Cellular Stress and Immune Activation in Celiac Disease: Is the Chaperone System a Key Player?

Celiac disease (CD) is a chronic immune-mediated enteropathy triggered by the ingestion of gluten in genetically predisposed individuals. While the adaptive immune response to deamidated gliadin peptides represents a central pathogenic mechanism, growing ev-idence suggests that epithelial stress and innate immune activation play a fundamental role in the onset and persistence of the disease. Heat shock proteins (HSPs), central reg-ulators of cellular proteostasis, have emerged as potential mediators at the interface between epithelial distress and immune signaling. This review discusses the involve-ment of major HSP families, including Hsp27, Hsp60, Hsp70, and Hsp90, in the patho-physiology of CD. The altered expression of Hsp27 and Hsp70 in the intestinal mucosa reflects a persistent state of epithelial stress that often persists despite a strict gluten-free diet (GFD). We focus specifically on Hsp60, whose extracellular release under stress conditions may allow it to function as a damage-associated molecular pattern (DAMP), engaging Toll-like receptors and promoting NF-κB- and inflammasome-dependent in-flammatory pathways. Although direct mechanistic evidence linking Hsp60 to CD re-mains limited, the convergence of epithelial stress signs, Toll-like receptor (TLRs) up-regulation, and prolonged innate immune activation supports the hypothesis of a stress-induced inflammatory amplification circuit in the coeliac mucosa. Further studies are essential to clarify the pathogenic relevance and potential therapeutic implications of this proposed axis.