Homeostatic regulation of T follicular helper and antibody response to particle antigens by IL-1Ra of medullary sinus macrophage origin. Homeostatic regulation of T follicular helper and antibody response to particle antigens by IL-1Ra of medullary sinus macrophage origin

HBV vaccine is composed of surface antigen (HBsAg) that spontaneously assembles into subvirus particles. Factors that impede its humoral immunity in 5-10% of vaccinees remain elusive. Herein we showed that the low-level interleukin-1 receptor antagonist (IL-1Ra) can predict antibody protection both in mice and humans. Mechanistically, murine IL-1Ra inhibited Tfh cell expansion and subsequent GC dependent humoral immunity, resulting in significantly weakened protection against HBV challenge. Compared to soluble antigens, HBsAg particle antigen displayed a unique capture/uptake and innate immune activation, including IL-1Ra expression, preferably of medullary sinus macrophages (MSM). In humans, a unique polymorphism in RelA/p65 binding site of IL-1Ra enhancer associated IL-1Ra levels with ethnicity dependent vaccination outcome. Therefore, the differential IL-1Ra response to particle antigens probably creates a suppressive milieu for Tfh/GC development, and neutralization of IL-1Ra would resurrect antibody response in HBV vaccine non-responders. Overall design: mRNA profiles of wt mouse lymph node and spleen derived CD169+ macrophages 2h after HBsAg and ova immunization

乙型肝炎病毒（Hepatitis B Virus, HBV）疫苗由可自发组装为亚病毒颗粒的乙型肝炎表面抗原（Hepatitis B Surface Antigen, HBsAg）构成。约5%~10%的疫苗接种者的体液免疫会受到抑制，其潜在机制至今尚未明确。本研究发现，低水平的白细胞介素-1受体拮抗剂（Interleukin-1 Receptor Antagonist, IL-1Ra）可在小鼠与人类样本中预测抗体保护性应答。机制研究显示，小鼠体内的IL-1Ra可抑制滤泡辅助性T细胞（Follicular Helper T Cell, Tfh）的扩增，以及后续依赖生发中心（Germinal Center, GC）的体液免疫过程，进而显著削弱抗HBV攻毒的保护效力。相较于可溶性抗原，HBsAg颗粒抗原具备独特的捕获/摄取能力与固有免疫激活特性，其中髓窦巨噬细胞（Medullary Sinus Macrophages, MSM）会优先表达IL-1Ra。在人类群体中，IL-1Ra增强子的RelA/p65结合位点存在独特多态性，该多态性将IL-1Ra水平与种族依赖性的疫苗接种结局相关联。综上，颗粒抗原诱导的IL-1Ra应答差异可能为Tfh/GC发育营造了抑制性微环境，而中和IL-1Ra可恢复HBV疫苗无应答者的抗体应答。整体实验设计：野生型（wild-type, wt）小鼠经HBsAg与卵清蛋白（Ovalbumin, OVA）免疫2小时后，采集其淋巴结及脾脏来源的CD169阳性巨噬细胞的mRNA转录组图谱。