Journal Article

Trained Immunity in Autoimmunity: Friend, Foe, or Therapeutic Target?

Abreu, Hugo, Chiocchetti, Annalisa, Raineri, Davide, Cappellano, Giuseppe

2026

Overview

For decades, immunology has followed a clear paradigm: immunological memory resides only within the adaptive immunity, as a unique property of lymphocytes giving the host the ability to recognize specific antigens and offer long-term protection. However, this raises an important question: how valid is this belief in light of new evidence? The discovery of trained immunity shows that innate immune cells can also develop lasting functional changes. This finding prompts a profound reconsideration of the traditional framework. Trained immunity is a functional reprogramming of the innate immune cells driven by long-term epigenetic and metabolic reprogramming, resulting in enhanced responses upon subsequent exposure to the same pathogen or even to unrelated stimuli. The presence of pattern recognition receptors (PRRs) on innate immune cells already suggested a certain level of specificity in this compartment thanks to the engagement of a PRR by a pathogen-associated molecular pattern (PAMP) inducing memory-like properties in the responding cell. While such partial specificity can enhance protection, it may also amplify aberrant inflammatory circuits, thereby contributing to the initiation or worsening of autoimmune and chronic inflammatory diseases. This dual nature of trained immunity raises important questions for the field: is trained immunity ultimately harmful or beneficial in autoimmunity, and can its mechanisms be harnessed therapeutically rather than pathologically? The present Perspective will address these issues by examining recent findings that reveal the specificity, pathogenic potential, and translational opportunities in given examples of autoimmune diseases (ADs).

• Publisher: MDPI AG,Multidisciplinary Digital Publishing Institute (MDPI)
• Subject: Adaptive immunity / Antigens / Autoimmune diseases / Autoimmunity / B cells / BCG / BCG vaccines / Chronic illnesses / Disease / DNA methylation / Epigenetic inheritance / Epigenetics / Health aspects / Immune response / Immune system / Immunity (Disease) / Immunological memory / Infections / Inflammatory diseases / innate immune system / Lymphocytes / Metabolism / Metabolites / Multiple sclerosis / Neurodegeneration / Pathogenesis / Pathogens / Pattern recognition receptors / Rheumatoid arthritis / Therapeutic targets / trained immunity