Hawkes Jason E, Chan Tom C, Krueger James G
Laboratory for Investigative Dermatology, Rockefeller University, New York, NY.
Laboratory for Investigative Dermatology, Rockefeller University, New York, NY.
J Allergy Clin Immunol. 2017 Sep;140(3):645-653. doi: 10.1016/j.jaci.2017.07.004.
Psoriasis is caused by a complex interplay between the immune system, psoriasis-associated susceptibility loci, autoantigens, and multiple environmental factors. Over the last 2 decades, research has unequivocally shown that psoriasis represents a bona fide T cell-mediated disease primarily driven by pathogenic T cells that produce high levels of IL-17 in response to IL-23. The discovery of the central role for the IL-23/type 17 T-cell axis in the development of psoriasis has led to a major paradigm shift in the pathogenic model for this condition. The activation and upregulation of IL-17 in prepsoriatic skin produces a "feed forward" inflammatory response in keratinocytes that is self-amplifying and drives the development of mature psoriatic plaques by inducing epidermal hyperplasia, epidermal cell proliferation, and recruitment of leukocyte subsets into the skin. Clinical trial data for mAbs against IL-17 signaling (secukinumab, ixekizumab, and brodalumab) and newer IL-23p19 antagonists (tildrakizumab, guselkumab, and risankizumab) underscore the central role of these cytokines as predominant drivers of psoriatic disease. Currently, we are witnessing a translational revolution in the treatment and management of psoriasis. Emerging bispecific antibodies offer the potential for even better disease control, whereas small-molecule drugs offer future alternatives to the use of biologics and less costly long-term disease management.
银屑病是由免疫系统、银屑病相关易感基因座、自身抗原和多种环境因素之间复杂的相互作用引起的。在过去20年里，研究明确表明，银屑病是一种真正的T细胞介导的疾病，主要由致病性T细胞驱动，这些T细胞在IL-23的刺激下产生高水平的IL-17。IL-23/17型T细胞轴在银屑病发病机制中核心作用的发现，导致了该疾病致病模型的重大范式转变。银屑病前期皮肤中IL-17的激活和上调在角质形成细胞中产生一种“正反馈”炎症反应，这种反应会自我放大，并通过诱导表皮增生、表皮细胞增殖以及白细胞亚群募集到皮肤中，从而推动成熟银屑病斑块的形成。针对IL-17信号通路的单克隆抗体（司库奇尤单抗、依奇珠单抗和布罗达单抗）以及新型IL-23p19拮抗剂（替拉珠单抗、古塞奇尤单抗和瑞莎珠单抗）的临床试验数据强调了这些细胞因子作为银屑病主要驱动因素的核心作用。目前，我们正在见证银屑病治疗和管理方面的转化医学革命。新兴的双特异性抗体为更好地控制疾病提供了潜力，而小分子药物为生物制剂的使用提供了未来的替代方案，并降低了长期疾病管理的成本。
