Epitope spreading is an important mechanism for the development of autoantibodies (autoAbs) in autoimmune diseases. The study of epitope spreading in human autoimmune diseases is limited due to the major challenge of identifying the initial/primary target epitopes on autoantigens in autoimmune diseases. We have been studying the development of autoAbs in an endemic human autoimmune disease, Brazilian pemphigus foliaceus (or Fogo Selvagem (FS)). Our previous findings demonstrated that patients before (i.e. preclinical) and at the onset of FS have antibody (Ab) responses against other keratinocyte adhesion molecules in addition to the main target autoantigen of FS, desmoglein 1 (Dsg1), and anti-Dsg1 monoclonal Abs (mAbs) cross-reacted with an environmental antigen LJM11, a sand fly saliva protein. Since sand fly is prevalent in FS endemic regions, individuals in these regions could develop Abs against LJM11. The anti-LJM11 Abs could recognize different epitopes on LJM11, including an epitope that shares the structure similarity with an epitope on Dsg1 autoantigen. Thus, Ab response against this epitope on LJM11 could be the initial autoAb response detected in individuals in FS endemic regions, including those who eventually developed FS. Accordingly, this LJM11 and Dsg1 cross-reactive epitope on Dsg1 could be the primary target of the autoimmune response in FS. This investigation aimed to determine whether the autoAb responses against keratinocyte adhesion molecules are linked and originate from the immune response to LJM11. The anti-Dsg1 mAbs from preclinical FS and FS individuals were employed to determine their specificity or cross-reactivity to LJM11 and keratinocyte adhesion molecules. The cross-reactive epitopes on autoantigens were mapped. Our results indicate that all tested mAbs cross-reacted with LJM11 and keratinocyte adhesion molecules, and we identified an epitope on these keratinocyte adhesion molecules which is mimicked by LJM11. Thus, the cross-reactivity could be the mechanism by which the immune response against an environmental antigen triggers the initial autoAb responses. Epitope spreading leads to the pathogenic autoAb development and ensuing FS among genetically susceptible individuals.

表位扩散是自身免疫性疾病中自身抗体（autoAbs）发展的重要机制。由于在自身免疫性疾病中识别自身抗原上的初始/主要目标表位是一项重大挑战，因此对人类自身免疫性疾病中表位扩散的研究是有限的。我们一直在研究 autoAbs 在一种地方性人类自身免疫性疾病巴西天疱疮 foliaceus（或 Fogo Selvagem (FS)）中的发展。我们之前的研究结果表明，除了 FS 的主要靶自身抗原、桥粒芯蛋白 1 (Dsg1) 和抗 Dsg1 单克隆抗体外，患者在 FS 之前（即临床前）和发病时还具有针对其他角质形成细胞粘附分子的抗体 (Ab) 反应(mAbs) 与环境抗原 LJM11（一种沙蝇唾液蛋白）发生交叉反应。由于沙蝇在 FS 流行地区很普遍，这些地区的个体可以开发出针对 LJM11 的抗体。抗 LJM11 Abs 可以识别 LJM11 上的不同表位，包括与 Dsg1 自身抗原上的表位具有结构相似性的表位。因此，针对 LJM11 上该表位的抗体反应可能是在 FS 流行地区的个体中检测到的初始自身抗体反应，包括最终发展为 FS 的个体。因此，Dsg1 上的 LJM11 和 Dsg1 交叉反应性表位可能是 FS 自身免疫反应的主要目标。本研究旨在确定针对角质形成细胞粘附分子的 autoAb 反应是否相关并源自对 LJM11 的免疫反应。来自临床前 FS 和 FS 个体的抗 Dsg1 mAb 用于确定它们对 LJM11 和角质形成细胞粘附分子的特异性或交叉反应性。绘制了自身抗原上的交叉反应表位。我们的结果表明，所有测试的 mAb 都与 LJM11 和角质形成细胞粘附分子发生交叉反应，并且我们在这些角质形成细胞粘附分子上鉴定了一个被 LJM11 模拟的表位。因此，交叉反应可能是针对环境抗原的免疫反应触发初始 autoAb 反应的机制。表位扩散导致致病性 autoAb 发展并在遗传易感个体中导致 FS。交叉反应可能是针对环境抗原的免疫反应触发初始autoAb反应的机制。表位扩散导致致病性 autoAb 发展并在遗传易感个体中导致 FS。交叉反应可能是针对环境抗原的免疫反应触发初始autoAb反应的机制。表位扩散导致致病性 autoAb 发展并在遗传易感个体中导致 FS。