Increased severity of respiratory infections associated with elevated anti-LPS IgG2 which inhibits serum bactericidal killing.
Increased severity of respiratory infections associated with elevated anti-LPS IgG2 which inhibits serum bactericidal killing.
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DOI：
10.1084/jem.20132444
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发表时间：
2014-08-25
期刊：
影响因子：
--
通讯作者：
Stockley RA
中科院分区：
文献类型：
--
作者：
Wells TJ;Whitters D;Sevastsyanovich YR;Heath JN;Pravin J;Goodall M;Browning DF;O'Shea MK;Cranston A;De Soyza A;Cunningham AF;MacLennan CA;Henderson IR;Stockley RA
针对铜绿假单胞菌脂多糖o抗原的抗体可以阻断补体介导的细菌杀伤，并有助于呼吸道感染的严重程度。虽然由病原体或疫苗诱导的特异性抗体是防止感染威胁的关键组成部分，但某些病毒（如登革热）诱导的抗体会加强感染的发展。相比之下，细菌感染的抗体依赖性增强在很大程度上未被认识到。在这里，我们证明了在很大一部分支气管扩张和铜绿假单胞菌肺部感染的患者中，抗体可以保护细菌免受补体介导的杀伤。抗抗体诱导、补体介导杀伤的菌株产生含有o抗原的脂多糖。抑制抗体介导的杀伤是由过量产生o抗原特异性IgG2抗体引起的。将IgG2消耗到o抗原上可以恢复血清杀死带有长链o抗原的菌株的能力。血清介导的IgG2对铜绿假单胞菌杀伤能力受损的患者呼吸功能较不产生抑制抗体的患者差。我们认为IgG2与o抗原的过度结合可以保护细菌免受其他抗体的影响，这些抗体可以诱导补体介导的细菌杀伤。由于不同革兰氏阴性菌之间存在显著的o抗原结构共享，这种igg2介导的杀伤损伤可能在其他革兰氏阴性感染中起作用。这些发现对我们理解自然感染产生的保护作用和设计疫苗具有重要意义，疫苗应避免诱导这种阻断抗体。
An antibody directed against the O-antigen of Pseudomonas aeruginosa LPS can block complement-mediated bacterial killing and contributes to the severity of respiratory infection. Although specific antibody induced by pathogens or vaccines is a key component of protection against infectious threats, some viruses, such as dengue, induce antibody that enhances the development of infection. In contrast, antibody-dependent enhancement of bacterial infection is largely unrecognized. Here, we demonstrate that in a significant portion of patients with bronchiectasis and Pseudomonas aeruginosa lung infection, antibody can protect the bacterium from complement-mediated killing. Strains that resist antibody-induced, complement-mediated killing produce lipopolysaccharide containing O-antigen. The inhibition of antibody-mediated killing is caused by excess production of O-antigen–specific IgG2 antibodies. Depletion of IgG2 to O-antigen restores the ability of sera to kill strains with long-chain O-antigen. Patients with impaired serum-mediated killing of P. aeruginosa by IgG2 have poorer respiratory function than infected patients who do not produce inhibitory antibody. We suggest that excessive binding of IgG2 to O-antigen shields the bacterium from other antibodies that can induce complement-mediated killing of bacteria. As there is significant sharing of O-antigen structure between different Gram-negative bacteria, this IgG2-mediated impairment of killing may operate in other Gram-negative infections. These findings have marked implications for our understanding of protection generated by natural infection and for the design of vaccines, which should avoid inducing such blocking antibodies.
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影响因子：
3.1
作者：
Raghunathan, Dhaarini;Wells, Timothy J.;Henderson, Ian R.
通讯作者：
Henderson, Ian R.
影响因子：
2.1
作者：
Parham, NJ;Srinivasan, U;Henderson, IR
通讯作者：
Henderson, IR
DOI：
10.1016/s1473-3099(10)70166-3
发表时间：
2010-10
期刊：
The Lancet. Infectious diseases
影响因子：
--
作者：
Halstead SB;Mahalingam S;Marovich MA;Ubol S;Mosser DM
通讯作者：
Mosser DM
影响因子：
4.4
作者：
JEFFERIS, R;REIMER, CB;COOLEN, J
通讯作者：
COOLEN, J
影响因子：
10
作者：
Hill, SL;Mitchell, JL;Stockley, RA
通讯作者：
Stockley, RA