Department of Dermatology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, United States.
Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, United States.
Front Immunol. 2022 Sep 23;13:969278. doi: 10.3389/fimmu.2022.969278. eCollection 2022.
The pemphigus group of autoimmune blistering diseases encompasses pemphigus vulgaris (PV) and pemphigus foliaceus (PF). Lesion location in pemphigus has been elegantly postulated by the Desmoglein Compensation Hypothesis (DCH), which references the distribution of desmoglein (Dsg) proteins in the epidermis along with a patient's autoantibody profile to describe three different lesion phenotypes: PF is characterized by subcorneal lesions in the presence of anti-Dsg1 antibodies only, while lesions in PV are suprabasilar and accompanied by anti-Dsg3 antibodies only in mucosal PV, or both anti-Dsg3 and anti-Dsg1 in the case of mucocutaneous PV. While the validity of this hypothesis has been supported by several studies and is prominently featured in textbooks of dermatology, a number of logical inconsistencies have been noted and exceptions have been published in several small-scale studies. We sought to comprehensively assess the extent to which patient clinical and autoantibody profiles contradict the DCH, and characterize these contradictions in a large sample size of 266 pemphigus patients. Remarkably, we find that roughly half of active PV and PF patients surveyed present with a combination of lesion morphology and anti-Dsg3/1 levels that contradict the DCH, including: patients with a cutaneous only PV presentation, mucocutaneous disease in the absence of either Dsg3, Dsg1, or both, and mucosal disease in the absence of Dsg3 or presence of Dsg1. We also find stark differences in fidelity to the DCH based on ethnicity and HLA-association, with the lowest proportion of adherence in previously understudied populations. These findings underscore the need to expand our understanding of pemphigus morphology beyond the DCH, in particular for populations that have not been a focus in previous investigation.
天疱疮自身免疫性水疱病包括寻常型天疱疮（PV）和落叶型天疱疮（PF）。天疱疮的病变部位已被桥粒芯糖蛋白补偿假说（DCH）优雅地提出，该假说参考了表皮中桥粒芯糖蛋白（Dsg）蛋白的分布以及患者的自身抗体谱，来描述三种不同的病变表型：PF 仅在存在抗 Dsg1 抗体的情况下表现为亚表皮病变，而 PV 的病变位于基底上方，仅在黏膜 PV 中伴有抗 Dsg3 抗体，或在黏膜皮肤性 PV 中同时伴有抗 Dsg3 和抗 Dsg1 抗体。尽管这一假说已得到多项研究的支持，并在皮肤科教科书中得到突出体现，但也注意到了一些逻辑上的不一致，并在一些小规模研究中发表了一些例外情况。我们试图全面评估患者的临床和自身抗体特征与 DCH 之间的矛盾程度，并在 266 名天疱疮患者的大样本中对这些矛盾进行特征描述。值得注意的是，我们发现大约一半的活跃 PV 和 PF 患者的病变形态和抗 Dsg3/1 水平与 DCH 相矛盾，包括：仅表现为皮肤的 PV 患者、黏膜疾病而不存在 Dsg3、Dsg1 或两者均不存在，以及黏膜疾病而不存在 Dsg3 或存在 Dsg1。我们还发现，根据种族和 HLA 关联，对 DCH 的忠实程度存在明显差异，以前研究较少的人群的依从性比例最低。这些发现强调需要超越 DCH 来扩展我们对天疱疮形态的理解，特别是对于以前研究未关注的人群。
