Rewriting self and non-self: A narrative review on the conceptual evolution of autoimmunity

Abstract

The understanding of autoimmunity has evolved from conceptual denial to mechanistic clarity and targeted therapy over the past century. In earlier times, autoimmune diseases were considered rare aberrations, and the doctrine of Horror Autotoxicus, proposed by Paul Ehrlich, suggested that the immune system inherently avoids attacking self-tissues. Early experimental observations, including Landsteiner’s discovery of the ABO blood groups and Donath and Landsteiner’s characterization of autohemolysin, challenged this notion by demonstrating the existence of self-reactive antibodies. Landmark studies by Rose, Witebsky, Medawar, and Burnet established that immune tolerance is an active, regulated process, and that autoreactive lymphocytes can persist under physiological control. Advances in serology, immunogenetics, and molecular biology, including HLA associations, AIRE gene discovery, and autoantibody profiling, expanded understanding of organ-specific and systemic autoimmune diseases. The late 20th century introduced targeted therapies, including TNF-α inhibitors, B-cell depletion strategies, and regulatory T cell-based approaches, illustrating the interplay between immune dysregulation, environmental triggers, and therapeutic interventions. More recently, genomics, microbiome research, artificial intelligence, and checkpoint inhibition studies have further elucidated disease mechanisms and enabled precision medicine strategies. Autoimmunity is now recognized as a dynamic, polygenic, and systemically regulated phenomenon, where pathology arises from failed regulation rather than intrinsic pathogenicity of autoreactive cells. Integration of systems biology, translational research, and innovative therapeutics continues to advance the field toward immune reprogramming and sustained remission.