Department of Microbiology and Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea.
Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup, South Korea.
Front Cell Infect Microbiol. 2018 Jun 21;8:206. doi: 10.3389/fcimb.2018.00206. eCollection 2018.
subsp. (MAP) is the causative pathogen of chronic granulomatous enteropathy (Johne's disease) in animals, and has been focused on its association with various autoimmune diseases in humans, including Crohn's disease. The discovery of novel mycobacterial antigens and exploring their role in host immunity can contribute to the advancement of effective defense strategies including vaccines and diagnostic tools. In a preliminary study, we identified cellular extract proteins of MAP that strongly react with the blood of patients with Crohn's disease. In particular, MAP1981c, a putative nucleic acid-binding protein, showed high expression levels and strong reactivity to IgG and IgM in the sera of patients. Here, we investigated the immunological features of MAP1981c and focused on its interaction with dendritic cells (DCs), confirming its immunomodulatory ability. MAP1981c was shown to recognize Toll-like receptor (TLR) 4, and induce DC maturation and activation by increasing the expression of co-stimulatory (CD80 and CD86) and MHC class I/II molecules and the secretion of pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α) in DCs. This DC activation by MAP1981c was mediated by downstream signaling of TLR4 via MyD88- and TRIF-, MAP kinase-, and NF-κB-dependent signaling pathways. In addition, MAP1981c-treated DCs activated naïve T cells and induced the differentiation of CD4 and CD8 T cells to express T-bet, IFN-γ, and/or IL-2, but not GATA-3 and IL-4, thus indicating that MAP1981c contributes to Th1-type immune responses both and . Taken together, these results suggest that MAP1981c is a novel immunocompetent antigen that induces DC maturation and a Th1-biased response upon DC activation, suggesting that MAP1981c can be an effective vaccine and diagnostic target.
亚群（MAP）是动物慢性肉芽肿性肠炎（约翰氏病）的病原体，其与人类各种自身免疫性疾病的关联一直受到关注，包括克罗恩病。发现新的分枝杆菌抗原并探索其在宿主免疫中的作用，可以促进包括疫苗和诊断工具在内的有效防御策略的发展。在一项初步研究中，我们鉴定了与克罗恩病患者血液强烈反应的 MAP 细胞提取物蛋白。特别是，MAP1981c，一种假定的核酸结合蛋白，在患者血清中表现出高表达水平和对 IgG 和 IgM 的强反应性。在这里，我们研究了 MAP1981c 的免疫学特征，并专注于其与树突状细胞（DC）的相互作用，证实了其免疫调节能力。MAP1981c 被证明可以识别 Toll 样受体（TLR）4，并通过增加共刺激（CD80 和 CD86）和 MHC Ⅰ/Ⅱ分子的表达以及促炎细胞因子（IL-6、IL-1β和 TNF-α）的分泌来诱导 DC 成熟和激活。MAP1981c 对 DC 的这种激活是通过 TLR4 的下游信号转导通过 MyD88-和 TRIF-、MAP 激酶-和 NF-κB 依赖性信号通路介导的。此外，MAP1981c 处理的 DC 激活幼稚 T 细胞，并诱导 CD4 和 CD8 T 细胞分化为表达 T-bet、IFN-γ和/或 IL-2，但不表达 GATA-3 和 IL-4，因此表明 MAP1981c 有助于 Th1 型免疫反应。综上所述，这些结果表明 MAP1981c 是一种新的免疫活性抗原，可诱导 DC 成熟并在 DC 激活时诱导 Th1 偏倚反应，表明 MAP1981c 可以作为有效的疫苗和诊断靶标。
