Boyman O, Conrad C, Dudli C, Kielhorn E, Nickoloff B J, Nestle F O
Department of Dermatology, University Hospital of Zurich, Gloriastrasse 31, CH-8091 Zurich, Switzerland.
Br J Dermatol. 2005 Jun;152(6):1211-8. doi: 10.1111/j.1365-2133.2005.06701.x.
Psoriasis is a common and chronic relapsing inflammatory skin disorder. Although a role for T cells in mediating the induction and maintenance of psoriatic lesions is well established, mechanisms responsible for activation of T cells by antigen-presenting cells (APCs) during disease relapse are poorly understood.
(i) To determine whether expression of the common heat shock protein (HSP) receptor CD91 correlated with development of psoriasis in a mouse model of psoriasis, (ii) to characterize the lesional cells on which CD91 was expressed, and (iii) to investigate whether CD91+ cells in psoriasis showed signs of activation.
Two systems were used in order to study the above-mentioned objectives: (i) skin biopsies taken directly from patients with psoriasis (either psoriatic plaques or symptomless prepsoriatic skin) or from healthy donors, respectively, or (ii) (human) skin biopsies collected during development of psoriasis using a novel xenograft mouse model of psoriasis. The skin samples were then either processed for analysis by light microscopy, or labelled with fluorochrome-conjugated antibodies and analysed by confocal laser scanning microscopy.
We observed a markedly increased number of CD91+ cells which paralleled development of new psoriatic lesions in the psoriasis mouse model and in established psoriatic plaques compared with symptomless prepsoriatic or healthy skin. Morphology as well as cell-specific markers showed that CD91 was predominantly expressed by dermal dendritic APCs characterized by activation of nuclear factor-kappaB signalling and the presence of tumour necrosis factor-alpha, an important proinflammatory cytokine in the immunopathogenesis of psoriasis. In addition, HSP70, a ligand for CD91, was increased in keratinocytes in close vicinity to CD91-bearing APCs in psoriatic lesions.
These findings indicate massive presence of CD91+ dendritic cells juxtaposed to lesional keratinocytes expressing HSP70, and suggest a novel pathophysiological pathway and therapeutic target for this chronic inflammatory skin disease.
银屑病是一种常见的慢性复发性炎症性皮肤病。尽管T细胞在介导银屑病皮损的诱导和维持中所起的作用已得到充分证实，但对于疾病复发期间抗原呈递细胞（APC）激活T细胞的机制仍知之甚少。
（i）确定常见热休克蛋白（HSP）受体CD91的表达是否与银屑病小鼠模型中银屑病的发展相关；（ii）鉴定表达CD91的皮损细胞；（iii）研究银屑病中CD91+细胞是否显示激活迹象。
为研究上述目的使用了两种系统：（i）分别直接取自银屑病患者（银屑病斑块或无症状的银屑病前期皮肤）或健康供体的皮肤活检样本；（ii）使用新型银屑病异种移植小鼠模型在银屑病发展过程中收集的（人）皮肤活检样本。然后将皮肤样本进行处理，用于光学显微镜分析，或用荧光染料偶联抗体标记并通过共聚焦激光扫描显微镜分析。
我们观察到，与无症状的银屑病前期或健康皮肤相比，在银屑病小鼠模型和已形成的银屑病斑块中，CD91+细胞数量显著增加，这与新的银屑病皮损的发展平行。形态学以及细胞特异性标志物显示，CD91主要由真皮树突状APC表达，其特征为核因子-κB信号通路激活以及肿瘤坏死因子-α的存在，肿瘤坏死因子-α是银屑病免疫发病机制中的一种重要促炎细胞因子。此外，在银屑病皮损中，与携带CD91的APC紧邻的角质形成细胞中，CD91的配体HSP70增加。
这些发现表明，与表达HSP70的皮损角质形成细胞并列存在大量CD91+树突状细胞，并提示了这种慢性炎症性皮肤病的一种新的病理生理途径和治疗靶点。
