PATHOPHYSIOLOGY OF EXPERIMENTALLY INDUCED PEMPHIGUS

描述(改编自申请者的摘要)：长期目标 主要研究者的定义是对致病作用的定义 天疱疮和类天疱疮自身抗体在皮肤中的产生 损伤，主要是通过使用活体小鼠模型。 研究人员最近发现了一种新的自身免疫性水泡 与潜在肿瘤相关的粘膜皮肤综合征 他们将其命名为副肿瘤性天疱疮。他们相信他们的 初步研究支持以下关于病因学的假设 这种综合症的症状。(A)一组粘膜起泡患者和 皮肤损害和潜在的肿瘤在临床上和 免疫学上独特的副肿瘤综合征。(二)有没有 识别一种特征性的表皮复合体的自身抗体 MR 250 kD、230 kD、210 kD和190 kD抗原，通过免疫沉淀 代谢标记角质形成细胞。(C)这些病人的肿瘤 异常表达与之相同或交叉反应的抗原 上皮性抗原。(D)主要定向的自身抗体 抗肿瘤抗原，与皮肤结合并在皮肤内造成损害 受影响患者的粘膜。调查人员提供了初步的 数据显示：(1)所有病例的自身抗体具有相似的 (2)250 kD的抗原为桥粒蛋白1-a。 斑块蛋白-230kD的抗原是大疱性类天疱疮的230kD抗原 半桥粒蛋白；(3)来自这些患者的自身抗体导致 被动移植到小鼠体内的皮肤和食道损伤； 1例肿瘤(网状细胞肉瘤)有桥粒和 表达桥粒蛋白I，它与两种单抗都有反应 抗桥粒蛋白和患者血清自身抗体。本研究 我将研究这些观察所提出的以下几点：(1) 定义自身抗体的特异性；(2)定义自身抗体的身份 210kD和190kD抗原；(3)定义抗原的确切性质 通过这些肿瘤表达；(4)确定这些抗原是否表达 仅在受影响个体的肿瘤中，以及(5)定义其机制 抗体通过这种方式在活体内造成上皮损伤。这就是他们 相信是探索复杂关系的独特机会 在肿瘤免疫和自身免疫之间，因为这种疾病可能代表着 免疫反应针对肿瘤的另一个生物学例子 抗原可能与宿主组织的构成蛋白发生交叉反应， 对病人造成灾难性的“自身免疫”影响。 最后，研究人员定义了一个主要的免疫原区(MIR) 180kD大疱性类天疱疮抗原优先被 妊娠疱疹(HG)患者(妊娠期类天疱疮)。这是一个 与大多数受影响血清结合的41-氨基酸多肽 病人。调查人员有初步数据显示英国石油公司180kD 抗原存在于胎盘的羊膜上皮中。这个 研究人员将确定HG自身抗体的MIR是否表达 在羊膜上皮细胞中，用间接免疫荧光，原位和 Northern杂交。针对该表位的多克隆抗体 还将在体内测试它们的致病性。

DESCRIPTION (Adapted from the applicant's abstract): The long-term goals of the principal investigator are definition of the pathogenic role of pemphigus and pemphigoid autoantibodies in the production of cutaneous lesions, primarily through the use of an in vivo murine model. The investigators have recently identified a novel autoimmune blistering mucocutaneous syndrome that is associated with underlying neoplasms that they have termed paraneoplastic pemphigus. They believe that their preliminary studies support the following hypotheses regarding the etiology of this syndrome. (a) A subset of patients with blistering mucosal and cutaneous lesions and underlying neoplasms have a clinically and immunologically distinctive paraneoplastic syndrome. (b) They have autoantibodies that recognize a characteristic complex of epidermal antigens, Mr 250 KD, 230 KD, 210 KD, and 190 KD, by immunoprecipitation of metabolically labelled keratinocytes. (c) The tumors of these patients anomalously express antigens that are identical to or cross-reactive with the epithelial antigens. (d) The autoantibodies, directed primarily against tumor antigens, bind to and cause lesions within the skin and mucosa of the affected patients. The investigators present preliminary data showing that: (1) The autoantibodies of all cases have similar antigenic specificity; (2) the 250 KD Ag is desmoplakin 1 - a demonstrated plaque protein - and the 230 KD Ag is the 230 KD bullous pemphigoid Ag a hemidesmosomal protein; (3) the autoantibodies from these patients cause cutaneous and esophageal lesions in vivo by passive transfer into mice; (4) the tumor (a reticulum cell sarcoma) from one case possesses desmosomes and expresses desmoplakin I, that is reactive with both a monoclonal antibody against desmoplakin and the patients' serum autoantibodies. This study will examine the following points raised by these observations: (1) To define the specificity of the autoantibodies; (2) define the identity of the 210 and 190 KD antigens; (3) define the precise nature of antigens expressed by these tumors; (4) ascertain if these antigens are expressed only in the tumors of affected individuals, and (5) define the mechanisms by which the antibodies produce epithelial damage in vivo. This they believe is an unique opportunity to explore the complex relationship between tumor immunity and autoimmunity, for this disease may represent another biologic example in which immune response directed against tumor antigens may cross-react with constitutive proteins of host tissue, with disastrous "autoimmune" effects for the patient. Finally, the investigators have defined a major immunogenic region (MIR) of the 180 KD bullous pemphigoid antigen that is preferentially recognized by patients with Herpes gestationis (HG) (gestational pemphigoid). This is a 41-amino acid peptide that is bound by the majority of sera from affected patients. The investigators have preliminary data showing the BP 180 KD antigen is present in the amniotic epithelium of the placenta. The investigators will determine if the MIR for HG autoantibodies is expressed in amniotic epithelium, by use of indirect immunofluorescence, in situ and Northern blot hybridization. Polyclonal antibodies against the epitope will also be tested for their pathogenicity in vivo.