Shalev Itay, Wong Kit Man, Foerster Katharina, Zhu Yi, Chan Cecilia, Maknojia Asif, Zhang Jianhua, Ma Xue-Zhong, Yang Xiao Chun, Gao Julia Fang, Liu Hao, Selzner Nazia, Clark David A, Adeyi Oyedele, Phillips M James, Gorczynski Reginald R, Grant David, McGilvray Ian, Levy Gary
Multi Organ Transplant Program, University of Toronto, Toronto, Ontario, Canada.
Hepatology. 2009 Feb;49(2):387-97. doi: 10.1002/hep.22684.
Fulminant viral hepatitis (FH) remains an important clinical problem in which the underlying pathogenesis is not well understood. Here, we present insight into the immunological mechanisms involved in FH caused by murine hepatitis virus strain 3 (MHV-3), indicating a critical role for CD4(+)CD25(+) regulatory T cells (Tregs) and production of the novel Treg effector molecule FGL2. Before infection with MHV-3, susceptible BALB/cJ mice had increased numbers of Tregs and expression of fgl2 messenger RNA (mRNA) and FGL2 protein compared with resistant A/J mice. After MHV-3 infection, plasma levels of FGL2 in BALB/cJ mice were significantly increased, correlating with increased percentage of Tregs. Treatment with anti-FGL2 antibody completely inhibited Treg activity and protected susceptible BALB/cJ mice against MHV-3-liver injury and mortality. Adoptive transfer of wild-type Tregs into resistant fgl2(-/-) mice increased their mortality caused by MHV-3 infection, whereas transfer of peritoneal exudate macrophages had no adverse effect.
This study demonstrates that FGL2 is an important effector cytokine of Tregs that contributes to susceptibility to MHV-3-induced FH. The results further suggest that targeting FGL2 may lead to the development of novel treatment approaches for acute viral hepatitis infection.
暴发性病毒性肝炎（FH）仍然是一个重要的临床问题，其潜在发病机制尚未完全明确。在此，我们深入探讨了由鼠肝炎病毒3型（MHV-3）引起的FH所涉及的免疫机制，表明CD4(+)CD25(+)调节性T细胞（Tregs）和新型Treg效应分子FGL2的产生起着关键作用。在感染MHV-3之前，与抗性A/J小鼠相比，易感的BALB/cJ小鼠的Tregs数量增加，fgl2信使核糖核酸（mRNA）和FGL2蛋白的表达也增加。MHV-3感染后，BALB/cJ小鼠血浆中FGL2水平显著升高，与Tregs百分比增加相关。用抗FGL2抗体治疗可完全抑制Treg活性，并保护易感的BALB/cJ小鼠免受MHV-3肝损伤和死亡。将野生型Tregs过继转移到抗性fgl2(-/-)小鼠中会增加它们因MHV-3感染而导致的死亡率，而转移腹腔渗出巨噬细胞则没有不良影响。
本研究表明FGL2是Tregs的一种重要效应细胞因子，它促成了对MHV-3诱导的FH的易感性。结果进一步表明，靶向FGL2可能会导致开发针对急性病毒性肝炎感染的新治疗方法。
