BAFF-R and CD21 dysregulation inhibits memory B cell persistence in patients with common variable immunodeficiency

Structured AbstractO_ST_ABSBackgroundC_ST_ABSIndividuals with common variable immunodeficiency (CVID) are at increased risk of respiratory infections such as SARS-CoV-2 infection due to poorly understood defects within the memory B cell (MBC) compartment. The COVID-19 pandemic presented a unique opportunity to investigate the effects of a novel pathogen and vaccination on the immune system of patients with CVID. MethodsA cross-sectional, single-center, cohort study was used to evaluate the immunologic effect of SARS-CoV-2 vaccination and/or disease on the immune system. We examined the antibody levels, neutralization capacity, MBC, and CD4+ T follicular helper cell (TFH) response against two SARS-CoV-2 variants in 23 CVID patients and 51 age- and sex-matched healthy individuals with both vaccine-induced and hybrid immunity across multiple immunization events. ResultsOur study shows that while CVID patients mount a sufficient CD4+ TFH response against both ancestral and Omicron variants, and some levels of neutralizing antibodies, Spike-specific MBC formation is severely inhibited. Only CVID patients with hybrid immunity were able to generate switched MBCs against both variants. These MBCs were transient however, as Spike-specific switched MBCs did not persist over time in CVID patients. We found that the level of switched MBCs correlated with both CD21 and BAFF-R expression in patients, many of whom expressed low levels of either receptor. ConclusionTaken together, our study shows that CVID patients generate a sufficient CD4+ TFH response against SARS-CoV-2 but rarely cross-reactive MBCs, and suggest that this effect is correlated with CD21 and BAFF-R dysregulation which might cause switched MBC obsolescence. Trial registration21/54057. FundingLundbeck Foundation, Novo Nordisk Foundation and Odense University Hospital.