Naim Mahroum
Autoimmune diseases encompass nearly 100 distinct conditions characterized by dysregulated immune responses against self-antigens, resulting in tissue damage, chronic inflammation, and substantial morbidity. Over recent decades, the global burden of autoimmune diseases has increased, while their therapeutic management has undergone a paradigm shift from broad, nonspecific immunosuppression toward targeted biologic therapies. Among these, antibody-based therapeutics, including monoclonal antibodies targeting cytokines, cell-surface molecules, and co-stimulatory pathways, have transformed the treatment of numerous systemic and organ-specific autoimmune disorders. Nevertheless, important challenges remain, including primary non-response, secondary loss of efficacy related to immunogenicity or disease adaptation, increased susceptibility to infections, and mechanistic redundancy among therapeutic targets. This review provides a comprehensive overview of the cellular and molecular mechanisms underlying antibody-based therapies, summarizes major therapeutic target classes across autoimmune diseases, and examines their clinical and mechanistic limitations. Emerging therapeutic platforms, including bispecific antibodies, antibody-drug conjugates (ADCs), novel Fc-engineering, and cellular approaches such as CD19-targeted chimeric antigen receptor (CAR)-T therapy, are also discussed. Finally, antigen-specific immunotherapies designed to restore antigen-specific immune tolerance while preserving systemic host defense are explored. These approaches may represent an important next frontier in the treatment of autoimmune diseases, moving beyond broad systemic immune modulation toward more selective and durable immune control.