National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Proc Natl Acad Sci U S A. 2011 Apr 26;108(17):7148-53. doi: 10.1073/pnas.1103681108. Epub 2011 Apr 8.
The syndrome of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) is the most common periodic fever disease in children. However, the pathogenesis is unknown. Using a systems biology approach we analyzed blood samples from PFAPA patients whose genetic testing excluded hereditary periodic fevers (HPFs), and from healthy children and pediatric HPF patients. Gene expression profiling could clearly distinguish PFAPA flares from asymptomatic intervals, HPF flares, and healthy controls. During PFAPA attacks, complement (C1QB, C2, SERPING1), IL-1-related (IL-1B, IL-1RN, CASP1, IL18RAP), and IFN-induced (AIM2, IP-10/CXCL10) genes were significantly overexpressed, but T cell-associated transcripts (CD3, CD8B) were down-regulated. On the protein level, PFAPA flares were accompanied by significantly increased serum levels of chemokines for activated T lymphocytes (IP-10/CXCL10, MIG/CXCL9), G-CSF, and proinflammatory cytokines (IL-18, IL-6). PFAPA flares also manifested a relative lymphopenia. Activated CD4(+)/CD25(+) T-lymphocyte counts correlated negatively with serum concentrations of IP-10/CXCL10, whereas CD4(+)/HLA-DR(+) T lymphocyte counts correlated positively with serum concentrations of the counterregulatory IL-1 receptor antagonist. Based on the evidence for IL-1β activation in PFAPA flares, we treated five PFAPA patients with a recombinant IL-1 receptor antagonist. All patients showed a prompt clinical and IP-10/CXCL10 response. Our data suggest an environmentally triggered activation of complement and IL-1β/-18 during PFAPA flares, with induction of Th1-chemokines and subsequent retention of activated T cells in peripheral tissues. IL-1 inhibition may thus be beneficial for treatment of PFAPA attacks, with IP-10/CXCL10 serving as a potential biomarker.
周期性发热、口疮性口炎、咽炎和颈部淋巴结炎（PFAPA）综合征是儿童中最常见的周期性发热疾病。然而，其发病机制尚不清楚。我们采用系统生物学方法分析了经基因检测排除遗传性周期性发热（HPF）的 PFAPA 患者、健康儿童和儿科 HPF 患者的血液样本。基因表达谱分析可清楚地区分 PFAPA 发作、HPF 发作和健康对照。在 PFAPA 发作期间，补体（C1QB、C2、SERPING1）、IL-1 相关（IL-1B、IL-1RN、CASP1、IL18RAP）和 IFN 诱导（AIM2、IP-10/CXCL10）基因明显过表达，但 T 细胞相关转录物（CD3、CD8B）下调。在蛋白质水平，PFAPA 发作伴有趋化因子（激活 T 淋巴细胞的 IP-10/CXCL10、MIG/CXCL9）、G-CSF 和促炎细胞因子（IL-18、IL-6）的血清水平显著升高。PFAPA 发作还表现出相对的淋巴细胞减少症。活化的 CD4(+)/CD25(+)T 淋巴细胞计数与 IP-10/CXCL10 的血清浓度呈负相关，而 CD4(+)/HLA-DR(+)T 淋巴细胞计数与调节性 IL-1 受体拮抗剂的血清浓度呈正相关。根据 PFAPA 发作中 IL-1β 激活的证据，我们用重组 IL-1 受体拮抗剂治疗了 5 例 PFAPA 患者。所有患者均表现出迅速的临床和 IP-10/CXCL10 反应。我们的数据表明，在 PFAPA 发作期间，环境触发补体和 IL-1β/-18 的激活，诱导 Th1-趋化因子，并随后将活化的 T 细胞保留在外周组织中。因此，IL-1 抑制可能有益于 PFAPA 发作的治疗，IP-10/CXCL10 可作为潜在的生物标志物。
