细胞因子IL-18在X-连锁淋巴细胞异常增生症中导致HLH的作用及机制研究

X-linked lymphoproliferative disease (XLP) is a rare inherited immunodeficiency, and often triggered by Epstein–Barr virus (EBV) infection. The most common and fatal complication in XLP is recurrent EBV-associated hemophagocytic lymphohistiocytosis (HLH). The pathogenesis of HLH in XLP is still unknown and IFN-γ has been proved a critical cytokine in HLH. We previously found: (1) The induction of IFN-γ in CD4+T cell requires not only the signal of TCR-IFN-γ pathway but also cytokine-IFN-γ pathway, however the signal of TCR-IFN-γ was impaired in XLP patient; (2) The concentration of IL-18 and IFN-γ were strikingly elevated in patient presenting HLH while IL-18 was still elevated in patient presenting HLH remission period in XLP. We therefore hypothesize that IL-18 and IL-18-induced IFN-γ are over-activated in CD4+ T cells, and this is the major player in the pathogenesis of HLH and high IL-18 concentration is associated with recurrent HLH in XLP. The present study is proposed to clarify the regulatory mechanisms of IL-18 in HLH especially recurrent HLH in XLP. We also want to down-regulate cytokine-IFN-γ and IL-18 by using IL-18 binding protein (IL-18BP) to generate a potential intervention for HLH. In conclusion, we use such precious human model to investigate the control mechanism HLH in XLP and may provide useful information on theoretical basis in XLP and EBV associated disease.

X-连锁淋巴细胞异常增生症(XLP)是一种罕见的X连锁原发性免疫缺陷病，该病常由EB病毒感染触发免疫调节异常导致致死性或复发性噬血淋巴组织细胞增生症(HLH)。XLP患者HLH发病机制尚未阐明。干扰素-γ(IFN-γ)被公认是HLH发病的关键因素。前期研究发现：(1)XLP患者CD4+T细胞产生的IFN-γ主要是由细胞因子相关途径介导而非T细胞受体-IFN-γ途径；(2)XLP患者在HLH活动期IL-18及IFN-γ水平明显增加，而在HLH稳定期IL-18仍有明显增高。我们推测IL-18及其介导的细胞因子IFN-γ途径过度活化是XLP导致高发和复发HLH的关键。本研究拟利用近年来收集的XLP珍贵临床样本验证上述假说并提出IL-18在XLP患者的HLH发病中起关键作用并可能成为治疗靶点，进一步通过IL-18拮抗剂抑制该活化途径，验证提出的理论和治疗策略，为精准干预相关疾病治疗奠定理论基础。

X-连锁淋巴细胞异常增生症(XLP)是一种罕见的X连锁原发性免疫缺陷病，该病常由EB病毒感染触发免疫调节异常导致致死性或复发性噬血淋巴组织细胞增生症(HLH)。XLP患者HLH发病机制尚未阐明。干扰素-γ (IFN-γ) 被公认是HLH发病的关键因素。本研究发现并证实XLP患者CD4+T细胞产生的IFN-γ主要是由细胞因子相关途径介导产生的，并且IL-18这个细胞因子在该途径的活化中起到重要作用。IL-18BP作为IL-18的天然拮抗剂，对该途径的抑制性可成为该病治疗的新靶点。同时，本研究建立了XLP患者疾病的永生化细胞系，为罕见病的患者信息和数据的保存奠定了基础。