■我们在这里认为解剖三种皮肤病的病变中的炎症特征,其显示针对皮肤自身抗原的常见适应性免疫应答,但其特征在于不同的临床表型。寻常型天疱疮(PV)和大疱性类天疱疮(BP)是2型依赖性的,IgG自身抗体驱动的粘膜和皮肤的起泡疾病,分别靶向桥粒蛋白(Dsg)3和大疱性类天疱疮(BP)180。相比之下,扁平苔藓(LP)是皮肤和粘膜的常见慢性炎症性疾病,具有明显的真皮T细胞浸润。我们先前在一组LP患者中鉴定了针对Dsg3和BP180的外周1型和17型T细胞反应,强烈表明潜在的炎性T细胞特征可能驱动进化的表型。
■来自特征良好的LP患者的石蜡包埋皮肤活检(n=31),BP(n=19),PV(n=9),分析了天疱疮(PF)(n=2)。用穿孔活检切除具有最突出的炎性浸润的区域,并产生包含多个活检的组织微阵列(TMA)。使用多色免疫荧光,用抗多种细胞标志物的抗体对炎症浸润物进行染色,i.e.CD3ε,CD4,CD15,TCR-δ,细胞因子IL-17A,和转录因子,T-bet和GATA-3。
■在LP中,与GATA-3相比,表达T-bet的CD4+T细胞数量更高。相比之下,PV和BP皮肤病变中的CD4T细胞比T-bet更频繁地表达GATA-3。在所有三种病症中发现IL-17A+细胞和IL-17A+T细胞的程度相似。IL-17A+粒细胞在BP中比在LP或PV中更占优势。值得注意的是,LP中大部分IL-17A+细胞既不是T细胞也不是粒细胞。
■我们在炎性皮肤浸润中的发现清楚地表明,与PV和BP中2型T细胞的优势相比,LP中的1型特征占优势。与LP相比,粒细胞和较小程度的CD3+T细胞是BP和PV中IL-17A的细胞来源。这些数据强烈表明,不同的炎症细胞特征驱动LP临床上不同的表型演变。PV和BP尽管有共同的皮肤靶抗原。
We here thought to dissect the inflammatory signature in lesions of three skin disorders, which show a common adaptive immune response against autoantigens of the skin but are characterized by diverging clinical phenotypes. Pemphigus vulgaris (PV) and bullous pemphigoid (BP) are type-2-dependent, IgG autoantibody-driven blistering disorders of mucous membranes and skin, which target desmoglein (Dsg)3 and bullous pemphigoid (BP)180, respectively. In contrast, lichen planus (LP) is a common chronic inflammatory disease of the skin and mucous membranes with a pronounced dermal T cell infiltrate. We previously identified peripheral type 1 and 17 T cell responses against Dsg3 and BP180 in a cohort of LP patients strongly suggesting that the underlying inflammatory T cell signature may drive the evolving phenotype.
Paraffin-embedded skin biopsies from well-characterized patients with LP (n=31), BP (n=19), PV (n=9), and pemphigus foliaceus (PF) (n=2) were analysed. Areas with the most prominent inflammatory infiltrate were excised with punch biopsies and tissue microarrays (TMA) containing multiple biopsies were created. Using multicolor immunofluorescence, the inflammatory infiltrate was stained with antibodies against multiple cellular markers, i. e. CD3ϵ, CD4, CD15, TCR-δ, the cytokine IL-17A, and the transcription factors, T-bet and GATA-3.
In LP, there was a higher number of CD4+ T cells expressing T-bet compared to GATA-3. In contrast, CD4+ T cells in PV and BP skin lesions more frequently expressed GATA-3 than T-bet. IL-17A+ cells and IL-17A+ T cells were found to a similar extent in all the three disorders. IL-17A+ granulocytes were more predominant in BP than in LP or PV. Of note, the majority of IL-17A+ cells in LP were neither T cells nor granulocytes.
Our findings in inflammatory skin infiltrates clearly show a predominant type 1 signature in LP in contrast to a preponderance of type 2 T cells in PV and BP. In contrast to LP, granulocytes and to a much lesser extent CD3+ T cells were a cellular source of IL-17A in BP and PV. These data strongly suggest that different inflammatory cell signatures drive evolving clinically diverse phenotypes of LP, PV and BP despite common target antigens of the skin.