MUCOUS MEMBRANE PEMPHIGOID: ORGAN SPECIFIC PATHOGENESIS

粘膜类天疱疮：器官特异性发病机制

• 批准号: 6641311
• 负责人: KAILASH C BHOL
• 金额: $ 8.6万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-15 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6641311
• 关键词: MUCOUS; MEMBRANE; PEMPHIGOID; ORGAN; SPECIFIC

DESCRIPTION: (provided by applicant) The objective of this translational research grant application is to study a rare, and interesting potentially catastrophic, blistering autoimmune disease, which predominantly affects the mucous membranes known as mucous membrane pemphigoid (MMP). When it affects the oral cavity, eating and swallowing are exquisitely painful. Ocular involvement can frequently result in blindness. Since laryngeal disease can cause sudden asphyxiation and death, it mandates elective tracheostomy. Recently we described that, the anti-basement membrane zone (BMZ) antibodies found in the sera of MMP patients targets the cytoplasmic domain of human beta4 integrin. The clinical profile of mucosal involvement in MMP is variable, though the target antigen is present in all mucosae and skin. The investigator proposes to study the role of local factors involved in MMP. Using sera of patients with MMP, the investigator will identify binding of anti-BMZ antibodies to the basement membrane of the eye, nose, oral cavity, pharynx, esophagus, vagina and skin. Matching of clinical profiles with ability of patient's sera to bind to the BMZ of different mucosal tissues, or to different epitopes in the cytoplasmic domain of beta4 integrin will provide essential differences between systemic and local factors or the tissue microenvironments. The ability of sera from patients with MMP, and rabbit antibodies to bind to specific epitopes within the beta4 integrin, to produce sub-mucosal blisters in organ culture, using skin and different mucosal tissues, will be studied. Data from this study will provide important insights into how and why specific organs are involved, in a disease in which the autoantibody has the potential to cause disease in all tissues that contain the target antigen. Such advances can facilitate planning of future studies that focus on specific factors that may individually or collectively, play an important role in different organs in producing clinical disease, and this elucidate specific sites of pathology. The ability of the autoantibody to bind to specific tissues yet not produce clinical disease, might help understand and detect factors that can locally prevent disease manifestation and involvement. Such information can help generate site-specific therapy for purpose of clinical resolution and prevention of involvement. Thus MMP has the potential to be a model that could be applied to study many other multi systemic autoimmune diseases.

产品说明：（由申请人提供）这项转化研究资助申请的目的是研究一种罕见的、有趣的、潜在灾难性的、起泡的自身免疫性疾病，这种疾病主要影响粘膜，称为粘膜类天疱疮（MMP）。当它影响口腔时，进食和吞咽都非常痛苦。眼部受累常导致失明。由于喉部疾病可导致突然窒息和死亡，它要求选择性气管切开术。最近，我们描述了在MMP患者血清中发现的抗基底膜带（BMZ）抗体靶向人β 4整联蛋白的胞质结构域。尽管MMP的靶抗原存在于所有粘膜和皮肤中，但MMP的粘膜受累的临床特征是可变的。研究者建议研究局部因素在MMP中的作用。使用MMP患者的血清，研究者将鉴定抗BMZ抗体与眼、鼻、口腔、咽、食道、阴道和皮肤的基底膜的结合。将临床特征与患者血清结合不同粘膜组织的BMZ或β 4整联蛋白胞质结构域中的不同表位的能力相匹配，将提供全身和局部因素或组织微环境之间的本质差异。将使用皮肤和不同粘膜组织研究MMP患者血清和兔抗体结合β 4整联蛋白内特异性表位的能力，以在器官培养中产生粘膜下水疱。这项研究的数据将提供重要的见解，了解特定器官如何以及为什么参与疾病，其中自身抗体有可能在含有靶抗原的所有组织中引起疾病。这些进展可以促进未来研究的规划，这些研究集中在可能单独或共同在不同器官中产生临床疾病的特定因素上，并阐明病理学的特定部位。自身抗体结合特定组织但不产生临床疾病的能力，可能有助于理解和检测可以局部预防疾病表现和参与的因素。这些信息可以帮助制定针对特定部位的治疗方法，以达到临床解决和预防受累的目的。因此，MMP有可能成为一个模型，可应用于研究许多其他多系统性自身免疫性疾病。