Table_1_Desmoglein compensation hypothesis fidelity assessment in Pemphigus.docx

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.

天疱疮自身免疫性大疱病组包括寻常型天疱疮（PV）和落叶型天疱疮（PF）。天疱疮病变位置的提出得益于德斯莫格林蛋白补偿假说（DCH），该假说以表皮中德斯莫格林蛋白（Dsg）蛋白的分布以及患者的自身抗体谱为基础，描述了三种不同的病变表型：落叶型天疱疮仅表现为存在抗-Dsg1抗体的亚角质层病变，而寻常型天疱疮的病变位于基底层以上，且仅在黏膜型PV中伴随抗-Dsg3抗体，或在黏膜皮肤型PV中同时存在抗-Dsg3和抗-Dsg1。尽管这一假说的有效性已得到多项研究的支持，并在皮肤病学教科书中占有一席之地，但一些逻辑上的不一致性已在多项小规模研究中被指出，并有所例外。我们旨在全面评估患者临床和自身抗体谱与DCH相悖的程度，并在266名天疱疮患者的大样本中描述这些矛盾。令人惊讶的是，调查发现大约一半的活跃PV和PF患者呈现的病变形态和抗-Dsg3/1水平与DCH相悖，包括：仅表现为皮肤型PV的患者、无Dsg3、Dsg1或两者均无的黏膜皮肤病，以及无Dsg3或存在Dsg1的黏膜病。我们还发现，根据种族和HLA关联，对DCH的忠实度存在显著差异，在先前研究较少的群体中，依从比例最低。这些发现强调了超越DCH来拓展我们对天疱疮形态学的理解之必要性，尤其是对于先前研究中未关注的群体。