From Autoimmunity to Intestinal Tissue Damage: Insights From Potential Celiac Disease as a Paradigm of Disease...

Immune-mediated inflammatory diseases are undergoing a paradigm shift from treatment of established pathology toward prevention in at-risk individuals. Celiac disease (CeD), driven by an aberrant immune response to dietary gluten in genetically predisposed individuals, represents an ideal model to investigate the transition from tolerance to autoimmunity. Within this framework, potential celiac disease (PCD)-defined by CeD-specific autoantibodies in the absence of villous atrophy-has emerged as a clinically relevant condition whose natural history, heterogeneity, and predictors of progression are increasingly understood. Immunologic studies reveal that PCD is characterized by a blunted T helper type 1 response, preserved regulatory pathways, reduced epithelial stress signaling, and incomplete licensing of cytotoxic intraepithelial lymphocytes, preventing tissue destruction. This distinct immunologic landscape makes PCD a unique window to dissect mechanisms underlying loss of tolerance and to explore preventive strategies. Only a subset of PCD individuals progress to active CeD, with the highest risk concentrated in the first years after seroconversion, whereas others even stop producing autoantibodies despite consuming gluten. Clinical management remains controversial, but current guidelines discourage routine gluten-free diet in asymptomatic PCD both in children and in adults. In conclusion, PCD represents a heterogeneous but highly informative condition positioned at the crossroads between genetic susceptibility and mucosal damage. The identification of reliable progression markers and the development of targeted preventive interventions could transform CeD management and contribute broadly to the understanding and prevention of organ-specific autoimmunity.