Department of Medicine, Division of Rheumatology, Emory University, Atlanta, GA 30329, USA.
Emory Vaccine Center, Emory University, Atlanta, GA 30329, USA; Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
Cell Rep. 2018 Oct 9;25(2):321-327.e3. doi: 10.1016/j.celrep.2018.09.029.
The immune system responds preferentially to particular antigenic-epitopes contained within complex immunogens, such as proteins or microbes. This poorly understood phenomenon, termed "immunodominance," remains an obstacle to achieving polyvalent immune responses against multiple antigenic-epitopes through vaccination. We observed profound suppression in the hapten-specific antibody response in mice immunized with hapten-protein conjugate, mixed with an excess of protein, relative to that in mice immunized with hapten-protein alone. The suppression was robust (100-fold and 10-fold with a 10- or 2-fold excess of protein, respectively), stable over a 6-log range in antigen dose, observed within 10 days of vaccination, and resistant to boosting and adjuvants. Furthermore, there were reduced frequencies of antigen-specific germinal-center B cells and long-lived bone-marrow plasma cells. The mechanism of this "antigen-competition" was mediated largely by early access to T-helper cells. These results offer mechanistic insights into B cell competition during an immune response and suggest vaccination strategies against HIV, influenza, and dengue.
免疫系统优先针对复杂免疫原（如蛋白质或微生物）中包含的特定抗原表位作出反应。这种尚未被充分理解的现象被称为“免疫优势”，它仍然是通过疫苗接种实现针对多种抗原表位的多价免疫反应的障碍。我们观察到，与单独用半抗原-蛋白质免疫的小鼠相比，用半抗原-蛋白质缀合物与过量蛋白质混合免疫的小鼠对半抗原特异性抗体的反应受到显著抑制。这种抑制作用很强（用 10 倍或 2 倍过量的蛋白质，分别抑制 100 倍和 10 倍），在抗原剂量的 6 个对数范围内稳定，在接种后 10 天内观察到，并对加强免疫和佐剂有抗性。此外，抗原特异性生发中心 B 细胞和长寿骨髓浆细胞的频率降低。这种“抗原竞争”的机制主要是通过早期获得辅助性 T 细胞介导的。这些结果为免疫反应期间 B 细胞竞争提供了机制上的见解，并为针对 HIV、流感和登革热的疫苗接种策略提供了启示。
