Attenuation of IgE Affinity for FcεRI Radically Reduces the Allergic Response in Vitro and in Vivo
Attenuation of IgE Affinity for FcεRI Radically Reduces the Allergic Response in Vitro and in Vivo
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DOI：
10.1074/jbc.m804742200
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发表时间：
2008-10-31
影响因子：
4.8
通讯作者：
Beavil, Andrew J.
中科院分区：
文献类型：
--
作者：
Hunt, James;Bracher, Marguerite G.;Beavil, Andrew J.
IgE与其受体Fc epsilon RI (K-a类似于10（10)M(-1)）的高亲和力是肥大细胞持续致敏的原因。多价过敏原与Fc epsilon ri结合的IgE交联可导致细胞活化和促炎介质的释放，导致过敏性疾病的症状。我们之前已经证明，将IgE-Fc的epsilon RI相互作用限制在IgE-Fc的两个C - epsilon 3结构域中的一个上，这两个结构域共同构成了高亲和力的结合位点，导致亲和力降低了1000倍。这种衰减是通过小分子结合部分IgE: Fc epsilon RI界面或远端变张位点实现的，而不是完全阻断相互作用，这可能是治疗过敏性疾病的一种可行方法。然而，这种相互作用需要被破坏的程度尚不清楚，因为高亲和力对即时超敏反应的重要性从未被研究过。我们将先前在IgE-Fc中表征的突变R334S纳入人类IgE中，该突变将其对Fc ε - RI的亲和力降低了50倍。我们在体外和体内比较了野生型和R334S型IgE刺激过敏原诱导的肥大细胞活化的能力。我们证实了野生型和突变型IgE对Fc epsilon RI的亲和力之间的预期差异（类似于50倍），并发现，在体外，肥大细胞脱颗粒成比例地减少。体内的效果也很明显，被动皮肤过敏反应减少了75%。因此，我们已经证明IgE对Fc epsilon RI的高亲和力对过敏反应至关重要，即使这种亲和力的适度衰减在体内也有实质性的影响。
The high affinity of IgE for its receptor, Fc epsilon RI (K-a similar to 10(10)M(-1)), is responsible for the persistence of mast cell sensitization. Crosslinking of Fc epsilon RI-bound IgE by multivalent allergen leads to cellular activation and release of pro-inflammatory mediators responsible for the symptoms of allergic disease. We previously demonstrated that limiting the IgE-Fc epsilon RI interaction to just one of the two C epsilon 3 domains in IgE-Fc, which together constitute the high affinity binding site, results in 1000-fold reduced affinity. Such attenuation, effected by a small molecule binding to part of the IgE: Fc epsilon RI interface or a distant allosteric site, rather than complete blocking of the interaction, may represent a viable approach to the treatment of allergic disease. However, the degree to which the interaction would need to be disrupted is unclear, because the importance of high affinity for immediate hypersensitivity has never been investigated. We have incorporated into human IgE a mutation, R334S, previously characterized in IgE-Fc, which reduces its affinity for Fc epsilon RI similar to 50- fold. We have compared the ability of wild type and R334S IgE to stimulate allergen-induced mast cell activation in vitro and in vivo. We confirmed the expected difference in affinity between wild type and mutant IgE for Fc epsilon RI (similar to 50-fold) and found that, in vitro, mast cell degranulation was reduced proportionately. The effect in vivo was also marked, with a 75% reduction in the passive cutaneous anaphylaxis response. We have therefore demonstrated that the high affinity of IgE for Fc epsilon RI is critical to the allergic response, and that even moderate attenuation of this affinity has a substantial effect in vivo.