Genomic Risk Factors Driving Immune-Mediated Delayed Drug Hypersensitivity Reactions.
Genomic Risk Factors Driving Immune-Mediated Delayed Drug Hypersensitivity Reactions.
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DOI：
10.3389/fgene.2021.641905
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发表时间：
2021
影响因子：
3.7
通讯作者：
Phillips EJ
中科院分区：
文献类型：
--
作者：
Li Y;Deshpande P;Hertzman RJ;Palubinsky AM;Gibson A;Phillips EJ
药物不良反应（ADR）仍然与显著的死亡率相关。给药后超过6小时发生的迟发性超敏反应（DHR）是T细胞介导的，许多严重的DHR现在与人类白细胞抗原（HLA）风险等位基因相关，为临床预测和预防开辟了途径。然而，不完全阴性预测值（NPV），低阳性预测值（PPV），和大量需要测试（NNT），以防止一个案件实际上阻止了大规模和成本效益的筛选实施。HLA以外的其他因素导致严重T细胞介导的DHR的风险，包括药物代谢的变化，T细胞受体（TCR）的特异性，以及最近，通过内质网氨肽酶（ERAP）的HLA呈递的免疫肽组加工效率。积极的研究继续朝着确定其他高度多态性的因素可能会施加风险。这些包括先前与T细胞介导的HLA相关的感染性或自身免疫性疾病相关的那些，例如与HLA I类上位性连接以调节NK和T细胞介导的细胞毒性脱粒的杀伤细胞免疫球蛋白样受体（KIR），以及共抑制信号传导途径，其中癌症免疫疗法中的治疗性阻断现在与DHR的发生率增加相关。因此，该领域现在认识到易感性不仅仅是遗传学的静态产物，而是个体可能会经历动态风险，通过治疗干预和生态暴露驱动的表观遗传修饰而倾向于免疫激活。这篇综述提供了一个更新的概述，目前和拟议的遗传因素被认为是易感风险的严重T细胞介导的DHR。
Adverse drug reactions (ADRs) remain associated with significant mortality. Delayed hypersensitivity reactions (DHRs) that occur greater than 6 h following drug administration are T-cell mediated with many severe DHRs now associated with human leukocyte antigen (HLA) risk alleles, opening pathways for clinical prediction and prevention. However, incomplete negative predictive value (NPV), low positive predictive value (PPV), and a large number needed to test (NNT) to prevent one case have practically prevented large-scale and cost-effective screening implementation. Additional factors outside of HLA contributing to risk of severe T-cell-mediated DHRs include variation in drug metabolism, T-cell receptor (TCR) specificity, and, most recently, HLA-presented immunopeptidome-processing efficiencies via endoplasmic reticulum aminopeptidase (ERAP). Active research continues toward identification of other highly polymorphic factors likely to impose risk. These include those previously associated with T-cell-mediated HLA-associated infectious or auto-immune disease such as Killer cell immunoglobulin-like receptors (KIR), epistatically linked with HLA class I to regulate NK- and T-cell-mediated cytotoxic degranulation, and co-inhibitory signaling pathways for which therapeutic blockade in cancer immunotherapy is now associated with an increased incidence of DHRs. As such, the field now recognizes that susceptibility is not simply a static product of genetics but that individuals may experience dynamic risk, skewed toward immune activation through therapeutic interventions and epigenetic modifications driven by ecological exposures. This review provides an updated overview of current and proposed genetic factors thought to predispose risk for severe T-cell-mediated DHRs.