Genetics, Natural History, and Pathophysiology of Behcet's Disease

PFAPA是儿童中最常见的周期性发热综合征。值得注意的是，许多儿童的发热发作具有近似时钟的规律性，发热发作对糖皮质激素的敏感性，以及到青春期后期或成年早期时发热发作消失的趋势。PFAPA倾向于在家族中聚集，但发病机制尚不清楚。 我们询问了两个欧洲-美国队列和一个土耳其队列（n=231）的PFAPA患者的常见变异，这些变异以前与其他两种口咽溃疡性疾病（白塞氏病和复发性阿弗他口腔炎）相关。在一项荟萃分析中，我们发现IL 12 A上游的一个变异体（rs 17753641）与PFAPA密切相关（OR = 2.13，P = 6 × 10 e-9）。这种变异也与白塞病密切相关，并且与复发性阿弗他溃疡相关的变异存在强烈的连锁不平衡。我们证明，来自该风险等位基因杂合或纯合个体的单核细胞在IFN-γ和LPS刺激后产生的IL-12 p70水平显著高于来自无风险等位基因个体的单核细胞。我们还发现STAT 4、IL 10和CCR 1-CCR 3附近的变体是PFAPA的重要易感基因座，这表明PFAPA的发病机制涉及异常的抗原呈递细胞功能和T细胞活性和极化，从而涉及口咽粘膜的先天性和适应性免疫应答。 我们的研究结果说明复发性阿弗他口炎，PFAPA和白塞氏病之间的遗传相似性，将这些疾病放在一个共同的谱，与复发性阿弗他口炎的轻度结束，白塞氏病的严重结束，和PFAPA中间。我们建议将这些疾病命名为白塞氏谱系障碍，以突出它们之间的关系。HLA等位基因可能是影响表型的因素，沿着这一频谱，因为我们发现了新的I类和II类HLA协会PFAPA不同于白塞氏病和复发性阿弗他口炎。 在本报告所述期间，我们在PNAS上发表了一篇描述这些发现的手稿。

PFAPA is the most common periodic fever syndrome in children. It is notable for the near clocklike regularity of the febrile episodes in many children, the exquisite sensitivity of the febrile episodes to glucocorticoids, and the tendency to outgrow the episodes by late adolescence or early adulthood. PFAPA tends to cluster in families, but the pathogenesis is unknown. We queried two European-American cohorts and one Turkish cohort (n=231) of individuals with PFAPA for common variants previously associated with two other oropharyngeal ulcerative disorders, Behcets disease and recurrent aphthous stomatitis. In a meta-analysis, we found that a variant upstream of IL12A (rs17753641) is strongly associated with PFAPA (OR = 2.13, P = 6 X 10e-9). This variant is also strongly associated with Behcets disease and in strong linkage disequilibrium with variants associated with recurrent aphthous ulcers. We demonstrated that monocytes from individuals who are heterozygous or homozygous for this risk allele produce significantly higher levels of IL-12p70 upon IFN-gamma and LPS stimulation than those from individuals without the risk allele. We also found that variants near STAT4, IL10, and CCR1-CCR3 are significant susceptibility loci for PFAPA, suggesting that the pathogenesis of PFAPA involves abnormal antigen-presenting cell function and T cell activity and polarization, thereby implicating both innate and adaptive immune responses at the oropharyngeal mucosa. Our results illustrate genetic similarities among recurrent aphthous stomatitis, PFAPA, and Behcets disease, placing these disorders on a common spectrum, with recurrent aphthous stomatitis on the mild end, Behcets disease on the severe end, and PFAPA intermediate. We have proposed naming these disorders Behcets spectrum disorders to highlight their relationship. HLA alleles may be factors that influence phenotypes along this spectrum as we found new class I and II HLA associations for PFAPA distinct from Behcets disease and recurrent aphthous stomatitis. We published a manuscript describing these findings in the PNAS during the current reporting period.