Abstract：
Chronic nodular prurigo (CNPG) is an inflammatory skin disease that is maintained by a chronic itch-scratch cycle likely rooted in neuroimmunological dysregulation. This condition may be associated with atopy in some patients, and there are now promising therapeutic results from blocking type 2 cytokines such as IL-4, IL-13, and IL-31.
This study aimed to improve the understanding of pathomechanisms underlying CNPG as well as molecular relationships between CNPG and atopic dermatitis (AD).
We profiled skin lesions from patients with CNPG in comparison with AD and healthy control individuals using single-cell RNA sequencing combined with T-cell receptor sequencing.
We found type 2 immune skewing in both CNPG and AD, as evidenced by CD4+ helper T cells expressing IL13. However, only AD harbored an additional, oligoclonally expanded CD8A+IL9R+IL13+ cytotoxic T-cell population, and immune activation pathways were highly upregulated in AD, but less so in CNPG. Conversely, CNPG showed signatures of extracellular matrix organization, collagen synthesis, and fibrosis, including a unique population of CXCL14-IL24+ secretory papillary fibroblasts. Besides known itch mediators such as IL31 and oncostatin M, we also detected increased levels of neuromedin B in fibroblasts of CNPG lesions compared with AD and HC, with neuromedin B receptors detectable on some nerve endings.
These data show that CNPG does not harbor the strong disease-specific immune activation pathways that are typically found in AD but is rather characterized by upregulated stromal remodeling mechanisms that might have a direct impact on itch fibers.
This study aimed to improve the understanding of pathomechanisms underlying CNPG as well as molecular relationships between CNPG and atopic dermatitis (AD).
We profiled skin lesions from patients with CNPG in comparison with AD and healthy control individuals using single-cell RNA sequencing combined with T-cell receptor sequencing.
We found type 2 immune skewing in both CNPG and AD, as evidenced by CD4+ helper T cells expressing IL13. However, only AD harbored an additional, oligoclonally expanded CD8A+IL9R+IL13+ cytotoxic T-cell population, and immune activation pathways were highly upregulated in AD, but less so in CNPG. Conversely, CNPG showed signatures of extracellular matrix organization, collagen synthesis, and fibrosis, including a unique population of CXCL14-IL24+ secretory papillary fibroblasts. Besides known itch mediators such as IL31 and oncostatin M, we also detected increased levels of neuromedin B in fibroblasts of CNPG lesions compared with AD and HC, with neuromedin B receptors detectable on some nerve endings.
These data show that CNPG does not harbor the strong disease-specific immune activation pathways that are typically found in AD but is rather characterized by upregulated stromal remodeling mechanisms that might have a direct impact on itch fibers.
摘要：
背景：慢性结节性痒疹（CNPG）是一种慢性炎症性皮肤病，由慢性瘙痒-划痕周期维持，可能源于神经免疫失调。这种情况可能与某些患者的特应性有关，并且现在有来自阻断2型细胞因子如IL-4、IL-13和IL-31的有希望的治疗结果。然而，潜在的病理机制以及与特应性的分子关系仍然不明确。
方法：我们使用单细胞RNA测序结合T细胞受体测序，将CNPG患者的皮肤病变与特应性皮炎（AD）和健康对照（HC）个体进行比较。
结果：我们在CNPG和AD中发现了2型免疫偏移，如表达IL13的CD4+辅助性T细胞所证明。然而,只有AD有额外的，寡克隆扩增的CD8A+IL9R+IL13+细胞毒性T细胞群，免疫激活途径在AD中高度上调，但在CNPG中就更少了。相反，CNPG显示细胞外基质组织的特征，胶原蛋白合成，和纤维化，包括CXCL14-IL24+分泌型乳头状成纤维细胞的独特群体。除了已知的瘙痒介质，如IL31和制瘤素M(OSM)，与AD和HC相比，我们还检测到CNPG病变的成纤维细胞中神经介蛋白B（NMB）的水平升高，在一些神经末梢可检测到NMB受体。
结论：这些数据表明，CNPG并不具有通常在AD中发现的强大的疾病特异性免疫激活途径，但其特征是基质重塑机制上调，可能直接影响瘙痒纤维。
方法：我们使用单细胞RNA测序结合T细胞受体测序，将CNPG患者的皮肤病变与特应性皮炎（AD）和健康对照（HC）个体进行比较。
结果：我们在CNPG和AD中发现了2型免疫偏移，如表达IL13的CD4+辅助性T细胞所证明。然而,只有AD有额外的，寡克隆扩增的CD8A+IL9R+IL13+细胞毒性T细胞群，免疫激活途径在AD中高度上调，但在CNPG中就更少了。相反，CNPG显示细胞外基质组织的特征，胶原蛋白合成，和纤维化，包括CXCL14-IL24+分泌型乳头状成纤维细胞的独特群体。除了已知的瘙痒介质，如IL31和制瘤素M(OSM)，与AD和HC相比，我们还检测到CNPG病变的成纤维细胞中神经介蛋白B（NMB）的水平升高，在一些神经末梢可检测到NMB受体。
结论：这些数据表明，CNPG并不具有通常在AD中发现的强大的疾病特异性免疫激活途径，但其特征是基质重塑机制上调，可能直接影响瘙痒纤维。
