IL-10R blockade during chronic schistosomiasis mansoni results in the loss of B cells from the liver and the development of severe pulmonary disease.
IL-10R blockade during chronic schistosomiasis mansoni results in the loss of B cells from the liver and the development of severe pulmonary disease.
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DOI：
10.1371/journal.ppat.1002490
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发表时间：
2012-01
期刊：
影响因子：
6.7
通讯作者：
Pearce EJ
中科院分区：
文献类型：
--
作者：
Fairfax KC;Amiel E;King IL;Freitas TC;Mohrs M;Pearce EJ
在血吸虫病患者中，困在肝窦中的寄生虫卵成为CD4+ T细胞策划的肉芽肿细胞浸润的焦点。由于免疫反应无法清除感染，肝脏受到持续循环的局灶性炎症和愈合，导致血管阻塞和组织纤维化。随着时间的推移，调节机制的发展可以减轻这种情况，并最大限度地减少对新沉积卵子的炎症反应。在探索感染小鼠肝脏炎症浸润随时间的变化时，我们发现慢性感染期间血吸虫卵抗原特异性igg1分泌浆细胞的积累。通过阻断IL-10受体（一种与浆细胞发育有关的细胞因子），这一群体显著减少。引人注目的是，IL-10R阻断促进了门脉高压的发展和寄生虫卵在肺和心脏的积累。这并不反映更具侵略性的Th2细胞反应性、肝纤维化增加或Th1或Th17反应的出现。相反，在不能分泌类转换抗体的小鼠中，肺受累也很明显，这一发现表明抗体在预防严重疾病中的作用。抗il - 10r治疗的主要作用是失去表面IgG1染色阳性的髓系细胞群，并表现出调节/抗炎巨噬细胞的特征。这一发现表明，抗体可能通过与巨噬细胞的局部相互作用来促进肝脏内的保护作用。总之，我们的数据描述了il -10依赖性B细胞反应在慢性蠕虫感染期间组织损伤调节中的作用。血吸虫病是一种影响约2亿人的慢性疾病。免疫调节是慢性疾病的一个标志，可以保护宿主免受严重的病理影响。相当大比例的血吸虫病感染者未能经历这种保护性调节，并可能发展为门脉高压，导致肺部并发症。本研究表明，随着感染进展到慢性状态，血吸虫特异性抗体分泌B细胞在肝脏中积累，这种积累依赖于细胞因子白介素-10。阻断IL-10R不仅会导致肝脏中B细胞的损失，还会导致严重的肺部病理。我们在基因上无法产生正常抗体反应的小鼠的疾病进展中发现了类似的变化。我们认为，抗体对于触发其他免疫细胞巨噬细胞产生抗炎因子（包括IL-10）很重要。我们的数据表明，在慢性血吸虫病期间，IL-10促进肝脏内B细胞群的发展，该细胞负责减少炎症和预防肺部疾病的发展。我们的发现提供了一种小鼠模型，可能用于研究慢性血吸虫病肺并发症的发展。
In schistosomiasis patients, parasite eggs trapped in hepatic sinusoids become foci for CD4+ T cell-orchestrated granulomatous cellular infiltrates. Since the immune response is unable to clear the infection, the liver is subjected to ongoing cycles of focal inflammation and healing that lead to vascular obstruction and tissue fibrosis. This is mitigated by regulatory mechanisms that develop over time and which minimize the inflammatory response to newly deposited eggs. Exploring changes in the hepatic inflammatory infiltrate over time in infected mice, we found an accumulation of schistosome egg antigen-specific IgG1-secreting plasma cells during chronic infection. This population was significantly diminished by blockade of the receptor for IL-10, a cytokine implicated in plasma cell development. Strikingly, IL-10R blockade precipitated the development of portal hypertension and the accumulation of parasite eggs in the lungs and heart. This did not reflect more aggressive Th2 cell responsiveness, increased hepatic fibrosis, or the emergence of Th1 or Th17 responses. Rather, a role for antibody in the prevention of severe disease was suggested by the finding that pulmonary involvement was also apparent in mice unable to secrete class switched antibody. A major effect of anti-IL-10R treatment was the loss of a myeloid population that stained positively for surface IgG1, and which exhibited characteristics of regulatory/anti-inflammatory macrophages. This finding suggests that antibody may promote protective effects within the liver through local interactions with macrophages. In summary, our data describe a role for IL-10-dependent B cell responses in the regulation of tissue damage during a chronic helminth infection. Schistosomiasis is a chronic disease that affects approximately 200 million people. Immune modulation is a hallmark of chronic disease and serves to protect the host from severe pathology. A significant percentage of people infected with schistosomiasis fail to undergo this protective modulation and can develop portal hypertension with resulting pulmonary complications. Here we show that schistosome-specific antibody-secreting B cells accumulate in the liver as the infection progresses to the chronic state and that this accumulation is dependent on the cytokine Interleukin-10. Blocking the IL-10R results in not only the loss of B cells from the liver, but also the development of severe pulmonary pathology. We found similar changes in disease progression in mice genetically unable to mount normal antibody responses. We believe that antibody is important for triggering the production of anti-inflammatory factors, including IL-10 itself, by other immune cells called macrophages. Our data suggest that during chronic schistosomiasis IL-10 promotes the development of a population of B cells within the liver that is responsible for minimizing inflammation and preventing the development of disease in the lungs. Our findings provide a mouse model that may be of use for studying the development of pulmonary complications due to chronic schistosomiasis.
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