Université Côte d'Azur, INSERM U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France.
Bordeaux University, CNRS, ImmunoConcept, UMR 5164, 33000 Bordeaux, France.
Br J Dermatol. 2023 Aug 24;189(3):312-327. doi: 10.1093/bjd/ljad148.
Vitiligo is an autoimmune skin disorder characterized by loss of melanocytes. Protease-mediated disruption of junctions between keratinocytes and/or keratinocyte intrinsic dysfunction may directly contribute to melanocyte loss. House dust mite (HDM), an environmental allergen with potent protease activity, contributes to respiratory and gut disease but also to atopic dermatitis and rosacea.
To verify if HDM can contribute to melanocyte detachment in vitiligo and if so, by which mechanism(s).
Using primary human keratinocytes, human skin biopsies from healthy donors and patients with vitiligo, and 3D reconstructed human epidermis, we studied the effect of HDM on cutaneous immunity, tight and adherent junction expression and melanocyte detachment.
HDM increased keratinocyte production of vitiligo-associated cytokines and chemokines and increased expression of toll-like receptor (TLR)-4. This was associated with increased in situ matrix-metalloproteinase (MMP)-9 activity, reduced cutaneous expression of adherent protein E-cadherin, increased soluble E-cadherin in culture supernatant and significantly increased number of suprabasal melanocytes in the skin. This effect was dose-dependent and driven by cysteine protease Der p1 and MMP-9. Selective MMP-9 inhibitor, Ab142180, restored E-cadherin expression and inhibited HDM-induced melanocyte detachment. Keratinocytes from patients with vitiligo were more sensitive to HDM-induced changes than healthy keratinocytes. All results were confirmed in a 3D model of healthy skin and in human skin biopsies.
Our results highlight that environmental mite may act as an external source of pathogen-associated molecular pattern molecules in vitiligo and topical MMP-9 inhibitors may be useful therapeutic targets. Whether HDM contributes to the onset of flares in vitiligo remains to be tested in carefully controlled trials.
白癜风是一种以黑色素细胞丧失为特征的自身免疫性皮肤疾病。蛋白酶介导的角质形成细胞间连接的破坏和/或角质形成细胞内在功能障碍可能直接导致黑色素细胞丧失。屋尘螨（HDM）是一种具有强大蛋白酶活性的环境过敏原，它不仅与呼吸道和肠道疾病有关，还与特应性皮炎和酒渣鼻有关。
验证 HDM 是否会导致白癜风患者的黑色素细胞脱离，如果是，通过哪种机制。
我们使用原代人角质形成细胞、来自健康供体和白癜风患者的皮肤活检以及 3D 重建的人表皮，研究了 HDM 对皮肤免疫、紧密和黏附连接表达以及黑色素细胞脱离的影响。
HDM 增加了角质形成细胞产生的与白癜风相关的细胞因子和趋化因子，并增加了 Toll 样受体（TLR）-4 的表达。这与原位基质金属蛋白酶（MMP）-9 活性增加、皮肤黏附蛋白 E-钙黏蛋白表达减少、培养上清液中可溶性 E-钙黏蛋白增加以及皮肤中基底层以上黑色素细胞数量显著增加有关。这种作用是剂量依赖性的，由半胱氨酸蛋白酶 Der p1 和 MMP-9 驱动。选择性 MMP-9 抑制剂 Ab142180 恢复了 E-钙黏蛋白的表达，并抑制了 HDM 诱导的黑色素细胞脱离。与健康角质形成细胞相比，白癜风患者的角质形成细胞对 HDM 诱导的变化更为敏感。所有结果在健康皮肤的 3D 模型和人皮肤活检中都得到了证实。
我们的研究结果表明，环境中的螨虫可能在白癜风中充当病原体相关分子模式分子的外部来源，局部应用 MMP-9 抑制剂可能是有用的治疗靶点。HDM 是否会导致白癜风的发作，仍需要在精心控制的试验中进行测试。
