Exploring, Understanding and Intervening in IgE-dependent Mechanisms in Allergic Disease and Asthma

在英国，过敏性疾病的发病率，尤其是哮喘的发病率惊人地增加，迫切需要新的治疗方法。一种被称为免疫球蛋白E （IgE）的抗体在过敏反应中起着至关重要的作用，易过敏的人体内的IgE水平很高。这些IgE抗体识别进入气道（如草花粉）、肠道（食物过敏原）或皮肤（接触性过敏）的过敏原，然后引发过敏反应。我们知道，从抗IgE治疗的成功中，去除IgE可以缓解过敏症状。但是抗ige本身是一种抗体，非常昂贵，需要在诊所进行管理，并且只允许用于严重哮喘。通过了解人体如何产生IgE，以及IgE激活过敏反应的方式，我们期望发现抑制IgE的新方法，并开发更便宜，更广泛适用于不同过敏条件的化合物，并且更容易管理。体内产生抗体的细胞，即b细胞，根据某些信号从产生有益的保护性抗体转变为产生IgE；我们的目标是理解和防止这种转变。我们已经发现，这种转换可以发生在鼻子里，而不是像以前认为的那样，只发生在淋巴结里。现在，利用盖伊？我们可以详细研究这一过程。我们将使用超高分辨率显微镜（英国首个此类显微镜）研究IgE基因开启时b细胞核内的事件，然后研究这些产生IgE的细胞的存活和增殖。这项工作无疑将确定新的干预目标。我们还发现了超级抗原？哮喘患者体内是否存在触发抗体产生的细菌分子？航空公司。我们相信这些超级抗原可能会促进IgE的产生，在肺或鼻子，并将研究它们如何与IgE相互作用？开辟了治疗过敏的新途径。我们还将调查某些IgE分子在引发过敏方面比其他分子更活跃的说法。我们已经确定了IgE的分子结构，并发现当它引发过敏反应时，它会改变其形状。我们现在可以测试防止这种形状变化的化合物，与制药行业合作开发克服抗ige限制的小分子抑制剂。

The incidence of allergic disease, and asthma in particular, has increased alarmingly in the UK and there is an urgent need for new therapies. Antibodies of a type known as immunoglobulin E (IgE) are crucially involved in the allergic response, and individuals susceptible to allergies have high IgE levels. These IgE antibodies recognise allergens that enter the airways (e.g. grass pollen), the gut (food allergens) or the skin (contact allergies), and then trigger allergic reactions. We know, from the success of an anti-IgE treatment, that removal of IgE relieves allergic symptoms. But anti-IgE, itself an antibody, is very expensive, requires administration in the clinic, and is licensed only for severe asthma. By understanding how the body produces IgE, and the way IgE activates allergic reactions, we expect to discover new ways to inhibit IgE, and develop compounds that are cheaper, more widely applicable to different allergic conditions, and easier to administer. The cells in the body that make antibodies, B-cells, switch in response to certain signals from producing beneficial, protective antibodies to producing IgE; our aim is to understand and prevent this switch. We have discovered that switching can occur in the nose rather than, as previously thought, only in lymph nodes, and now, using nasal tissue available from a surgical procedure (to clear nasal passages) developed at Guy?s Hospital, we can study the process in detail. We shall use an ultra-high resolution microscope (the first of its kind in the UK) to study events within the B-cell nucleus as the genes for IgE are switched on, and then study the survival and proliferation of these IgE-producing cells. This work will undoubtedly identify new targets for intervention.We have also discovered that ?superantigens?, bacterial molecules that trigger antibody production, are present in asthmatic patients? airways. We believe that these superantigens may promote IgE production, in the lung or nose, and will study how they interact with IgE ? opening up a new approach to allergy treatment. We will also investigate the claim that certain IgE molecules are more active than others in triggering allergy. We have already determined the molecular structure of IgE and found that it changes its shape when it triggers an allergic reaction. We can now test compounds that prevent this change in shape, collaborating with the pharmaceutical industry to develop small-molecule inhibitors that overcome the limitations of anti-IgE.