David H. Smith Center for Vaccine Biology and Immunology, Aab Institute of Biomedical Sciences, University of Rochester Medical Center, Rochester, NY, United States.
Department of Dermatology, University of Rochester Medical Center, Rochester, NY, United States.
Front Immunol. 2022 Feb 21;13:817427. doi: 10.3389/fimmu.2022.817427. eCollection 2022.
Wiskott-Aldrich Syndrome (WAS) is characterized by recurrent infections, thrombocytopenia, and eczema. Here, we show that WASp-deficient mice on a BALB/c background have dysregulated cutaneous immune homeostasis with increased leukocyte accumulation in the skin, 1 week after birth. Increased cutaneous inflammation was associated with epithelial abnormalities, namely, altered keratinization, abnormal epidermal tight junctional morphology and increased trans-epidermal water loss; consistent with epidermal barrier dysfunction. Immune and physical barrier disruption was accompanied by progressive skin dysbiosis, highlighting the functional significance of the disrupted cutaneous homeostasis. Interestingly, the dysregulated immunity in the skin preceded the systemic elevation in IgE and lymphocytic infiltration of the colonic lamina propria associated with WASp deficiency. Mechanistically, the enhanced immune cell accumulation in the skin was lymphocyte dependent. Elevated levels of both Type 2 (IL-4, IL-5) and Type 17 (IL-17, IL-22, IL-23) cytokines were present in the skin, as well as the 'itch' factor IL-31. Unexpectedly, the canonical WAS-associated cytokine IL-4 did not play a role in the immune dysfunction. Instead, IL-17 was critical for skin immune infiltration and elevation of both Type 2 and Type 17 cytokines. Our findings reveal a previously unrecognized IL-17-dependent breakdown in immune homeostasis and cutaneous barrier integrity in the absence of WASp, targeting of which may provide new therapeutic possibilities for the treatment of skin pathologies in WAS patients.
威特综合征（Wiskott-Aldrich Syndrome，WAS）的特征为反复感染、血小板减少和湿疹。在这里，我们展示了在 BALB/c 背景下缺乏 WASp 的小鼠在出生后 1 周时，皮肤中白细胞积累增加，导致皮肤免疫稳态失调。增加的皮肤炎症与上皮异常有关，即角化异常、表皮紧密连接形态异常和经皮水分丢失增加；与表皮屏障功能障碍一致。免疫和物理屏障的破坏伴随着皮肤微生态失调的进行性发展，突出了失调的皮肤稳态的功能意义。有趣的是，皮肤失调的免疫先于与 WASp 缺乏相关的 IgE 系统性升高和结肠固有层淋巴细胞浸润。从机制上讲，皮肤中免疫细胞的积聚依赖于淋巴细胞。皮肤中存在高水平的 2 型（IL-4、IL-5）和 17 型（IL-17、IL-22、IL-23）细胞因子以及“瘙痒”因子 IL-31。出乎意料的是，经典的 WAS 相关细胞因子 IL-4 并未在免疫功能障碍中发挥作用。相反，IL-17 对于皮肤免疫浸润和 2 型和 17 型细胞因子的升高至关重要。我们的研究结果揭示了一种以前未被认识的 IL-17 依赖性免疫稳态和皮肤屏障完整性破坏，针对其的治疗可能为 WAS 患者的皮肤病理提供新的治疗可能性。
