Tjärnlund Anna, Rodríguez Ariane, Cardona Pere-Joan, Guirado Evelyn, Ivanyi Juraj, Singh Mahavir, Troye-Blomberg Marita, Fernández Carmen
Department of Immunology, Wenner-Gren Institute, Stockholm University, Svante Arrhenius väg 16, 10691 Stockholm, Sweden.
Int Immunol. 2006 May;18(5):807-16. doi: 10.1093/intimm/dxl017. Epub 2006 Mar 28.
It is generally accepted that cellular, and not humoral immunity, plays the crucial role in defense against intracellular bacteria. However, accumulating data indicate the importance of humoral immunity for the defense against a number of intracellular bacteria, including mycobacteria. We have investigated the role of secretory IgA, the main isotype found in mucosal tissues, in protection against mycobacterial infection, using polymeric IgR (pIgR)-deficient mice. Characterization of the humoral response induced after intra-nasal immunizations with the mycobacterial antigen PstS-1 revealed a loss of antigen-specific IgA response in saliva from the knockout mice. IgA level in the bronchoalveolar lavage of knockout mice was similar to wild-type level, although the IgA antibodies must have reached the lumen by other means than pIgR-mediated transport. Infection with Mycobacterium bovis bacillus Calmette-Guérin (BCG) demonstrated that the immunized pIgR-/- mice were more susceptible to BCG infection than immunized wild-type mice, based on higher bacterial loads in the lungs. This was accompanied by a reduced production of both IFN-gamma and tumor necrosis factor-alpha (TNF-alpha) in the lungs. Additionally, the pIgR-/- mice displayed reduced natural resistance to mycobacterial infection proved by significantly higher bacterial growth in their lungs compared with wild-type mice after infection with virulent Mycobacterium tuberculosis. The knockout mice appeared to have a delayed mycobacteria-induced immune response with reduced expression of protective mediators, such as IFN-gamma, TNF-alpha, inducible nitric oxide synthase and regulated upon activation normal T cell sequence, during early infection. Collectively, our results show that actively secreted IgA plays a role in protection against mycobacterial infections in the respiratory tract, by blocking entrance of bacilli into the lungs, in addition to modulation of the mycobacteria-induced pro-inflammatory response.
一般认为，在抵御细胞内细菌的过程中，起关键作用的是细胞免疫而非体液免疫。然而，越来越多的数据表明，体液免疫对于抵御包括分枝杆菌在内的多种细胞内细菌具有重要意义。我们利用聚合免疫球蛋白受体（pIgR）缺陷小鼠，研究了黏膜组织中主要的免疫球蛋白亚型——分泌型IgA在抵御分枝杆菌感染中的作用。用分枝杆菌抗原PstS - 1进行鼻内免疫后，对诱导的体液免疫反应进行表征，结果显示基因敲除小鼠唾液中抗原特异性IgA反应缺失。基因敲除小鼠支气管肺泡灌洗液中的IgA水平与野生型水平相似，尽管IgA抗体必定是通过除pIgR介导的转运之外的其他方式到达管腔的。用卡介苗（BCG）感染牛分枝杆菌的实验表明，基于肺中更高的细菌载量，免疫后的pIgR - / - 小鼠比免疫后的野生型小鼠更易受到BCG感染。这伴随着肺中γ干扰素和肿瘤坏死因子 - α（TNF - α）产生的减少。此外，与感染强毒结核分枝杆菌后的野生型小鼠相比，pIgR - / - 小鼠肺中细菌生长显著更高，这证明其对分枝杆菌感染的天然抵抗力降低。在早期感染期间，基因敲除小鼠似乎具有延迟的分枝杆菌诱导的免疫反应，保护性介质如γ干扰素、TNF - α、诱导型一氧化氮合酶以及活化后正常T细胞序列相关分子的表达减少。总体而言，我们的结果表明，主动分泌的IgA通过阻止杆菌进入肺部以及调节分枝杆菌诱导的促炎反应，在呼吸道抵御分枝杆菌感染中发挥作用。
