Abstract：
BACKGROUND: Palmoplantar pustulosis (PPP) is an inflammatory disease characterized by relapsing eruptions of neutrophil-filled, sterile pustules on the palms and soles that can be clinically difficult to differentiate from non-pustular palmoplantar psoriasis (palmPP) and dyshidrotic palmoplantar eczema (DPE).
OBJECTIVE: We sought to identify overlapping and unique PPP, palmPP, and DPE drivers to provide molecular insight into their pathogenesis.
METHODS: We performed bulk RNA sequencing of lesional PPP (n = 33), palmPP (n = 5), and DPE (n = 28) samples, as well as 5 healthy nonacral and 10 healthy acral skin samples.
RESULTS: Acral skin showed a unique immune environment, likely contributing to a unique niche for palmoplantar inflammatory diseases. Compared to healthy acral skin, PPP, palmPP, and DPE displayed a broad overlapping transcriptomic signature characterized by shared upregulation of proinflammatory cytokines (TNF, IL-36), chemokines, and T-cell-associated genes, along with unique disease features of each disease state, including enriched neutrophil processes in PPP and to a lesser extent in palmPP, and lipid antigen processing in DPE. Strikingly, unsupervised clustering and trajectory analyses demonstrated divergent inflammatory profiles within the 3 disease states. These identified putative key upstream immunologic switches, including eicosanoids, interferon responses, and neutrophil degranulation, contributing to disease heterogeneity.
CONCLUSIONS: A molecular overlap exists between different inflammatory palmoplantar diseases that supersedes clinical and histologic assessment. This highlights the heterogeneity within each condition, suggesting limitations of current disease classification and the need to move toward a molecular classification of inflammatory acral diseases.
OBJECTIVE: We sought to identify overlapping and unique PPP, palmPP, and DPE drivers to provide molecular insight into their pathogenesis.
METHODS: We performed bulk RNA sequencing of lesional PPP (n = 33), palmPP (n = 5), and DPE (n = 28) samples, as well as 5 healthy nonacral and 10 healthy acral skin samples.
RESULTS: Acral skin showed a unique immune environment, likely contributing to a unique niche for palmoplantar inflammatory diseases. Compared to healthy acral skin, PPP, palmPP, and DPE displayed a broad overlapping transcriptomic signature characterized by shared upregulation of proinflammatory cytokines (TNF, IL-36), chemokines, and T-cell-associated genes, along with unique disease features of each disease state, including enriched neutrophil processes in PPP and to a lesser extent in palmPP, and lipid antigen processing in DPE. Strikingly, unsupervised clustering and trajectory analyses demonstrated divergent inflammatory profiles within the 3 disease states. These identified putative key upstream immunologic switches, including eicosanoids, interferon responses, and neutrophil degranulation, contributing to disease heterogeneity.
CONCLUSIONS: A molecular overlap exists between different inflammatory palmoplantar diseases that supersedes clinical and histologic assessment. This highlights the heterogeneity within each condition, suggesting limitations of current disease classification and the need to move toward a molecular classification of inflammatory acral diseases.
摘要：
背景：掌plant脓疱病（PPP）是一种炎症性疾病，其特征是中性粒细胞填充的复发性爆发，手掌和脚底上的无菌脓疱，在临床上很难与非脓疱性掌足底银屑病（palmPP）和汗肿性掌足底湿疹（DPE）区分开。
目标：为了确定重叠和独特的PPP，palmPP,和DPE驱动因素，以提供对其发病机理的分子洞察。
方法：我们对病变PPP（n=33）进行了大量RNA测序，掌上PP（n=5），和DPE(n=28)样品，以及5个健康的非肢端和10个健康的肢端皮肤样本。
结果：肢端皮肤显示出独特的免疫环境，可能有助于掌plant炎性疾病的独特生态位。与健康的肢端皮肤相比，PPP,palmPP,和DPE显示出广泛重叠的转录组特征，其特征是促炎细胞因子（TNF，IL36),趋化因子,和T细胞相关基因，以及每种疾病状态的独特疾病特征，包括富含中性粒细胞的过程在PPP和较小程度的掌上PP，和DPE中的脂质抗原加工。引人注目的是，无监督聚类和轨迹分析显示在三种疾病状态下存在不同的炎症谱.这些确定的关键上游免疫开关，包括类花生酸,干扰素反应，中性粒细胞脱颗粒,导致疾病异质性。
结论：我们证明了不同炎性掌足底疾病之间的分子重叠，取代了临床和组织学评估，然而，突出了每种情况下的异质性，提示当前疾病分类的局限性和需要向炎症性疾病的分子分类迈进。
目标：为了确定重叠和独特的PPP，palmPP,和DPE驱动因素，以提供对其发病机理的分子洞察。
方法：我们对病变PPP（n=33）进行了大量RNA测序，掌上PP（n=5），和DPE(n=28)样品，以及5个健康的非肢端和10个健康的肢端皮肤样本。
结果：肢端皮肤显示出独特的免疫环境，可能有助于掌plant炎性疾病的独特生态位。与健康的肢端皮肤相比，PPP,palmPP,和DPE显示出广泛重叠的转录组特征，其特征是促炎细胞因子（TNF，IL36),趋化因子,和T细胞相关基因，以及每种疾病状态的独特疾病特征，包括富含中性粒细胞的过程在PPP和较小程度的掌上PP，和DPE中的脂质抗原加工。引人注目的是，无监督聚类和轨迹分析显示在三种疾病状态下存在不同的炎症谱.这些确定的关键上游免疫开关，包括类花生酸,干扰素反应，中性粒细胞脱颗粒,导致疾病异质性。
结论：我们证明了不同炎性掌足底疾病之间的分子重叠，取代了临床和组织学评估，然而，突出了每种情况下的异质性，提示当前疾病分类的局限性和需要向炎症性疾病的分子分类迈进。
