Haben Irma, Hartmann Wiebke, Breloer Minka
Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
PLoS Negl Trop Dis. 2014 Sep 25;8(9):e3170. doi: 10.1371/journal.pntd.0003170. eCollection 2014 Sep.
One-third of the human population is infected with parasitic worms. To avoid being eliminated, these parasites actively dampen the immune response of their hosts. This immune modulation also suppresses immune responses to third-party antigens such as vaccines. Here, we used Litomosoides sigmodontis-infected BALB/c mice to analyse nematode-induced interference with vaccination. Chronic nematode infection led to complete suppression of the humoral response to thymus-dependent vaccination. Thereby the numbers of antigen-specific B cells as well as the serum immunoglobulin (Ig) G titres were reduced. TH2-associated IgG1 and TH1-associated IgG2 responses were both suppressed. Thus, nematode infection did not bias responses towards a TH2 response, but interfered with Ig responses in general. We provide evidence that this suppression indirectly targeted B cells via accessory T cells as number and frequency of vaccine-induced follicular B helper T cells were reduced. Moreover, vaccination using model antigens that stimulate Ig response independently of T helper cells was functional in nematode-infected mice. Using depletion experiments, we show that CD4+Foxp3+ regulatory T cells did not mediate the suppression of Ig response during chronic nematode infection. Suppression was induced by fourth stage larvae, immature adults and mature adults, and increased with the duration of the infection. By contrast, isolated microfilariae increased IgG2a responses to vaccination. This pro-inflammatory effect of microfilariae was overruled by the simultaneous presence of adults. Strikingly, a reduced humoral response was still observed if vaccination was performed more than 16 weeks after termination of L. sigmodontis infection. In summary, our results suggest that vaccination may not only fail in helminth-infected individuals, but also in individuals with a history of previous helminth infections.
全球三分之一的人口感染了寄生虫。为了避免被清除，这些寄生虫会主动抑制宿主的免疫反应。这种免疫调节也会抑制对第三方抗原（如疫苗）的免疫反应。在这里，我们使用感染了巴西日圆线虫的BALB/c小鼠来分析线虫对疫苗接种的干扰。慢性线虫感染导致对胸腺依赖性疫苗接种的体液反应完全受到抑制。因此，抗原特异性B细胞数量以及血清免疫球蛋白（Ig）G滴度均降低。与TH2相关的IgG1和与TH1相关的IgG2反应均受到抑制。因此，线虫感染并非使反应偏向TH2反应，而是总体上干扰了Ig反应。我们提供的证据表明，这种抑制作用是通过辅助性T细胞间接靶向B细胞的，因为疫苗诱导的滤泡性B辅助性T细胞的数量和频率降低了。此外，使用独立于T辅助细胞刺激Ig反应的模型抗原进行疫苗接种，在感染线虫的小鼠中是有效的。通过清除实验，我们表明CD4+Foxp3+调节性T细胞在慢性线虫感染期间并未介导Ig反应的抑制。抑制作用由第四期幼虫、未成熟成虫和成熟成虫诱导，并随着感染持续时间的增加而增强。相比之下，分离出的微丝蚴增加了对疫苗接种的IgG2a反应。微丝蚴的这种促炎作用被成虫的同时存在所抵消。令人惊讶的是，如果在巴西日圆线虫感染终止后16周以上进行疫苗接种，仍会观察到体液反应降低。总之，我们的结果表明，疫苗接种不仅可能在感染蠕虫的个体中失败，而且在有既往蠕虫感染史的个体中也可能失败。
