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

PFAPA是儿童最常见的周期性发热综合征。值得注意的是，在许多儿童中，发热发作具有接近时钟的规律性，发热发作对糖皮质激素非常敏感，并且在青春期晚期或成年早期就有逐渐消失的趋势。PFAPA倾向于家族聚集，但发病机制尚不清楚。

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.