Institute of Pharmacology, Philipps-Universität Marburg, Marburg, Germany.
Department of Dermatology and Allergology, Philipps-Universität Marburg, Marburg, Germany.
Front Immunol. 2023 Jun 20;14:1203776. doi: 10.3389/fimmu.2023.1203776. eCollection 2023.
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.
我们在这里分析了三种皮肤疾病病变中的炎症特征，这些疾病表现出针对皮肤自身抗原的共同适应性免疫反应，但具有不同的临床表型。寻常型天疱疮（PV）和大疱性类天疱疮（BP）是依赖于 2 型、IgG 自身抗体驱动的黏膜和皮肤水疱性疾病，分别针对桥粒芯糖蛋白 3（Dsg）3 和大疱性类天疱疮 180（BP180）。相比之下，扁平苔藓（LP）是一种常见的皮肤和黏膜慢性炎症性疾病，具有明显的真皮 T 细胞浸润。我们之前在一组 LP 患者中发现了针对 Dsg3 和 BP180 的外周 1 型和 17 型 T 细胞反应，这强烈表明潜在的炎症性 T 细胞特征可能驱动了疾病的表型进展。
对经充分特征描述的 LP（n=31）、BP（n=19）、PV（n=9）和落叶型天疱疮（PF）（n=2）患者的石蜡包埋皮肤活检进行分析。使用打孔活检术切除具有最显著炎症浸润的区域，并创建包含多个活检的组织微阵列（TMA）。使用多色免疫荧光技术，用针对多种细胞标志物的抗体对炎症浸润进行染色，例如 CD3ϵ、CD4、CD15、TCR-δ、细胞因子 IL-17A 以及转录因子 T-bet 和 GATA-3。
在 LP 中，表达 T-bet 的 CD4+T 细胞数量高于 GATA-3。相比之下，PV 和 BP 皮肤病变中的 CD4+T 细胞更常表达 GATA-3 而不是 T-bet。在所有三种疾病中，均发现了相似数量的 IL-17A+细胞和 IL-17A+T 细胞。在 BP 中，IL-17A+粒细胞比 LP 或 PV 中更为常见。值得注意的是，LP 中的大多数 IL-17A+细胞既不是 T 细胞也不是粒细胞。
我们在炎症性皮肤浸润中的发现清楚地表明，LP 中存在占主导地位的 1 型特征，而 PV 和 BP 中则存在占主导地位的 2 型 T 细胞。与 LP 不同，粒细胞以及较少程度的 CD3+T 细胞是 BP 和 PV 中 IL-17A 的细胞来源。这些数据强烈表明，尽管存在皮肤的共同靶抗原，但不同的炎症细胞特征可能驱动 LP、PV 和 BP 临床表型的不断演变。
