背景:非感染性(炎性)皮肤肉芽肿性疾病包括皮肤结节病(CS),环状肉芽肿(GA),脂类坏死病(NL),和坏死的黄色肉芽肿(NXG)。这些疾病在组织学上共享巨噬细胞主导的炎症,但是炎症结构和细胞外基质改变的模式各不相同。这些差异的潜在分子解释仍不清楚。
目的:了解这些疾病的空间基因表达特征。
方法:我们在CS病例中进行了空间转录组学,GA,NL,和NXG以空间分辨的方式比较免疫激活模式和其他分子特征。
结果:CS的特征是极化,空间组织的T辅助细胞(Th)1主要反应与经典巨噬细胞激活。GA的特点是混合,但是Th1和Th2极化的空间组织模式具有经典和替代巨噬细胞激活。NL显示伴随着Th1,Th2和Th17免疫的激活以及巨噬细胞激活的混合模式。1型免疫的激活是共有的,CS,GA,和NL并包括IL-32的上调。NXG显示CXCR4-CXCL12/14趋化因子信号的上调和放大的交替巨噬细胞极化。细胞外基质的组织学改变与缺氧和糖酵解程序以及2型免疫激活有关。
结论:炎性皮肤肉芽肿性疾病表现出明显的、空间上有组织的免疫激活,与标志性组织学改变相关。
BACKGROUND: Noninfectious (inflammatory) cutaneous granulomatous disorders include cutaneous sarcoidosis (CS), granuloma annulare (GA), necrobiosis lipoidica (NL), and necrobiotic xanthogranuloma (NXG). These disorders share macrophage-predominant inflammation histologically, but the inflammatory architecture and the pattern of extracellular matrix alteration varies. The underlying molecular explanations for these differences remain unclear.
OBJECTIVE: We sought to understand spatial gene expression characteristics in these disorders.
METHODS: We performed spatial transcriptomics in cases of CS, GA, NL, and NXG to compare patterns of immune activation and other molecular features in a spatially resolved fashion.
RESULTS: CS is characterized by a polarized, spatially organized type 1-predominant response with classical macrophage activation. GA is characterized by a mixed but spatially organized pattern of type 1 and type 2 polarization with both classical and alternative macrophage activation. NL showed concomitant activation of type 1, type 2, and type 3 immunity with a mixed pattern of macrophage activation. Activation of type 1 immunity was shared among, CS, GA, and NL and included upregulation of IL-32. NXG showed upregulation of CXCR4-CXCL12/14 chemokine signaling and exaggerated alternative macrophage polarization. Histologic alteration of extracellular matrix correlated with hypoxia and glycolysis programs and type 2 immune activation.
CONCLUSIONS: Inflammatory cutaneous granulomatous disorders show distinct and spatially organized immune activation that correlate with hallmark histologic changes.