背景:感染后莱姆关节炎(LA)与关节中的免疫失调和自身反应性T细胞和B细胞反应有关。在这里,我们探讨了宿主遗传变异在这一结果中的作用。
方法:在147例LA患者(87例感染后LA和60例抗生素反应性LA)中确定了253702个单核苷酸多态性(SNPs)的频率,并在90例偏头痛红斑患者或普通人群中进行比较(n=2504)。通过评估候选SNP对LA患者的临床结果以及血液和滑液中免疫反应的影响来评估候选SNP的功能结果。
结果:感染后LA患者与抗生素反应性LA患者相比,与晚期角化包膜(LCE3)基因相关的六个SNP的出现频率更高(70%vs30%;比值比,2;P<0.01)。这些SNP与血清中炎性Th17细胞因子水平升高相关,但与白细胞介素27(一种调节性细胞因子)水平降低相关。这意味着它们可能导致血液中Th17免疫失调。此外,感染后LA的患者,这些Th17介质的水平与滑液中的自身抗体反应直接相关,提供LCE3SNP之间的可能链接,适应不良的系统性Th17免疫,和关节中的自反应反应。
结论:LCE3基因座的变异,牛皮癣和牛皮癣关节炎中已知的遗传风险因素,与全身Th17免疫失调和关节自身抗体反应增强有关。这些发现强调了宿主遗传易感性和系统性Th17免疫在感染后(抗生素难治性)莱姆关节炎发病机理中的重要性。
BACKGROUND: Postinfectious Lyme arthritis (LA) is associated with dysregulated immunity and autoreactive T- and B-cell responses in joints. Here we explored the role of host genetic variation in this outcome.
METHODS: The frequency of 253 702 single-nucleotide polymorphisms (SNPs) was determined in 147 patients with LA (87 with postinfectious LA and 60 with antibiotic-responsive LA), and for comparison in 90 patients with erythema migrans or the general population (n = 2504). Functional outcome of candidate SNPs was assessed by evaluating their impact on clinical outcome and on immune responses in blood and synovial fluid in patients with LA.
RESULTS: Six SNPs associated with late cornified envelope (LCE3) genes were present at greater frequency in patients with postinfectious LA compared to those with antibiotic-responsive LA (70% vs 30%; odds ratio, 2; P < .01). These SNPs were associated with heightened levels of inflammatory Th17 cytokines in serum but lower levels of interleukin 27, a regulatory cytokine, implying that they may contribute to dysregulated Th17 immunity in blood. Moreover, in patients with postinfectious LA, the levels of these Th17 mediators correlated directly with autoantibody responses in synovial fluid, providing a possible link between LCE3 SNPs, maladaptive systemic Th17 immunity, and autoreactive responses in joints.
CONCLUSIONS: Variation in the LCE3 locus, a known genetic risk factor in psoriasis and psoriatic arthritis, is associated with dysregulated systemic Th17 immunity and heightened autoantibody responses in joints. These findings underscore the importance of host genetic predisposition and systemic Th17 immunity in the pathogenesis of postinfectious (antibiotic-refractory) Lyme arthritis.