BACKGROUND: Major depression can increase susceptibility to viral infections and autoimmune diseases. B cell responses are crucial for immune defense against infections but can trigger autoimmunity when deregulated. However, it remains unclear whether compromised B-cell homeostasis in major depression contributes to an increased risk of infection and autoimmunity. METHODS: Chronic unpredictable mild stress (CUMS) procedure was applied to adult C57BL/6 J mice to generate a reliable depression model. Mice were immunized with (4-hydroxy-3-nitrophenyl) acetyl (NP) keyhole limpet hemocyanin (NP-KLH) to elicit B-cell-mediated humoral immune responses. CUMS mice were subjected to a collagen-induced arthritis model or a Bm12-induced systemic lupus erythematosus model to assess the contribution of major depression to autoimmunity. RNA sequencing was performed to understand the effects of CUMS on B-cell homeostasis at the transcriptomic level. RESULTS: CUMS mice exhibited an impaired humoral immune response, as evidenced by reduced germinal centers (GCs), plasma cells, and antigen-specific antibodies. Unimmunized CUMS mice displayed aberrant spontaneous expansion of GC B cells, plasma cells, age-associated B cells and autoantibody production. CUMS mice also demonstrated a greater exacerbation of autoimmune manifestations. RNA sequencing revealed that genes involved in B-cell-mediated immune response were downregulated in B cells from CUMS mice, while the pathways related to autoimmunity seem to be upregulated. LIMITATIONS: Further research is needed to understand the specific targets, mechanisms, and role of B cell dysfunction in major depression. CONCLUSIONS: Our results provide novel insights into B-cell-dependent mechanisms that involve the association of increased susceptibility to infections and autoimmunity in major depression.