Fang Hui, Xu Lixin, Chen Trina Y, Cyr Julianne M, Frucht David M
Division of Monoclonal Antibodies, Office of Biotechnology Products, Office of Pharmaceutical Science, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Bethesda, MD 20892, USA.
J Immunol. 2006 May 15;176(10):6155-61. doi: 10.4049/jimmunol.176.10.6155.
Protective host immune responses to anthrax infection in humans and animal models are characterized by the development of neutralizing Abs against the receptor-binding anthrax protective Ag (PA), which, together with the lethal factor (LF) protease, composes anthrax lethal toxin (LT). We now report that B cells, in turn, are targets for LT. Anthrax PA directly binds primary B cells, resulting in the LF-dependent cleavage of the MAPK kinases (MAPKKs) and disrupted signaling to downstream MAPK targets. Although not directly lethal to B cells, anthrax LT treatment causes severe B cell dysfunction, greatly reducing proliferative responses to IL-4-, anti-IgM-, and/or anti-CD40 stimulation. Moreover, B cells treated with anthrax LT in vitro or isolated from mice treated with anthrax LT in vivo have a markedly diminished capacity to proliferate and produce IgM in response to TLR-2 and TLR-4 ligands. The suppressive effects of anthrax LT on B cell function occur at picomolar concentrations in vitro and at sublethal doses in vivo. These results indicate that anthrax LT directly inhibits the function of B cells in vitro and in vivo, revealing a potential mechanism through which the pathogen could bypass protective immune responses.
在人类和动物模型中，宿主对炭疽感染的保护性免疫反应的特征是产生针对受体结合性炭疽保护性抗原（PA）的中和抗体，PA与致死因子（LF）蛋白酶共同构成炭疽致死毒素（LT）。我们现在报告，B细胞反过来也是LT的作用靶点。炭疽PA直接结合原代B细胞，导致MAPK激酶（MAPKKs）的LF依赖性裂解，并破坏向下游MAPK靶点的信号传导。虽然炭疽LT对B细胞无直接致死性，但它会导致严重的B细胞功能障碍，极大地降低对IL-4、抗IgM和/或抗CD40刺激的增殖反应。此外，体外经炭疽LT处理或体内经炭疽LT处理的小鼠分离出的B细胞，对TLR-2和TLR-4配体的增殖和产生IgM的能力明显减弱。炭疽LT对B细胞功能的抑制作用在体外皮摩尔浓度和体内亚致死剂量下均会出现。这些结果表明，炭疽LT在体外和体内均可直接抑制B细胞功能，揭示了病原体可能绕过保护性免疫反应的潜在机制。
