Immunopathogenesis of hidradenitis suppurativa and response to anti-TNF-α therapy
Immunopathogenesis of hidradenitis suppurativa and response to anti-TNF-α therapy
复制标题
化脓性汗腺炎的免疫发病机制及对抗肿瘤坏死因子-α治疗的反应
DOI：
10.1172/jci.insight.139932
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发表时间：
2020-10-02
期刊：
影响因子：
8
通讯作者：
Rosenblum, Michael D.
中科院分区：
文献类型：
--
作者：
Lowe, Margaret M.;Naik, Haley B.;Rosenblum, Michael D.
化脓性汗炎（HS）是一种高度流行的病态炎症性皮肤病，治疗选择有限。HS患者皮肤中的主要细胞类型和炎症途径知之甚少，目前尚不清楚哪些患者会对TNF-α阻断有反应。我们发现，临床和组织学上健康的外观皮肤（即，非病变皮肤）在具有免疫调节途径相对丧失的HS患者中是功能障碍的。HS皮肤病变的特征在于2型常规树突状细胞的定量和定性功能障碍、相对减少的调节性T细胞、记忆B细胞的流入以及主要在终末期纤维化皮肤中的浆细胞/浆母细胞浸润。在分子水平上，与健康皮肤和银屑病患者皮肤相比，IL-1通路和1型T细胞反应存在相对偏倚。抗TNF-α治疗显著减弱了B细胞活化，对其他炎症途径的影响极小。最后，我们在抗TNF-α治疗前确定了皮肤中的免疫激活特征，该特征与随后对这种方式缺乏反应相关。我们的研究结果揭示了HS的基本免疫发病机制，并为未来的研究提供了分子基础，重点是根据对TNF-α阻断的临床反应的可能性对患者进行分层。
Hidradenitis suppurativa (HS) is a highly prevalent, morbid inflammatory skin disease with limited treatment options. The major cell types and inflammatory pathways in skin of patients with HS are poorly understood, and which patients will respond to TNF-alpha blockade is currently unknown. We discovered that clinically and histologically healthy appearing skin (i.e., nonlesional skin) is dysfunctional in patients with HS with a relative loss of immune regulatory pathways. HS skin lesions were characterized by quantitative and qualitative dysfunction of type 2 conventional dendritic cells, relatively reduced regulatory T cells, an influx of memory B cells, and a plasma cell/plasmablast infiltrate predominantly in end-stage fibrotic skin. At the molecular level, there was a relative bias toward the IL-1 pathway and type 1 T cell responses when compared with both healthy skin and psoriatic patient skin. Anti-TNF-alpha therapy markedly attenuated B cell activation with minimal effect on other inflammatory pathways. Finally, we identified an immune activation signature in skin before anti-TNF-alpha treatment that correlated with subsequent lack of response to this modality. Our results reveal the fundamental immunopathogenesis of HS and provide a molecular foundation for future studies focused on stratifying patients based on likelihood of clinical response to TNF-alpha blockade.