PATHOPHYSIOLOGY OF EXPERIMENTALLY INDUCED PEMPHIGUS

描述（改编自申请人的摘要）：长期目标 的主要研究者的定义的致病作用， 天疱疮和类天疱疮自身抗体在皮肤 损伤，主要通过使用体内鼠模型。 研究人员最近发现了一种新的自身免疫性水泡 皮肤粘膜综合征与潜在肿瘤相关， 他们称之为副肿瘤性天疱疮 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。 (a)一部分粘膜起泡的患者， 皮肤病变和潜在的肿瘤具有临床和 免疫特异性副肿瘤综合征 (b)他们有 自身抗体识别一种特征性的表皮复合物， 抗原，Mr 250 KD，230 KD，210 KD，和190 KD，通过免疫沉淀， 代谢标记的角质细胞。 (c)这些病人的肿瘤 有害地表达与以下抗原相同或交叉反应的抗原 上皮抗原 (d)自身抗体主要针对 抗肿瘤抗原，结合并引起皮肤内的损伤， 受影响患者的皮肤。 调查人员提出了初步的 结果表明：（1）所有病例的自身抗体具有相似的 抗原特异性：（2）250 KD抗原为桥粒斑蛋白1 - a 斑块蛋白-和230 KD抗原是230 KD大疱性类天疱疮抗原 半桥粒蛋白;（3）来自这些患者的自身抗体引起 通过被动转移到小鼠体内的皮肤和食管病变;（4） 一例肿瘤（网状细胞肉瘤）具有桥粒， 表达桥粒斑蛋白I，其可与单克隆抗体 抗桥粒斑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） 确定自身抗体的特异性;（2）确定 210和190 KD抗原;（3）确定抗原的确切性质 这些肿瘤表达的抗原;（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）定义机制 抗体通过其在体内产生上皮损伤。 他们这样 我相信这是一个独特的机会， 肿瘤免疫和自身免疫之间的联系，因为这种疾病可能代表了 另一个生物学的例子是针对肿瘤的免疫反应 抗原可与宿主组织的组成蛋白交叉反应， 对病人造成灾难性的“自身免疫”影响。 最后，研究人员已经确定了一个主要的免疫原性区域（MIR）， 180 KD大疱性类天疱疮抗原优先被 妊娠期疱疹（HG）（妊娠类天疱疮）患者。 这是一 41-受影响的大多数血清结合的氨基酸肽 患者 调查人员有初步数据显示BP 180 KD 抗原存在于胎盘的羊膜上皮中。 的 研究者将确定HG自身抗体的MIR是否表达 在羊膜上皮中，通过使用间接免疫荧光，原位 北方印迹杂交。 针对表位的多克隆抗体 还将测试它们在体内的致病性。

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.