Passively administered pooled human immunoglobulins exert IL-10 dependent anti-inflammatory effects that protect against fatal HSV encephalitis.
Passively administered pooled human immunoglobulins exert IL-10 dependent anti-inflammatory effects that protect against fatal HSV encephalitis.
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DOI：
10.1371/journal.ppat.1002071
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发表时间：
2011-06
期刊：
影响因子：
6.7
通讯作者：
Cantin E
中科院分区：
文献类型：
--
作者：
Ramakrishna C;Newo AN;Shen YW;Cantin E
HSV-1是人类散发性脑炎的主要原因。易感129 S6小鼠的HSV感染导致由包括单核细胞和嗜中性粒细胞的大量炎性脑干病变引起的致命性脑炎（HSE）。在病原微生物感染或自身免疫性疾病期间，IgG诱导促炎反应并募集先天效应细胞。相比之下，高剂量静脉内免疫球蛋白（IVIG）是各种自身免疫性和炎性疾病的有效治疗方法，因为IVIG中1-3%的唾液酸化IgG（sIgG）部分产生了强效抗炎作用。我们研究了感染后24小时给予IVIG预防致命HSE的能力。我们发现了一种由低剂量IVIG介导的新的抗炎途径，该途径通过独立于HSV特异性抗体或sIgG调节CNS炎症来保护129 S6小鼠免受致命的HSE。IVIG抑制致病性CD 11b + Ly 6C高单核细胞的CNS浸润，并抑制其体外自发脱粒。FcγRIIb表达是IVIG介导的抑制CD 45 + Ly 6Clow单核细胞CNS浸润所必需的，但不是抑制Ly 6Cligh单核细胞发育所必需的。IVIG增加了T细胞在CNS中的蓄积，非sIgG组分诱导外周淋巴器官中FoxP 3 + CD 4 + T调节细胞（TCRs）和FoxP 3 − ICOS+ CD 4 + T细胞的急剧扩增。从HSV感染的IVIG处理的小鼠中纯化的TCL 4保护过继转移的小鼠免于致命的HSE，但不保护对照小鼠。由ICOS+ CD 4 + T细胞产生的IL-10在IVIG处理的小鼠而不是对照小鼠的CNS中积累，对于诱导保护性抗炎反应是必需的。我们的研究结果通过揭示一种新的sIgG非依赖性抗炎途径来显著增强对IVIG抗炎和免疫调节能力的理解，该途径负责诱导分泌免疫抑制细胞因子IL-10的调节性T细胞，并进一步揭示IVIG治疗病毒诱导的炎性疾病的治疗潜力。我们发现，致命的HSV脑炎（HSE）是由过度脑干炎症。一旦脑干炎症开始，仅抑制病毒复制的抗病毒药物在预防致命的HSE方面是无效的。输注高剂量的汇集的人IgG（IVIG）是用于各种自身免疫性疾病的有效抗炎治疗。一种抗炎机制取决于IVIG中存在的有限量（1-3%）的唾液酸化IgG（sIgG），因此需要高剂量的IVIG。我们发现了一种新的抗炎途径，由低剂量的IVIG介导，不依赖于sIgG，通过抑制CNS炎症来预防致命的HSE。IVIG的非sIgG部分诱导调节性CD 4 + T细胞在脑干中产生免疫抑制细胞因子IL-10。重要的是，我们表明IL-10对于抑制致病性炎症巨噬细胞的产生至关重要。因此，IVIG具有非凡的能力来平衡宿主对病毒感染的炎症反应，从而促进病毒清除，而不会对中枢神经系统造成旁观者损害，从而导致所有感染小鼠的存活。总的来说，我们的研究结果为理解IVIG的抗炎活性提供了重要的新见解，并进一步揭示了其用于治疗病毒性炎症性疾病的潜力。
HSV-1 is the leading cause of sporadic encephalitis in humans. HSV infection of susceptible 129S6 mice results in fatal encephalitis (HSE) caused by massive inflammatory brainstem lesions comprising monocytes and neutrophils. During infection with pathogenic microorganisms or autoimmune disease, IgGs induce proinflammatory responses and recruit innate effector cells. In contrast, high dose intravenous immunoglobulins (IVIG) are an effective treatment for various autoimmune and inflammatory diseases because of potent anti-inflammatory effects stemming in part from sialylated IgGs (sIgG) present at 1–3% in IVIG. We investigated the ability of IVIG to prevent fatal HSE when given 24 h post infection. We discovered a novel anti-inflammatory pathway mediated by low-dose IVIG that protected 129S6 mice from fatal HSE by modulating CNS inflammation independently of HSV specific antibodies or sIgG. IVIG suppressed CNS infiltration by pathogenic CD11b+ Ly6Chigh monocytes and inhibited their spontaneous degranulation in vitro. FcγRIIb expression was required for IVIG mediated suppression of CNS infiltration by CD45+ Ly6Clow monocytes but not for inhibiting development of Ly6Chigh monocytes. IVIG increased accumulation of T cells in the CNS, and the non-sIgG fraction induced a dramatic expansion of FoxP3+ CD4+ T regulatory cells (Tregs) and FoxP3− ICOS+ CD4+ T cells in peripheral lymphoid organs. Tregs purified from HSV infected IVIG treated, but not control, mice protected adoptively transferred mice from fatal HSE. IL-10, produced by the ICOS+ CD4+ T cells that accumulated in the CNS of IVIG treated, but not control mice, was essential for induction of protective anti-inflammatory responses. Our results significantly enhance understanding of IVIG's anti-inflammatory and immunomodulatory capabilities by revealing a novel sIgG independent anti-inflammatory pathway responsible for induction of regulatory T cells that secrete the immunosuppressive cytokine IL-10 and further reveal the therapeutic potential of IVIG for treating viral induced inflammatory diseases. We show that fatal HSV encephalitis (HSE) is caused by excessive brainstem inflammation. Once brainstem inflammation is initiated, antiviral drugs that inhibit only viral replication are ineffective in protecting against fatal HSE. Infusion of high doses of pooled human IgG (IVIG) is an effective anti-inflammatory treatment for various autoimmune diseases. One anti-inflammatory mechanism depends on sialylated IgGs (sIgG) present in limiting amounts (1–3%) in IVIG, hence the need for high doses of IVIG. We discovered a novel anti-inflammatory pathway mediated by low doses of IVIG independent of sIgG that prevented fatal HSE by suppressing CNS inflammation. The non-sIgG fraction of IVIG induced regulatory CD4+ T cells that produced the immunosuppressive cytokine IL-10 in the brainstem. Importantly, we show that IL-10 is critical for suppressing the generation of pathogenic inflammatory macrophages. Thus, IVIG has a remarkable ability to balance the host inflammatory responses to virus infection and thereby promotes virus clearance without bystander damage to the CNS, accounting for survival of all infected mice. Overall, our results provide important new insights in understanding IVIG's anti-inflammatory activity and further reveal its potential for use in treatment of viral inflammatory diseases.
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影响因子：
6.5
作者：
Bazin, Renee;Lemieux, Real;Tremblay, Tony
通讯作者：
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影响因子：
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作者：
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DOI：
10.1073/pnas.0810163105
发表时间：
2008-12-16
影响因子：
11.1
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作者：
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作者：
Anthony, Robert M.;Ravetch, Jeffrey V.
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