Hidradenitis suppurativa (HS) is a chronic, debilitating inflammatory skin disease with a poorly understood immunopathogenesis. Here, we report that HS lesional skin is characterized by the expansion of innate lymphocytes and T cells expressing CD2, an essential activation receptor and adhesion molecule. Lymphocytes expressing elevated CD2 predominated with unique spatial distribution throughout the epidermis and hypodermis in the HS lesion. CD2 + cells were mainly innate lymphocytes expressing the NK cell marker, CD56, and CD4 + T cells. Importantly, these CD2 + cells interacted with CD58 (LFA3) expressing epidermal keratinocytes and fibroblasts in the hypodermis. Granzyme A bright NKT cells (CD2 + CD3 + CD56 bright ) clustered with α-SMA expressing fibroblasts juxtaposed to epithelialized tunnels and fibrotic regions of the hypodermis. Whereas NK cells (CD2 + CD56 dim ) were perforin + , granzymes A + and B + , and enriched adjacent to hyperplastic follicular epidermis and tunnels of HS showing presence of apoptotic cells. The cytokines IL-12, IL-15, and IL-18, which enhance NK cell maturation and function were significantly elevated in HS. Ex vivo HS skin explant cultures treated with CD2:CD58 interaction-blocking anti-CD2 monoclonal antibody attenuated secretion of inflammatory cytokines/chemokines and suppressed inflammatory gene signature. Additionally, CD2:CD58 blockade altered miRNAs involved in NK/NKT differentiation and/or function. In summary, we show that a cellular network of heterogenous NKT and NK cell populations drives inflammation and is critical in the pathobiology of HS, including tunnel formation and fibrosis. Finally, CD2 blockade is a viable immunotherapeutic approach for the effective management of HS.

中文翻译：

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表达 CD2 的先天性淋巴细胞和 T 细胞是化脓性汗腺炎免疫发病机制的关键效应物


化脓性汗腺炎 （HS） 是一种慢性、使人衰弱的炎症性皮肤病，免疫发病机制知之甚少。在这里，我们报道了 HS 病变皮肤的特征是先天淋巴细胞和表达 CD2 的 T 细胞的扩增，CD2 是一种必需的活化受体和粘附分子。表达 CD2 升高的淋巴细胞在 HS 病变的整个表皮和皮下组织具有独特的空间分布。CD2 + 细胞主要是表达 NK 细胞标志物、 CD56 和 CD4 + T 细胞的先天性淋巴细胞。重要的是，这些 CD2 + 细胞与皮下组织中表达 CD58 （LFA3） 的表皮角质形成细胞和成纤维细胞相互作用。颗粒酶 A 明亮的 NKT 细胞 （CD2 + CD3 + CD56 明亮） 与表达 α-SMA 的成纤维细胞并列，与皮下组织的上皮化隧道和纤维化区域并列。而 NK 细胞 （CD2 + CD56 dim ） 是穿孔素 + 、颗粒酶 A + 和 B + ，并在增生滤泡表皮和 HS 隧道附近富集，显示存在凋亡细胞。增强 NK 细胞成熟和功能的细胞因子 IL-12 、 IL-15 和 IL-18 在 HS 中显著升高。用 CD2：CD58 相互作用阻断抗 CD2 单克隆抗体处理的离体 HS 皮肤外植体培养物减弱了炎性细胞因子/趋化因子的分泌并抑制了炎症基因特征。此外，CD2：CD58 阻断改变了参与 NK/NKT 分化和/或功能的 miRNA。总之，我们表明异质性 NKT 和 NK 细胞群的细胞网络驱动炎症，并且在 HS 的病理生物学中至关重要，包括隧道形成和纤维化。最后，CD2 阻断是有效管理 HS 的可行免疫治疗方法。