Response of murine and normal human skin to injection of allogeneic blood-derived psoriatic immunocytes - Detection of T cells expressing receptors typically present on natural killer cells, including CD94, CD158, and CD161
Response of murine and normal human skin to injection of allogeneic blood-derived psoriatic immunocytes - Detection of T cells expressing receptors typically present on natural killer cells, including CD94, CD158, and CD161
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DOI：
10.1001/archderm.135.5.546
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发表时间：
1999-05-01
影响因子：
--
通讯作者：
Porcelli, SA
中科院分区：
文献类型：
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作者：
Nickoloff, BJ;Wrone-Smith, T;Porcelli, SA
背景：银屑病的遗传学和免疫学基础尚不清楚。通过使用严重的联合免疫缺陷小鼠-人皮肤模型，T细胞已显示出诱导银屑病，这指出了这种免疫活性细胞的病理作用。在正在进行的研究中使用这种模型，一个以前被忽视的子集的免疫细胞表达受体通常存在于自然杀伤（NK）细胞被发现，这可能会揭示新的光遗传易感性psorias.Observations：免疫细胞从银屑病患者被注射到移植同种异体正常人皮肤和产生银屑病斑块。此外，扰乱的表皮环境扩散，诱导相邻小鼠表皮厚度增加20倍以上，网钉显著伸长。因此，在同种异体人或异种小鼠皮肤中观察到的不是预测的移植物抗宿主反应，而是注射银屑病免疫细胞触发银屑病。为了探索解释银屑病T细胞缺乏致细胞病变效应的潜在机制，进行免疫染色以检测通常存在于NK细胞上的抑制性受体。这些受体包括可抑制NK细胞增殖、细胞因子释放和/或细胞毒性（即杀伤细胞抑制性受体[KIR]）的表面分子，以及可激活NK细胞细胞毒性（即杀伤细胞激活性受体[KAR]）的表面分子。皮肤移植物中的血液来源的银屑病免疫细胞表达CD 94、CD 158 a、CD 158 b、NKB 1和CD 161。此外，增生的人类和小鼠角质形成细胞均表达主要组织相容性复合体（MHC）I类CD 1d蛋白，该蛋白已被证明是表达CD 161和其他NK细胞相关受体的T细胞的特异性配体。由于已知几种KIR和KAR识别各种I类MHC等位基因，由于银屑病的遗传和易感性与各种I类MHC分子有关，我们提出了一种新的假说，即假定致病性T细胞表达各种KIR和KAR。这些相互作用可以在没有任何外源性抗原的情况下产生直接活化，并且同时在该同种异体和异种实验环境中阻断这些活化的免疫细胞的细胞毒性效应子功能。此外，表达CD 161的人T细胞可能能够与表皮角质形成细胞表达的人和鼠CD 1d相互作用。这些意想不到的发现表明银屑病是一种免疫性疾病，其中致病性T细胞而不是表皮角质形成细胞是首要的。功能性研究将确定是否用阻断剂靶向这一先前被忽视的免疫细胞群体将产生银屑病的新的免疫抑制战略途径，以及疾病易感性和/或发病模式是否可以通过涉及这些配体-受体相互作用的遗传异常来解释。
Background: The genetic and immunological basis for psoriasis is unknown. Through the use of a severe combined immunodeficient mouse-human skin model, T cells have been shown to induce psoriasis, which points to a pathological role for such immunocompetent cells. During ongoing studies using this model, a previously overlooked subset of immunocytes expressing receptors typically present on natural killer (NK) cells was discovered, which may shed new light on the genetic susceptibility for psoriasis.Observations: Immunocytes from a psoriatic patient were injected into engrafted allogeneic normal human skin and produced a psoriatic plaque. Moreover, the disturbed epidermal environment spread to induce a greater than 20-fold increase in thickness of adjacent mouse epidermis with prominent elongation of rete pegs. Thus, rather than observing the predicted graft-vs-host reaction in the allogeneic human or xenogeneic mouse skin, injection of psoriatic immunocytes triggered psoriasis. To explore a potential mechanism to explain the lack of cytopathic effect by psoriatic T cells, immunostaining to detect inhibitory receptors normally present on NK cells was performed. These receptors include surface molecules that can inhibit NK cell proliferation, cytokine release, and/or cytotoxicity tie, killer cell inhibitory receptors [KIRs]), as well as those that may activate NK cell cytotoxicity tie, killer cell activating receptors [KARs]). The blood-derived psoriatic immunocytes in the skin graft expressed CD94, CD158a, CD158b, NKB1, and CD161. Furthermore, both hyperplastic human and murine keratinocytes express the major histocompatibility complex (MHC) class I-like CD1d protein, which has been shown to be a specific ligand of T cells expressing CD161 and other NK cell-associated receptors.Conclusions: Since several KIRs and KARs are known to recognize various class I MHC alleles, and because psoriasis inheritance and susceptibility has been linked to various class I MHC molecules, we propose a novel hypothesis in which the pathogenic T cells are postulated to express an assortment of KIRs and KARs. These interactions may produce direct activation without any exogenous antigen, and at the same time block the cytotoxic effector function of these activated immunocytes in this allogeneic and xenogeneic experimental setting. In addition, human T cells expressing CD161 may be capable of interacting with human and murine CD1d expressed by the epidermal keratinocytes. These unexpected findings demonstrate that psoriasis is an immunological disease in which pathogenic T cells rather than epidermal keratinocytes are of primary importance. Functional studies will determine if targeting this previously overlooked population of immunocytes with blocking reagents will generate a novel immunotherapeutic strategic pathway for psoriasis, and whether disease susceptibility and/or incidence patterns can be explained by genetic abnormalities involving these ligand-receptor interactions.