B cell abnormalities and autoantibody production in patients with partial RAG deficiency

Mutations in the recombination activating gene 1 (RAG1) and RAG2 in humans are associated with a broad spectrum of clinical phenotypes, from severe combined immunodeficiency to immune dysregulation. Partial (hypomorphic) RAG deficiency (pRD) in particular, frequently leads to hyperinflammation and autoimmunity, with several underlying intrinsic and extrinsic mechanisms causing a break in tolerance centrally and peripherally during T and B cell development. However, the relative contributions of these processes to immune dysregulation remain unclear. In this review, we specifically focus on the recently described tolerance break and B cell abnormalities, as well as consequent molecular and cellular mechanisms of autoantibody production in patients with pRD.

Automated summary

Mutations in RAG1 and RAG2 genes in humans are associated with various clinical phenotypes, ranging from severe combined immunodeficiency to immune dysregulation. Partial RAG deficiency often leads to hyperinflammation and autoimmunity, with intrinsic and extrinsic mechanisms causing a break in tolerance during T and B cell development. This review focuses on the recently described tolerance break, B cell abnormalities, and the molecular and cellular mechanisms of autoantibody production in patients with partial RAG deficiency.