Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
Department of Ophthalmology, Flinders University, Adelaide, SA, Australia.
Front Immunol. 2019 Jul 23;10:1544. doi: 10.3389/fimmu.2019.01544. eCollection 2019.
One of the primary targets of immune checkpoint inhibition is the negative immune regulatory molecule CTLA-4. Immune-related adverse events are commonly observed following CTLA-4 inhibition in melanoma treatment, and a spectrum of these conditions are also observed in individuals with germline haploinsufficiency of . Here we describe a heterozygous missense variant of in a young girl with childhood-onset autoimmune hepatitis and polyarthritis, the latter responding to treatment with CTLA-4-Ig fusion protein. This variant lay within the highly conserved MYPPPY motif of CTLA-4: a critical structural determinant of ligand binding, which is also bound by the anti-CTLA-4 monoclonal antibody ipilimumab. Within the spectrum of variants reported, missense variants in the MYPPPY motif were overrepresented when compared to variants within a control population, highlighting the physiological importance of this motif in both the genetic and pharmacological regulation of autoimmunity and anti-tumor immunity.
免疫检查点抑制的主要靶点之一是负性免疫调节分子 CTLA-4。在黑色素瘤治疗中 CTLA-4 抑制后常观察到免疫相关不良事件，在种系杂合性不足的个体中也观察到这些情况的谱。在这里，我们描述了一名年轻女孩的 杂合错义变体，该女孩患有儿童期发作的自身免疫性肝炎和多发性关节炎，后者对 CTLA-4-Ig 融合蛋白治疗有反应。该变体位于 CTLA-4 的高度保守的 MYPPPY 基序内：配体结合的关键结构决定因素，也被抗 CTLA-4 单克隆抗体 ipilimumab 结合。与对照人群中的变体相比，在报告的 变体谱中，MYPPPY 基序中的错义变体过表达，突出了该基序在自身免疫和抗肿瘤免疫的遗传和药理学调节中的生理重要性。
