Multilayer concept of autoimmune mechanisms and manifestations in inborn errors of immunity: Relevance for precision therapy

Autoimmunity in inborn errors of immunity (IEI) has a multifactorial pathogenesis and develops upon a genetic predisposition in conjunction with gene regulation, environmental modifiers, and infectious triggers. Based on incremental data availability due to up-front application of omics-technologies, a more granular and dynamic view of mechanisms and manifestations is warranted. Here we present a comprehensive novel concept of autoimmunity in IEI that considers multiple layers of interdependent elements and connects 101 causative genes or deletions according to the quality of the allelic variants with 47 molecular pathways and 22 immune effector mechanisms. Furthermore, we list 50 resulting manifestations together with the corresponding human phenotype ontology (HPO) terms and review the types and frequencies of the most relevant clinical presentations. Together, this concept, i), extends the historical anatomical view of central versus peripheral tolerance towards multiple interdependent mechanisms of immune tolerance, ii), delineates the mechanisms underlying the protean clinical manifestations, and thereby, iii), points towards the most suitable precision therapy for autoimmunity in IEI. The multilayer concept of autoimmune mechanisms and manifestations in IEI will facilitate research design and provide clinical guidance on the use of precision medicine irrespective of the data depth available in each health care scenario.