Immunogenomic Landscape of B cells in Patients with Septic Shock

Background. B cells play a critical role in protecting against infections. Decreased cell number, altered phenotype and function were found in B cells from patients with sepsis/septic shock, however, the underlying molecular mechanisms were not elucidated. In the present study, we aimed to explore the B cells composition, gene expressions and B cell receptor (BCR) characterization in patients with septic shock. Methods. B cells were isolated from peripheral blood of patients with septic shock and healthy controls (HCs). Bulk RNA sequencing, single-cell RNA and BCR sequencing were performed. Subsequent cellular and molecular experiments were conducted to verify the analysis. Results. We found expansion of plasmablast population in patients with septic shock. However, both the BCR clonotype diversity and clonality were decreased. The CA8 expression was higher in B cells and promoted plasmablast proliferation through Akt signaling pathway. We further discovered that adrenomedullin (ADM) expression was up-regulated in septic shock-derived B cells compared with HCs. Moreover, B cells from patients displayed abnormal mitochondria structure and stimulation of ADM in vitro promoted B cell apoptosis through ribonucleotide reductase regulatory subunit M2 (RRM2)-related cell death. Conclusion. Our study provides a comprehensive genomic picture of B cells from patients with septic shock. We explored the underlying molecular mechanism involved in abnormal B cell compartment and function, which would be promising targets for lymphopenia and immunosuppression in sepsis/septic shock patients.