Institute for Specific Prophylaxis and Tropical Medicine, Medical University of Vienna, Vienna 1090, Austria.
J Immunol. 2013 Sep 1;191(5):2426-36. doi: 10.4049/jimmunol.1300293. Epub 2013 Jul 19.
Low responsiveness/nonresponsiveness is characterized by an insufficient immune response upon primary and/or booster vaccination and affects 1-10% of vaccinees. In the current study, we aimed to investigate whether nonresponsiveness is an Ag/vaccine-specific phenomenon and to clarify underlying immunological mechanisms. Nonresponders to tick-borne encephalitis (TBE) or hepatitis B Ag with a history of previous TBE vaccinations were booster vaccinated with TBE and influenza vaccine and compared with TBE high responders in terms of humoral and cellular immune response. Postboosters in TBE high responder existing TBE titers increased, and solid humoral responses to influenza vaccine were induced. In TBE nonresponders, low to undetectable prevaccination TBE titers remained low, whereas sufficient influenza Abs were induced. In both TBE groups, a positive correlation of humoral and cellular immune response was seen as high/low TBE titers were associated with sufficient/lack of Ag-specific T cell proliferation. Furthermore, responses to influenza were robust in terms of Abs and cytokine production. In contrast, in hepatitis B nonresponders, sufficient humoral responses to TBE and influenza Ags were induced despite lacking specific IL-2 and IFN-γ production. Importantly, these patients showed high IL-10 baseline levels in vitro. HLA-DR subtypes associated with hepatitis B nonresponsiveness were overrepresented in this group, and high IL-10 levels were linked to these subtypes. Whereas TBE and hepatitis B nonresponders had increased IL-10-producing FOXP3(+) T regulatory cells upon vaccination, only in hepatitis B nonresponders, showing elevated prevaccination IL-10 levels, a prominent population of B regulatory cells was detected. We conclude that immunological pathways of nonresponsiveness follow different patterns depending both on vaccine Ag and genetic predisposition of the vaccinee.
低反应性/无反应性的特征是初次和/或加强免疫时免疫反应不足，影响 1-10%的疫苗接种者。在本研究中，我们旨在研究无反应性是否是一种抗原/疫苗特异性现象，并阐明潜在的免疫学机制。既往接种过蜱传脑炎（TBE）疫苗但对 TBE 抗原无反应或无应答的个体，用 TBE 和流感疫苗进行加强免疫，并与 TBE 高应答者在体液和细胞免疫反应方面进行比较。TBE 高应答者在加强免疫后，现有的 TBE 滴度增加，对流感疫苗产生了坚实的体液反应。在 TBE 无应答者中，低至无法检测到的预接种 TBE 滴度仍然较低，而流感 Abs 则被诱导产生。在这两个 TBE 组中，体液和细胞免疫反应呈正相关，因为高/低 TBE 滴度与足够/缺乏 Ag 特异性 T 细胞增殖相关。此外，在 Abs 和细胞因子产生方面，对流感的反应非常强烈。相比之下，在乙型肝炎无应答者中，尽管缺乏特异性的 IL-2 和 IFN-γ产生，但对 TBE 和流感 Ags 仍诱导出足够的体液反应。重要的是，这些患者在体外表现出高基础水平的 IL-10。与乙型肝炎无反应性相关的 HLA-DR 亚型在该组中过度表达，并且高 IL-10 水平与这些亚型相关。虽然 TBE 和乙型肝炎无应答者在接种疫苗后产生了更多的 IL-10 产生的 FOXP3(+)调节性 T 细胞，但仅在乙型肝炎无应答者中，检测到了大量的 B 调节细胞，这些细胞在接种前就存在高水平的 IL-10。我们的结论是，无反应性的免疫途径取决于疫苗抗原和疫苗接种者的遗传易感性，遵循不同的模式。
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