Outsourcing preparatory work based on a systematic literature review for the development of adverse outcome pathways (AOPs) relevant for the capacity of proteins to trigger celiac disease

A systematic literature review (SR) registered in PROSPERO (CRD42023412241) and compliant with EFSA guidelines and the PRISMA statement on systematic reviews, was performed for the retrieval of relevant studies on adverse outcome pathways for the capacity of proteins to trigger celiac disease (CD). Search queries, together with grey literature search, resulted in the identification of relevant documents that were used to collect original data by means of data extraction, categorisation, risk of bias appraisal and data synthesis of high‐level information. A summary table was used to propose AOPs for CD. The investigation revealed that gluten, non‐gluten proteins, bacterial peptides, viral peptides, and a 55 kDa autoantigen played a role in various molecular initiating events (MIEs), with gluten proteins being the most common initiators. Furthermore, several shared characteristics were identified in the resulting AOPs across various MIEs, with structural mimicry emerging as a prominent recurring pattern, i.e., when foreign proteins or peptides have a similar structure to gluten. The studies emphasized the resemblance between the TFIIA protein and gliadin, the ability of gluten‐reactive T cells to react to bacterial peptides, and the identification of viral proteins by anti‐transglutaminase IgA antibodies in individuals with CD. These observations emphasize that CD is an intricate interaction between genetic and environmental factors, where structural mimicry connects these components and contributes to the autoimmune response in individuals with CD. This work aims to facilitate the path towards the development of a consolidated AOP pertinent to proteins triggering CD consistently to the principles defined by the OECD, in particular for the assessment of the risk of bias and for the data reporting.