Molecular mimicry revisited: novel perspectives on autoimmune disease initiation and progression

Molecular mimicry has long been implicated as one possible mechanism linking pathogen infection to autoimmunity, yet firm proof of its contribution to disease initiation and/or progression remains incompletely defined. In this review, we revisit the concept of molecular mimicry in light of recent advances in immunology, structural biology, and systems medicine. Beyond classical sequence homology, emerging evidence highlights the importance of structural and conformational epitope similarity, post-translational modifications, and context-dependent antigen presentation in shaping cross-reactive immune responses. We discuss how these factors influence the activation of autoreactive T and B cells, the breakdown of immune tolerance, and the establishment of chronic autoimmune disease. We further reevaluate the body of evidence for molecular mimicry as inducer and/or accelerator of specific autoimmune diseases ranging from mere association to proven causative relationship. Thereby, we further examine novel experimental approaches that have refined the identification of mimicry candidates and improved our understanding of their pathogenic relevance. By integrating classical paradigms with contemporary findings, this review provides a detailed outline for understanding molecular mimicry as a dynamic and multi-layered contributor to autoimmune disease.