Galectins in Modulating Immune Responsiveness of IgE-bearing Cells

过敏性疾病是由对其他无害的抗原的免疫反应扭曲引起的，在 这种或那种形式，影响了多达25%的美国人口，其中不成比例的 增加，特别是在患有哮喘和与食物有关的过敏的儿童中。特定的约束性 携带高亲和力受体的细胞免疫球蛋白(Fc、ε、RI)是过敏性疾病发病机制的标志 随后与变应原的相互作用会导致嗜碱性粒细胞、肥大细胞和树突状细胞等细胞 释放促进和/或放大疾病的促炎介质和细胞因子。特别是， Ig E/FcεRI的交联会触发嗜碱性粒细胞释放组胺和LTC4，但也会释放IL-4和IL-13- 过敏性素质的核心介质和细胞因子。最近，这些活动一直是 用小鼠模型证实并在体内扩展，其中一些表明存在一个“轴” 上皮细胞(EC)来源的细胞因子激活嗜碱性粒细胞产生IL-4(&IL-13)。相比之下，验证性的 这些EC细胞因子激活人嗜碱性粒细胞的结果尚未公布。在探索这一点时 翻译差异，我们意外地发现了一种非常健壮且可能是唯一的模式 依赖于EC的人嗜碱性粒细胞的激活，需要细胞与细胞之间的黏附，并依赖于IgE。 初步数据现在指向这种激活模式(在与A549-肺共同培养嗜碱性粒细胞后发现 EC)由Galectin-3(Gal-3)介导，Galectin-3(Gal-3)是一种已知与IgE结合的凝集素。这也是有道理的 对这种反应的另一种水平的调控--由Gal-9介导的，它也与近100种IgE结合-- 比GAL-3亲和力强，但缺乏Ig E/FcεRI的交联性。AIM 1进一步研究 描述嗜碱性粒细胞依赖于EC激活的参数，目的是扩大 GAL-3依赖的激活包括原代人类上皮细胞(PHEC)。Gal-3/Gal-9的相互作用是 也将在PHEC中使用基因操作以及微球被 涂上这些半乳糖凝集素。信号通路也将被探索，并被认为与那些 与标准过敏性释放有关。目标2将检验Gal-3/9也相互作用的假设 调节其他携带IgE的细胞的活动，初步证据表明Gal-3也诱导DC 亚型可分泌大量促炎细胞因子(即肿瘤坏死因子-α/白介素6)。最后，AIM-3 研究了Gal3/9对EC的调节，假设它们的表达受到Pro-9的反向调节。 炎性细胞因子/介体与先天免疫刺激。总体而言，这些结果最终可能会提供 对几个与IgE相关的不明现象的洞察，这些IgE承载细胞和Gal-3都是 牵连，从过敏性疾病(如哮喘、慢性荨麻疹和特应性皮炎)到非过敏性疾病 过敏情况，包括自身免疫性(狼疮性肾炎)、癌症，以及可以想象的伤口愈合。

Allergic diseases are caused by skewed immune responses to otherwise harmless antigens, and, in one form or another, affect up to 25% of the population in the United States, with a disproportionately increase especially among children with asthma and food-related hypersensitivities. The binding of specific IgE to cells bearing high affinity receptors (FcεRI) is hallmark for the pathogenesis of allergic disease in that subsequent interaction with allergen causes cells such as basophils, mast cells, and dendritic cells to release pro-inflammatory mediators and cytokines that promote and/or amplify disease. In particular, crosslinking of IgE/FcεRI triggers basophils to release histamine and LTC4 but also IL-4 and IL-13 – mediators and cytokines central to the allergic diathesis. More recently, these activities have been confirmed and extended in vivo using mouse models, with some showing evidence for an “axis” whereby epithelial cell (EC)-derived cytokines activate basophils to produce IL-4 (& IL-13). In contrast, confirmatory results of these EC cytokines activating human basophils have not been forthcoming. In exploring this translational discrepancy, we serendipitously uncovered a remarkably robust, and potentially unique, mode of EC-dependent activation of human basophils that requires cell-to-cell adhesion and is IgE-dependent. Preliminary data now point to this mode of activation (discovered after co-culturing basophils with A549-lung EC) as being mediated by galectin-3 (Gal-3) –a lectin long known to bind IgE. There is also rationale for yet another level of regulation to this response –one mediated by Gal-9, which also binds IgE with nearly 100- fold greater affinity than does Gal-3 but lacks IgE/FcεRI crosslinking capabilities. Aim 1 studies further characterize the parameters underlying EC-dependent activation of basophils, with the goal of extending Gal-3-dependent activation to include primary human epithelial cells (PHEC). The Gal-3/Gal-9 interplay is also to be addressed in PHEC using genetic manipulation as well as a model whereby microspheres are coated with these galectins. Signaling pathways will also be explored and are thought to differ from those associated with standard anaphylactic release. Aim 2 will test the hypothesis that Gal-3/9 interplay also regulates the activities of other IgE-bearing cells, with preliminary evidence that Gal-3 also induces DC subtypes to secrete large quantities of pro-inflammatory cytokines (i.e. TNF-α/IL-6). Finally, Aim-3 investigates the regulation of Gal3/9 on EC, hypothesizing that their expression is counter-regulated by pro- inflammatory cytokines/mediators vs. innate immune stimuli. Overall, these results could ultimately provide insight into several unexplained IgE-related phenomena for which these IgE-bearing cells and Gal-3 are all implicated, ranging from allergic disease (e.g. asthma, chronic urticaria, and atopic dermatitis) to non- allergic conditions, including autoimmunity (lupus nephritis), cancer, and conceivably wound healing.