RAG deficiencies: Recent advances in disease pathogenesis and novel therapeutic approaches

Eur J Immunol. 2021 May;51(5):1028-1038. doi: 10.1002/eji.202048880. Epub 2021 Mar 22.

Abstract

The RAG1 and RAG2 proteins initiate the process of V(D)J recombination and therefore play an essential role in adaptive immunity. While null mutations in the RAG genes cause severe combined immune deficiency with lack of T and B cells (T- B- SCID) and susceptibility to life-threatening, early-onset infections, studies in humans and mice have demonstrated that hypomorphic RAG mutations are associated with defects of central and peripheral tolerance resulting in immune dysregulation. In this review, we provide an overview of the extended spectrum of RAG deficiencies and their associated clinical and immunological phenotypes in humans. We discuss recent advances in the mechanisms that control RAG expression and function, the effects of perturbed RAG activity on lymphoid development and immune homeostasis, and propose novel approaches to correct this group of disorders.

Keywords: Genotype-phenotype correlation; Immune tolerance; RAG; VDJ recombination.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • DNA-Binding Proteins / genetics*
  • Diagnosis, Differential
  • Disease Management
  • Disease Models, Animal
  • Genetic Association Studies
  • Genetic Predisposition to Disease*
  • Genetic Therapy
  • Genotype
  • Homeodomain Proteins / genetics*
  • Humans
  • Mutation
  • Nuclear Proteins / genetics*
  • Phenotype
  • Severe Combined Immunodeficiency / diagnosis
  • Severe Combined Immunodeficiency / etiology*
  • Severe Combined Immunodeficiency / therapy*
  • V(D)J Recombination / genetics*

Substances

  • DNA-Binding Proteins
  • Homeodomain Proteins
  • Nuclear Proteins
  • RAG2 protein, human
  • RAG-1 protein