Hagge Deanna A, Scollard David M, Ray Nashone A, Marks Vilma T, Deming Angelina T, Spencer John S, Adams Linda B
Department of Health and Human Services, Health Resources and Services Administration, Healthcare Systems Bureau, National Hansen's Disease Programs, Baton Rouge, Louisiana, United States of America; Mycobacterial Research Laboratories, Anandaban Hospital, Kathmandu, Nepal.
Department of Health and Human Services, Health Resources and Services Administration, Healthcare Systems Bureau, National Hansen's Disease Programs, Baton Rouge, Louisiana, United States of America.
PLoS Negl Trop Dis. 2014 Sep 11;8(9):e3149. doi: 10.1371/journal.pntd.0003149. eCollection 2014 Sep.
Although immunopathology dictates clinical outcome in leprosy, the dynamics of early and chronic infection are poorly defined. In the tuberculoid region of the spectrum, Mycobacterium leprae growth is restricted yet a severe granulomatous lesion can occur. The evolution and maintenance of chronic inflammatory processes like those observed in the leprosy granuloma involve an ongoing network of communications via cytokines. IL-10 has immunosuppressive properties and IL-10 genetic variants have been associated with leprosy development and reactions.
METHODOLOGY/PRINCIPAL FINDINGS: The role of IL-10 in resistance and inflammation in leprosy was investigated using Mycobacterium leprae infection of mice deficient in IL-10 (IL-10-/-), as well as mice deficient in both inducible nitric oxide synthase (NOS2-/-) and IL-10 (10NOS2-/-). Although a lack of IL-10 did not affect M. leprae multiplication in the footpads (FP), inflammation increased from C57Bl/6 (B6)<IL-10-/-<NOS2-/-<10NOS2-/-. While IL-10-/- mice exhibited modest FP induration compared to B6, NOS2-/- and 10NOS2-/- mice developed markedly enlarged FP marking distinct phases: early (1 month), peak (3-4 months), and chronic (8 months). IFN-γ-producing CD4+CD44+ cells responding to M. leprae cell wall, membrane, and cytosol antigens and ML2028 (Ag85B) were significantly increased in the evolved granuloma in NOS2-/- FP compared to B6 and IL-10-/- during early and peak phases. In 10NOS2-/- FP, CD4+CD44+ and especially CD8+CD44+ responses were augmented even further to these antigens as well as to ML0380 (GroES), ML2038 (bacterioferritin), and ML1877 (EF-Tu). Moreover, fragmented nerves containing CD4+ cells were present in 10NOS2-/- FP.
CONCLUSIONS/SIGNIFICANCE: The 10NOS2-/- strain offers insight on the regulation of granuloma formation and maintenance by immune modulators in the resistant forms of leprosy and presents a new model for investigating the pathogenesis of neurological involvement.
尽管免疫病理学决定了麻风病的临床结局，但早期和慢性感染的动态过程仍不清楚。在麻风病光谱的结核样型区域，麻风分枝杆菌的生长受到限制，但仍可发生严重的肉芽肿病变。像麻风病肉芽肿中观察到的那些慢性炎症过程的演变和维持涉及通过细胞因子进行的持续通信网络。白细胞介素10（IL-10）具有免疫抑制特性，IL-10基因变异与麻风病的发生和反应有关。
方法/主要发现：利用IL-10缺陷小鼠（IL-10-/-）以及诱导型一氧化氮合酶（NOS2-/-）和IL-10双缺陷小鼠（10NOS2-/-）感染麻风分枝杆菌，研究了IL-10在麻风病抵抗和炎症中的作用。尽管缺乏IL-10并不影响麻风分枝杆菌在足垫（FP）中的繁殖，但炎症程度从C57Bl/6（B6）<IL-10-/-<NOS2-/-<10NOS2-/-逐渐增加。与B6相比，IL-10-/-小鼠的足垫出现轻度硬结，而NOS2-/-和10NOS2-/-小鼠的足垫明显肿大，呈现出不同阶段：早期（1个月）、高峰期（3-4个月）和慢性期（8个月）。在早期和高峰期，与B6和IL-10-/-相比，NOS2-/-足垫中对麻风分枝杆菌细胞壁、细胞膜和胞质抗原以及ML2028（Ag85B）产生γ干扰素的CD4+CD44+细胞显著增加。在10NOS2-/-足垫中，对这些抗原以及ML0380（GroES）、ML2038（细菌铁蛋白）和ML1877（EF-Tu）的CD4+CD44+反应，尤其是CD8+CD44+反应进一步增强。此外，在10NOS2-/-足垫中存在含有CD4+细胞的断裂神经。
结论/意义：10NOS2-/-品系为研究麻风病抵抗形式中免疫调节剂对肉芽肿形成和维持的调节提供了见解，并为研究神经受累的发病机制提供了新模型。
