Kidney disease impairs B cells response against infection via inhibiting germinal center formation and antibody titers

Immunity to infections is crucial to healthy life. However, recent Covid-19 pandemic has shown that comorbidity such as kidney disease and associated uremia impairs immunity against infections. Uremic patients show high susceptible to infections and also exhibit poor antibody responses to vaccine. The mechanisms by which uremia negatively impacts antibody response is unknown. Using multiple mouse models of uremia, we assessed B cells response to model antigen NP-KLH in alum. We show that uremia inhibits both canonical germinal center (GC) and non-canonical extra-follicular B cells response following NP-KLH immunization. Immunized uremic mice demonstrated compromised affinity maturation, isotype switching, antigen-specific antibody secreting cells, antibody titer and T follicular helper cells response. Consequently, uremic mice exhibited diminished GC and antibody response following prime-boost immunization. B cells showed increased cell cycle arrest, apoptosis and impaired migration between light and dark zone in the uremic GCs. We identified uremic toxin hippuric acid as a major driver of loss of mitochondrial membrane potential leading to increased apoptosis in mouse and human B cells. Finally, we show that GC B cells, T follicular helper cells and antibody response were similarly diminished in uremic mice during influenza virus infection, a major cause of mortality in patients with kidney disease. These results shed light on how uremic toxin(s) suppress antimicrobial immunity and vaccine response in individuals with kidney disease. Knowledge gained from this study may pave the path for developing effective therapeutic and preventive strategies in uremic patients against infections including SARS-CoV-2. R01AI142354, R01AI162616 and R21AI159058