Ponsford Mark J, Rae William, Klocperk Adam
Immunodeficiency Centre for Wales, University Hospital of Wales, Cardiff University, Cardiff.
Department of Medicine, University of Cambridge, Cambridge, UK.
Curr Opin Allergy Clin Immunol. 2018 Dec;18(6):445-452. doi: 10.1097/ACI.0000000000000481.
Understanding the pathophysiology of monogenic primary immunodeficiency (PID) with atopic presentation has pivotal implications for intervention strategies and potentially wider polygenic atopic-related traits. This review will discuss advances in gene discovery arising from monogenic defects at the interface between PID and atopy, notably the hyper-IgE syndromes.
Key molecular pathways underlying development of primary atopic diseases have recently been proposed. We test this classification through reviewing novel genes reported in the last 2 years and compare insights from pathway-analysis of genome-wide association studies (GWAS) of atopic-related traits.Growing access to next-generation sequencing (NGS) has resulted in a surge in gene discovery, highlighting the utility and some pitfalls of this approach in clinical practice. The variability of presenting phenotypes reveals important gene-dosage effects. This has important implications for therapeutic strategies such as protein stabilization and modulators of JAK-STAT or TH2-cytokine signalling. We also consider the therapeutic implications raised by CARD11 deficiency, and wider applications of NGS including polygenic risk score in atopy.
Disorders presenting at the interface between PID and allergy are often difficult to diagnose, with serious consequences if missed. Application of NGS has already provided critical insights to pathways enabling targeted therapeutic interventions, and potential wider translation to polygenic disorders.
了解具有特应性表现的单基因原发性免疫缺陷（PID）的病理生理学，对干预策略以及可能更广泛的多基因特应性相关性状具有关键意义。本综述将讨论在PID和特应性交界区的单基因缺陷所引发的基因发现进展，尤其是高IgE综合征。
最近提出了原发性特应性疾病发展的关键分子途径。我们通过回顾过去2年报道的新基因来检验这种分类，并比较来自特应性相关性状全基因组关联研究（GWAS）的通路分析的见解。越来越容易获得的下一代测序（NGS）导致基因发现激增，凸显了这种方法在临床实践中的实用性和一些缺陷。呈现表型的变异性揭示了重要的基因剂量效应。这对诸如蛋白质稳定化以及JAK-STAT或TH2细胞因子信号传导调节剂等治疗策略具有重要意义。我们还考虑了CARD11缺陷引发的治疗意义，以及NGS在特应性中的更广泛应用，包括多基因风险评分。
出现在PID和过敏交界区的疾病通常难以诊断，若漏诊会产生严重后果。NGS的应用已经为实现靶向治疗干预的途径提供了关键见解，并有可能更广泛地应用于多基因疾病。
