Katchar Kia, Drouin Elise E, Steere Allen C
Arthritis Res Ther. 2013 Nov 7;15(6):R183. doi: 10.1186/ar4373.
Natural killer (NK) and natural killer T (NKT) cells provide a first line of defense against infection. However, these cells have not yet been examined in patients with Lyme arthritis, a late disease manifestation. Lyme arthritis usually resolves with antibiotic treatment. However, some patients have persistent arthritis after spirochetal killing, which may result from excessive inflammation, immune dysregulation and infection-induced autoimmunity.
We determined the frequencies and phenotypes of NK cells and invariant NKT (iNKT) cells in paired peripheral blood (PB) and synovial fluid (SF) samples from eight patients with antibiotic-responsive arthritis and fifteen patients with antibiotic-refractory arthritis using flow cytometry and cytokine analyses.
In antibiotic-responsive patients, who were seen during active infection, high frequencies of CD56bright NK cells were found in SF, the inflammatory site, compared with PB (P <0.001); at both sites, a high percentage of cells expressed the activation receptor NKG2D and the chaperone CD94, a low percentage expressed inhibitory killer immunoglobulin-like receptors (KIR), and a high percentage produced IFN-γ. In antibiotic-refractory patients, who were usually evaluated near the conclusion of antibiotics when few if any live spirochetes remained, the phenotype of CD56bright cells in SF was similar to that in patients with antibiotic-responsive arthritis, but the frequency of these cells was significantly less (P = 0.05), and the frequencies of CD56dim NK cells tended to be higher. However, unlike typical NKdim cells, these cells produced large amounts of IFN-γ, suggesting that they were not serving a cytotoxic function. Lastly, iNKT cell frequencies in the SF of antibiotic-responsive patients were significantly greater compared with that of antibiotic-refractory patients where these cells were often absent (P = 0.003).
In patients with antibiotic-responsive arthritis, the high percentage of activated, IFN-γ-producing CD56bright NK cells in SF and the presence of iNKT cells suggest that these cells still have a role in spirochetal killing late in the illness. In patients with antibiotic-refractory arthritis, the frequencies of IFN-γ-producing CD56bright and CD56dim NK cells remained high in SF, even after spirochetal killing, suggesting that these cells contribute to excessive inflammation and immune dysregulation in joints, and iNKT cells, which may have immunomodulatory effects, were often absent.
自然杀伤（NK）细胞和自然杀伤T（NKT）细胞为抵御感染提供了第一道防线。然而，在莱姆关节炎（一种晚期疾病表现）患者中，尚未对这些细胞进行研究。莱姆关节炎通常通过抗生素治疗得以缓解。然而，一些患者在螺旋体被清除后仍有关节炎持续存在，这可能是由于过度炎症、免疫失调以及感染诱导的自身免疫所致。
我们使用流式细胞术和细胞因子分析，测定了8例对抗生素有反应的关节炎患者和15例对抗生素难治的关节炎患者的配对外周血（PB）和滑液（SF）样本中NK细胞和不变NKT（iNKT）细胞的频率及表型。
在活跃感染期就诊的对抗生素有反应的患者中，与PB相比，在炎症部位SF中发现了高频率的CD56bright NK细胞（P <0.001）；在两个部位，高比例的细胞表达激活受体NKG2D和伴侣蛋白CD94，低比例的细胞表达抑制性杀伤细胞免疫球蛋白样受体（KIR），且高比例的细胞产生IFN-γ。在对抗生素难治的患者中，这些患者通常在抗生素治疗接近尾声时（此时几乎没有存活的螺旋体）接受评估，SF中CD56bright细胞的表型与对抗生素有反应的关节炎患者相似，但这些细胞的频率显著更低（P = 0.05），且CD56dim NK细胞的频率往往更高。然而，与典型的NKdim细胞不同，这些细胞产生大量的IFN-γ，表明它们不发挥细胞毒性功能。最后，与对抗生素难治的患者相比，对抗生素有反应的患者的SF中iNKT细胞频率显著更高，而在对抗生素难治的患者中这些细胞往往缺失（P = 0.003）。
在对抗生素有反应的关节炎患者中，SF中高比例的活化、产生IFN-γ的CD56bright NK细胞以及iNKT细胞的存在表明，这些细胞在疾病后期的螺旋体清除中仍发挥作用。在对抗生素难治的关节炎患者中，即使在螺旋体被清除后，SF中产生IFN-γ的CD56bright和CD56dim NK细胞频率仍然很高，表明这些细胞导致关节中的过度炎症和免疫失调，而可能具有免疫调节作用的iNKT细胞往往缺失。
