Peroumal Doureradjou, Jawale Chetan V, Choi Wonseok, Rahimi Hossein, Antos Danielle, Li De-Dong, Wang Shuxia, Manakkat Vijay Godhev K, Mehta Isha, West Raymond, Thangaraju Muthusamy, Nolin Thomas D, Das Jishnu, Alcorn John F, Biswas Partha S
Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA.
Nat Commun. 2024 Dec 30;15(1):10842. doi: 10.1038/s41467-024-55187-w.
Antibody-mediated protection against pathogens is crucial to a healthy life. However, the recent SARS-CoV-2 pandemic has shown that pre-existing comorbid conditions including kidney disease account for compromised humoral immunity to infections. Individuals with kidney disease are not only susceptible to infections but also exhibit poor vaccine-induced antibody response. Using multiple mouse models of kidney disease, we demonstrate that renal dysfunction inhibits germinal center (GC) response against T-dependent antigens. GC B cells exhibit increased apoptosis in kidney disease. Uremic toxin hippuric acid drives loss of mitochondrial membrane potential, leading to increased apoptosis of GC B cells in a G-protein-coupled receptor 109A dependent manner. Finally, GC B cells and antibody titer are diminished in mice with kidney disease following influenza virus infection, a major cause of mortality in individuals with renal disorders. These results provide a mechanistic understanding of how renal dysfunction suppresses humoral immunity in patients with kidney disease.
抗体介导的病原体防护对健康生活至关重要。然而，近期的新冠疫情表明，包括肾脏疾病在内的既往并存疾病会导致对感染的体液免疫受损。肾病患者不仅易受感染，而且疫苗诱导的抗体反应也较差。我们使用多种肾病小鼠模型证明，肾功能不全抑制生发中心（GC）对T细胞依赖性抗原的反应。GC B细胞在肾病中凋亡增加。尿毒症毒素马尿酸导致线粒体膜电位丧失，以G蛋白偶联受体109A依赖的方式导致GC B细胞凋亡增加。最后，流感病毒感染后，肾病小鼠的GC B细胞和抗体滴度降低，流感病毒感染是肾病患者死亡的主要原因。这些结果为肾功能不全如何抑制肾病患者的体液免疫提供了机制性认识。
