Celiac disease (CeD) is a frequent immune-mediated disease that affects not only the small intestine but also many extraintestinal sites. The role of
gluten proteins as dietary triggers, HLA-DQ2 or -DQ8 as major necessary
genetic predisposition, and
tissue transglutaminase (TG2) as mechanistically involved
autoantigen, are unique features of CeD. Recent research implicates many cofactors working in synergism with these key triggers, including the intestinal microbiota and their metabolites, nongluten dietary triggers, intestinal barrier defects, novel immune cell phenotypes, and mediators and
cytokines. In addition, apart from HLA-DQ2 and -DQ8, multiple and complex predisposing genetic factors and interactions have been defined, most of which overlap with predispositions in other, usually
autoimmune, diseases that are linked to CeD. The resultant better understanding of CeD pathogenesis, and its manifold manifestations has already paved the way for novel therapeutic approaches beyond the lifelong strict
gluten-free diet, which poses a burden to patients and often does not lead to complete mucosal healing. Thus, supported by improved mouse models for CeD and in vitro organoid cultures, several targeted
therapies are in phase 2-3 clinical studies, such as highly effective
gluten-degrading oral
enzymes, inhibition of TG2,
cytokine therapies, induction of tolerance to
gluten ingestion, along with adjunctive and preventive approaches using beneficial probiotics and
micronutrients. These developments are supported by novel noninvasive markers of CeD severity and activity that may be used as companion diagnostics, allow easy-to perform and reliable monitoring of patients, and finally support personalized
therapy for CeD.