Self or Nonself: End of a Dogma?

Marie DuhamelMichel Salzet^*

• Biology, Lille University of Science and Technology, Villeneuve-d'Ascq, France

Immunologists increasingly see self versus non-self as a flexible concept, shaped by context and guided by many subtle signals. While the classical paradigm held that the immune system simply recognises and destroys foreign entities, discoveries show that immune responses are finely tuned by tissue signals, symbiotic microbes, metabolic cues, hygiene considerations, molecular mimicry and epigenetic changes. Maternal-fetal tolerance and microchimeric cells illustrate how genetically foreign cells can integrate into a host, challenging the assumption that foreign equals automatic attack. Research into the microbiome, the virome and the phenomenon of trained innate immunity continue to demonstrate beneficial and essential relationships between the body and entities once classified as non-self. Over the past decade, the notion of a binary immune distinction has shifted to a model in which the immune system continuously interprets damage or perturbation, manages complex ecological relationships with commensal or latent organisms, and recalibrates in response to life stage and environment. Core processes such as clonal deletion, negative selection and MHC-bound peptide recognition still underpin many immune mechanisms and remain highly relevant in transplant rejection and the prevention of autoimmunity. However, modern immunology emphasises that the self is not a fixed, once-and-for-all property. Rather, it is fluid and continually reshaped by microbial symbioses, epigenetic reprogramming and immunoregulatory networks across the lifespan.