上皮来源的Ig在上皮免疫稳态、炎-癌转化及上皮性肿瘤发生发展中的意义

Epithelial tissue is a special tissue, which is mainly composed of epithelial cells by tight junction. Epithelial tissue, including the skin and mucosa (covering all of the body surface, body cavity,mucosa) and the composition of the inner and outer glands of the glandular epithelium. The common function of epithelial cells is to maintain epithelial homeostasis by its rapid self-renewal and its unique immune function. The another feature of epithelial tissue is the frequent occurrence of inflammation or malignant tumor, it is a fact that most malignant tumor is originated from epithelial cells, so far, the reason remains unclear.Our previous evidences suggested that epithelial cells can spontaneous express immunoglobulin (Ig), the epithelial cell-derived Igs are involved in maintenance of epithelial microenvironment under physiological or pathological condition, especially the epithelial cell-derived Igs can promote chronic inflammation, inflammation-cancer transformation and immune escape of epithelial tumor. In this study, the colon epithelium will be as model, we will be from a new perspective to study the role of Ig in epithelial immune homeostasis, chronic inflammation, and inflammation-cancer transformation. Focus on the study of differences on Ig class, VDJ or VJ pattern and glycosylation among normal epithelium, inflammatory cells and epithelial tumor cells; explore the pro-inflammatory role and its mechanism of Igs during epithelial chronic inflammation, inflammation-cancer transformation and in the cancer microenvironment; and study the promoting role of epithelial cell-derived Igs for tumor immune escape and its mechanism. In addition, to evaluate if the epithelial tumor/cancer cell-derived Igs has application potential for the treatment of epithelial tumor/cancer as novel target.

上皮组织主要由上皮细胞紧密连接构成的特殊组织，分别包括皮肤黏膜上皮（覆盖所有体表、体腔、黏膜）及构成内外分泌腺的腺上皮组织。上皮细胞所承担的共同功能是依赖其快速自我更新及其独特的免疫功能维持上皮的稳态。上皮组织是炎症及肿瘤的高发组织，体内大部分恶性肿瘤都起源于上皮细胞，迄今其原因尚未解明。我们前期的研究提示，上皮细胞可自发表达免疫球蛋白（Ig），上皮来源的Ig参与上皮生理及病理微环境的形成，可能通过促进慢性炎症及免疫逃逸等机制参与炎-癌转化及上皮肿瘤的发生发展。本研究拟以肠上皮为模型，从全新角度明确上皮来源的Ig在上皮免疫稳态、慢性炎症及炎-癌转化过程中的作用。重点探讨不同类型Ig在正常上皮、炎性上皮及肿瘤性上皮的差异；探讨这类Ig在上皮慢性炎症、炎-癌转化及肿瘤微环境中的促炎作用及其机制；及其在肿瘤免疫逃逸中的作用及其机制；明确以肿瘤性上皮来源的Ig为靶点治疗肿瘤的前景。

上皮组织主要由上皮细胞紧密连接构成的特殊组织，分别包括皮肤黏膜上皮（覆盖所有体表、体腔、黏膜）及构成内外分泌腺的腺上皮组织。上皮细胞所具有的共同特征及功能是依赖其快速自我更新及其独特的免疫功能维持上皮的稳态。上皮组织是炎症及肿瘤的高发组织，体内大部分恶性肿瘤都起源于上皮细胞，迄今其原因尚未解明。我们前期的研究提示，上皮细胞可自发表达免疫球蛋白（Ig），上皮来源的Ig参与上皮生理及病理微环境的形成，可能通过促进慢性炎症及免疫逃逸等机制参与炎-癌转化及上皮肿瘤的发生发展。本研究拟从全新角度探讨上皮来源的Ig在上皮免疫稳态、慢性炎症及炎-癌转化过程中的作用。重点探讨不同类型Ig在正常上皮、炎性上皮及肿瘤性上皮的差异；探讨这类Ig在上皮慢性炎症、炎-癌转化及肿瘤微环境中的促炎作用及机制；及其在肿瘤免疫逃逸中作用及机制。所获得的重要结果如下：（1）发现炎症区上皮细胞表达Ig水平明显增加，其中肺上皮以IgA及游离轻链（Igκ）为主，肠上皮以IgG及 Igκ表达为主,而癌上皮细胞主要表达IgG,而且发生高频突变，重要的是上皮性肿瘤细胞高表达的IgG在CH1上发生了独特的唾液酸修饰。（2）首先肺上皮细胞分泌TD抗原特异性抗体参与获得性体液免疫应答。（3）发现非B细胞产生的游离Igĸ呈现疏水性，其可与integrinβ1结合促进FAK通路活化，阻断游离Igĸ活性可抑制细胞的增殖及存活；在炎症条件下Igĸ游离轻链具有促炎作用，机制研究发现Igĸ游离轻链通过促进中性粒细胞的活化及产生ROS实现的。（4）明确了上皮来源的IgG依赖其唾液酸化修饰通过与T细胞表面唾液酸受体Sialec结合抑制效应性T细胞的增殖。唾液酸化IgG可明显促进肿瘤生长。（5）此外还发现并提出了半个世纪以来免疫学领域笃信的克隆选择学说需要补充及重新诠释相关的实验证据；Igκ做为一个新鉴定的心肌细胞结构蛋白参与心肌细胞的收缩。上述发现不但拓展了免疫学经典理论，还发现了Siglec/唾液酸化IgG是潜在的免疫检查点。