Persistent Chronic Inflammation and Infection by Chikungunya Arthritogenic Alphavirus in Spite of a Robust Host Immune Response
Persistent Chronic Inflammation and Infection by Chikungunya Arthritogenic Alphavirus in Spite of a Robust Host Immune Response
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DOI：
10.4049/jimmunol.0900255
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发表时间：
2010-05-15
影响因子：
4.4
通讯作者：
Gasque, Philippe
中科院分区：
文献类型：
--
作者：
Hoarau, Jean-Jacques;Bandjee, Marie-Christine Jaffar;Gasque, Philippe
甲病毒，包括基孔肯雅病毒（CHIKV），在人类中产生短暂的疾病，但导致慢性失能性关节痛/关节炎的严重形式已被报道的机制基本上是不明确的。CHIKV的发病机制在一项前瞻性队列研究中得到了解决，该研究将来自留尼汪岛的49名住院患者在感染后12个月分为两组。在“恢复”或“慢性”组中分析整个疾病过程中的临床和免疫学参数的综合分析，以鉴定CHIKV疾病后关节炎样病理学的预后标志物。我们发现，慢性组主要包括更多的老年患者（>60岁）和更高的病毒载量（高达10（10））病毒每毫升血液）在急性期。值得注意的是，快速的先天免疫抗病毒反应在两组中通过强有力的树突状/NK/CD 4/CD 8细胞活化和相当弱的Th 1/Th 2细胞因子反应来证明。有趣的是，由PBMC中高水平的IFN-α mRNA和循环IL-12见证的抗病毒免疫应答仅在慢性组中持续数月。CHIKV（RNA和蛋白质）在感染后18个月的慢性患者的血管周围滑膜巨噬细胞中被浸润的NK和T细胞（CD 4（++），但罕见的细胞毒性CD 8）包围。在损伤的滑膜组织中观察到成纤维细胞增生、强烈的血管生成、高水平基质金属蛋白酶2引起的组织病变和急性细胞死亡[高裂解聚（ADP-核糖）聚合酶染色]。这些观察到的细胞和分子事件可能导致慢性关节痛/关节炎，甲氨蝶呤根据经验用于有效治疗，但在病毒持续存在的情况下具有免疫抑制功能。免疫学杂志，2010，184：5914-5927。
Alphaviruses, including Chikungunya virus (CHIKV), produce a transient illness in humans, but severe forms leading to chronic incapacitating arthralgia/arthritis have been reported by mechanisms largely ill-characterized. The pathogenesis of CHIKV was addressed in a prospective cohort study of 49 hospitalized patients from Reunion Island subsequently categorized into two distinct groups at 12 mo postinfection. Comprehensive analyses of the clinical and immunological parameters throughout the disease course were analyzed in either the "recovered" or the "chronic" groups to identify prognostic markers of arthritis-like pathology after CHIKV disease. We found that the chronic group consisted mainly of more elderly patients (>60 y) and with much higher viral loads (up to 10(10)) viruses per milliliter of blood) during the acute phase. Remarkably, a rapid innate immune antiviral response was demonstrated by robust dendritic/NK/CD4/CD8 cell activation and accompanied by a rather weak Th1/Th2 cytokine response in both groups. Interestingly, the antiviral immune response witnessed by high levels of IFN-alpha mRNA in PBMCs and circulating IL-12 persisted for months only in the chronic group. CHIKV (RNA and proteins) was found in perivascular synovial macrophages in one chronic patient 18 mo postinfection surrounded by infiltrating NK and T cells (CD4(++) but rare cytotoxic CD8). Fibroblast hyperplasia, strong angiogenesis, tissue lesions given the high levels of matrix metalloproteinase 2, and acute cell death [high cleaved poly (ADP-ribose) polymerase staining] were observed in the injured synovial tissue. These observed cellular and molecular events may contribute to chronic arthralgia/arthritis targeted by methotrexate used empirically for effective treatment but with immunosuppressive function in a context of viral persistence. The Journal of Immunology, 2010, 184: 5914-5927.