The identification of disease alleles underlying human autoinflammatory diseases can provide important insights into the mechanisms that maintain neutrophil homeostasis. Here, we focused our attention on generalized pustular psoriasis (GPP), a potentially life-threatening disorder presenting with cutaneous and systemic neutrophilia. Following the whole-exome sequencing of 19 unrelated affected individuals, we identified a subject harboring a homozygous splice-site mutation (c.2031−2A>C) in MPO. This encodes myeloperoxidase, an essential component of neutrophil azurophil granules. MPO screening in conditions phenotypically related to GPP uncovered further disease alleles in one subject with acral pustular psoriasis (c.2031−2A>C;c.2031−2A>C) and in two individuals with acute generalized exanthematous pustulosis (c.1705C>T;c.2031−2A>C and c.1552_1565del;c.1552_1565del). A subsequent analysis of UK Biobank data demonstrated that the c.2031−2A>C and c.1705C>T (p.Arg569Trp) disease alleles were also associated with increased neutrophil abundance in the general population (p = 5.1 × 10⁻⁶ and p = 3.6 × 10⁻⁵, respectively). The same applied to three further deleterious variants that had been genotyped in the cohort, with two alleles (c.995C>T [p.Ala332Val] and c.752T>C [p.Met251Thr]) yielding p values < 10⁻¹⁰. Finally, treatment of healthy neutrophils with an MPO inhibitor (4-Aminobenzoic acid hydrazide) increased cell viability and delayed apoptosis, highlighting a mechanism whereby MPO mutations affect granulocyte numbers. These findings identify MPO as a genetic determinant of pustular skin disease and neutrophil abundance. Given the recent interest in the development of MPO antagonists for the treatment of neurodegenerative disease, our results also suggest that the pro-inflammatory effects of these agents should be closely monitored.

识别人类自身炎性疾病的潜在疾病等位基因可为维持嗜中性粒细胞稳态的机制提供重要见解。在这里，我们将注意力集中在全身性脓疱性牛皮癣（GPP）上，这是一种潜在的威胁生命的疾病，表现为皮肤和全身性中性粒细胞增多。在对19个无关的受影响个体进行全基因组测序后，我们确定了一个在MPO中具有纯合剪接位点突变（c.2031-2A> C）的受试者。它编码髓过氧化物酶，嗜中性粒细胞嗜酸性粒细胞颗粒的重要组成部分。MPO在表型与GPP相关的条件下进行筛查发现，在一个患有脓疱性牛皮癣（c.2031-2A> C; c.2031-2A> C）的受试者和两名患有急性全身性皮疹性脓疱病（c.1705C> T的患者）中，进一步发现了疾病等位基因; c.2031-2A> C和c.1552_1565del; c.1552_1565del）。随后对UK Biobank数据的分析表明，一般人群中c.2031−2A> C和c.1705C> T（p.Arg569Trp）疾病等位基因也与嗜中性白细胞丰富度增加相关（p = 5.1×10 ^-6和p ＝ 3.6×10 ^-5。这同样适用于在该队列中已进行基因分型的三个其他有害变异，具有两个等位基因（c.995C> T [p.Ala332Val]和c.752T> C [p.Met251Thr]），产生p值<10 ^-10。最后，用MPO抑制剂（4-氨基苯甲酸酰肼）治疗健康的中性粒细胞可增加细胞生存力并延迟细胞凋亡，从而突出了MPO突变影响粒细胞数量的机制。这些发现确定MPO是脓疱性皮肤疾病和中性粒细胞丰富度的遗传决定因素。鉴于最近对开发用于治疗神经退行性疾病的MPO拮抗剂的兴趣，我们的研究结果还表明，应密切监测这些药物的促炎作用。