This chapter investigates the role of B cells in autoimmune diseases and their potential in tumor immunity. It underscores the link between aberrant B cell signaling and autoimmune conditions, where dysregulation leads to immune response imbalance and tissue damage. The chapter highlights monoclonal antibody therapies as a promising treatment approach, targeting B cells to modulate function and restore immune equilibrium. Particular attention is given to Rituximab and Belimumab, two mAbs that have shown efficacy in treating autoimmune diseases by depleting B cells or inhibiting BAFF, respectively. The chapter also discusses the mechanisms of B cell activation and the implications of self-tolerance breakdown in autoimmunity. The exploration of B cell mechanosensing and its pathological significance in disease contexts provides a foundation for developing more effective immunotherapies, emphasizing the need for a deeper understanding of B cell biology in disease pathogenesis and treatment.