Malaghan Institute of Medical Research, Victoria University of Wellington, Gate 7, Kelburn Parade, Wellington, 6012, New Zealand.
High-Value Nutrition National Science Challenge, New Zealand.
Immunol Cell Biol. 2019 Jan;97(1):39-53. doi: 10.1111/imcb.12199. Epub 2018 Oct 14.
Antibody-mediated immunity is highly protective against disease. The majority of current vaccines confer protection through humoral immunity, but there is high variability in responsiveness across populations. Identifying immune mechanisms that mediate low antibody responsiveness may provide potential strategies to boost vaccine efficacy. Here, we report diverse antibody responsiveness to unadjuvanted as well as adjuvanted immunization in substrains of BALB/c mice, resulting in high and low antibody response phenotypes. Furthermore, these antibody phenotypes were not affected by changes in environmental factors such as the gut microbiota composition. Antigen-specific B cells following immunization had a marked difference in capability to class switch, resulting in perturbed IgG isotype antibody production. In vitro, a B-cell intrinsic defect in the regulation of class-switch recombination was identified in mice with low IgG antibody production. Whole genome sequencing identified polymorphisms associated with the magnitude of antibody produced, and we propose candidate genes that may regulate isotype class-switching capability. This study highlights that mice sourced from different vendors can have significantly altered humoral immune response profiles, and provides a resource to interrogate genetic regulators of antibody responsiveness. Together these results further our understanding of immune heterogeneity and suggest additional research on the genetic influences of adjuvanted vaccine strategies is warranted for enhancing vaccine efficacy.
抗体介导的免疫具有高度的疾病保护作用。大多数现有的疫苗通过体液免疫提供保护，但在人群中对其反应的变异性很高。确定介导低抗体反应的免疫机制可能为提高疫苗效力提供潜在策略。在这里，我们报告了 BALB/c 小鼠亚系中未佐剂和佐剂免疫的不同抗体反应性，导致高和低抗体反应表型。此外，这些抗体表型不受环境因素（如肠道微生物群组成）变化的影响。免疫后抗原特异性 B 细胞在类别转换能力上有明显差异，导致 IgG 同型抗体产生受到干扰。在体外，在 IgG 抗体产量低的小鼠中鉴定到 B 细胞内在的类别转换重组调节缺陷。全基因组测序确定了与抗体产生量相关的多态性，我们提出了可能调节同种型类别转换能力的候选基因。这项研究强调了来自不同供应商的小鼠可能具有明显改变的体液免疫反应谱，并提供了一个资源来研究抗体反应性的遗传调节剂。这些结果进一步加深了我们对免疫异质性的理解，并表明有必要对佐剂疫苗策略的遗传影响进行更多研究，以提高疫苗效力。
