Hypomorphic RAG mutations cause a spectrum of clinical manifestations.

recombination activity levels shape TCR and BCR repertoire and influence the immune phenotype.

Tissue barrier disruption contributes to systemic signs.

Altered B-cell tolerance checkpoints sustain immune dysregulation.

Increased immunogloblulin-E (IgE) levels associated with eosinophilia represent a common finding observed in Omenn syndrome, a severe immunodeficiency caused by decreased V(D)J recombination, leading to restricted T- and B-cell receptor repertoire. V(D)J recombination is initiated by the lymphoid-restricted recombination-activating gene (RAG) recombinases. The lack of RAG proteins causes a block in lymphocyte differentiation, resulting in T-B- severe combined immunodeficiency. Conversely, hypomorphic mutations allow the generation of few T and B cells, leading to a spectrum of immunological phenotypes, in which immunodeficiency associates to inflammation, immune dysregulation, and autoimmunity. Elevated IgE levels are frequently observed in hypomorphic RAG patients. Here, we describe the role of RAG genes in lymphocyte differentiation and maintenance of immune tolerance.

© 2022 The Author(s). Published by Elsevier Ltd.