴在HIV-1慢性感染疾病进展中的作用机制，从而为针对IL-22设计新的治疗策略提供科学依据。

阐明导致HIV-1慢性感染疾病进展的免疫学机制对于临床治疗具有重要意义。近期研究表明，HIV-1慢性感染主要删除肠道CD4 T细胞，导致免疫超活化和免疫功能耗竭。.IL-22由免疫细胞产生具有促进组织修复和抵御病原体感染的作用。我们研究结果表明HIV-1慢性感染者 IL-22表达降低，肠道粘膜部位更为严重，进而导致肠道粘膜屏障功能丧失，大量细菌代谢产物如LPS等进入循环系统，最终加剧机体免疫超活化。更为重要的是我们发现，在肠道内IL-22主要来源于3型天然淋巴细胞而不是CD4T细胞，HIV患者肠道内ILC3s大量删除。进一步研究发现病毒感染导致的ILC3s删除依赖于pDC-IFN-I-Fas/FasL通路，体内删除pDCs或者体外阻断fas通路均可有效逆转ILC3s删除，HIV感染通过pDC和IFN-I诱导ILC3s表达fas水平增加，从而使其对fas/fasl凋亡途径敏感，最终走向凋亡。上述发现揭示了HIV慢性感染肠道粘膜屏障损伤的重要通路，为相关免疫治疗提供了科学依据。