Pichler Werner J, Yawalkar Nikhil, Britschgi Markus, Depta Jan, Strasser Ingrid, Schmid Simone, Kuechler Petra, Naisbitt Dean
Division of Allergology, Clinic for Rheumatology and Clinical Immunology/Allergology, Inselspital, University of Bern, Bern, Switzerland.
Am J Clin Dermatol. 2002;3(4):229-38. doi: 10.2165/00128071-200203040-00001.
Hypersensitivity reactions to drugs can cause a variety of skin diseases like maculopapular, bullous and pustular eruptions. In recent years increasing evidence indicates the important role of T cells in these drug-induced skin diseases. Analysis of such drug-specific T cell clones has revealed that drugs can be recognized by alpha beta-T cell receptors, not only if bound covalently to peptides, but also if the drug binds in a rather labile way to the presenting major histocompatibility complex (MHC)-peptide. This presentation is sufficient to stimulate T cells. In maculopapular exanthema (MPE), histopathological analysis typically shows a dominant T cell infiltration together with a vacuolar interface dermatitis. Immunohistochemical studies demonstrate the presence of cytotoxic CD4+ and to a lesser degree of CD8+ T cells, which contain perforin and granzyme B. They are close to keratinocytes that show signs of cell destruction. Expression of Fas ligand is barely detectable, suggesting that cytotoxic granule exocytosis may be the dominant pathway leading to keratinocyte cell damage. While in MPE, the killing of cells seems to be predominantly mediated by CD4+ T cells, patients with bullous skin disease show a strong CD8+ T cell migration to the epidermis. This is probably due to a preferential presentation of the drug by MHC class I molecules, and a more extensive killing of cells that present drugs on MHC class I molecules. This might lead to bullous skin diseases. In addition to the presence of cytotoxic T cells, drug-specific T cells also orchestrate the inflammatory skin reaction through the release and induction of various cytokines [i.e. interleukin (IL)-5, IL-6, tumor necrosis factor-alpha and interferon-gamma] and chemokines (RANTES, eotaxin or IL-8). The increased expression of these mediators seems to contribute to the generation of tissue and blood eosinophilia, a hallmark of many drug-induced allergic reactions. However, in acute generalized exanthematous pustulosis (a peculiar form of drug allergy), neutrophils represent the predominant cell type within pustules, probably due to their recruitment by IL-8 secreting drug specific T cells and keratinocytes.
药物超敏反应可引发多种皮肤疾病，如斑丘疹、大疱性和脓疱性皮疹。近年来，越来越多的证据表明T细胞在这些药物性皮肤病中发挥着重要作用。对这类药物特异性T细胞克隆的分析显示，药物不仅可以被αβ-T细胞受体识别，当它与肽共价结合时如此，而且当药物以相当不稳定的方式与呈递的主要组织相容性复合体（MHC）-肽结合时也能被识别。这种呈递足以刺激T细胞。在斑丘疹性皮疹（MPE）中，组织病理学分析通常显示以T细胞浸润为主，同时伴有空泡状界面性皮炎。免疫组织化学研究表明存在细胞毒性CD4+ T细胞，以及程度较轻的CD8+ T细胞，它们含有穿孔素和颗粒酶B。它们靠近显示细胞破坏迹象的角质形成细胞。几乎检测不到Fas配体的表达，这表明细胞毒性颗粒胞吐作用可能是导致角质形成细胞损伤的主要途径。在MPE中，细胞杀伤似乎主要由CD4+ T细胞介导，而大疱性皮肤病患者表现出强烈的CD8+ T细胞向表皮迁移。这可能是由于MHC I类分子对药物的优先呈递，以及对在MHC I类分子上呈递药物的细胞更广泛的杀伤。这可能导致大疱性皮肤病。除了存在细胞毒性T细胞外，药物特异性T细胞还通过释放和诱导各种细胞因子[即白细胞介素（IL）-5、IL-6、肿瘤坏死因子-α和干扰素-γ]和趋化因子（RANTES、嗜酸性粒细胞趋化因子或IL-8）来协调炎症性皮肤反应。这些介质表达的增加似乎有助于组织和血液嗜酸性粒细胞增多的产生，这是许多药物性过敏反应的一个标志。然而，在急性泛发性脓疱病（一种特殊形式的药物过敏）中，中性粒细胞是脓疱内的主要细胞类型，这可能是由于它们被分泌IL-8的药物特异性T细胞和角质形成细胞募集所致。
