Beyond gluten: the multifaceted regulation of MHC class II in celiac disease pathogenesis

Celiac disease (CD) is a complex immune-mediated disorder influenced by genetic predispositio and environmental triggers, which human leukocyte antigen (HLA)-DQ2/8 playing a central role in disease pathogenesis. Gluten peptides deamidated by tissue transglutaminase 2 (tTG2) bind to CD4⁺ T cells via major histocompatibility complex (MHC) class II molecules, initiating an inflammatory cascade that damages the intestinal mucosa. Although many individuals carry HLA-DQ2/8 alleles, only a subset develops CD, suggesting the contribution of additional regulatory factors. This review examines the critical function of the MHC class II transactivator (CIITA) in regulating HLA-DQ expression through post-translational modifications, including phosphorylation, acetylation, and ubiquitination, and its interactions with histone acetyltransferases (HATs). We highlight how gliadin-induced mitogen-activated protein kinase (MAPK) signaling enhances CIITA activation, thereby amplifying MHC II expression and gluten antigen presentation. Emerging evidence also implicates protein kinase Cδ (PKCδ) as a key modulator of interferon gamma (IFN-γ)-driven CIITA expression and a target of tTG-mediated autoimmunity in CD. Moreover, hormonal influences, vitamin D deficiency, and gut microbiota-derived metabolites (e.g., butyrate) may fine-tune MHC II expression, contributing to sex-biased prevalence and geographic variability. Therapeutically, targeting CIITA regulatory nodes could complement gluten-free diets (GFD). By integrating genetic, epigenetic, and environmental perspectives, this review advances our understanding of CD pathogenesis.