Recent advances in understanding RAG deficiencies.

Andrew Gennery

doi:10.12688/f1000research.17056.1

Abstract

Recombination-activating genes ( RAG) 1 and RAG2 initiate the molecular processes that lead to lymphocyte receptor formation through VDJ recombination. Nonsense mutations in RAG1/ RAG2 cause the most profound immunodeficiency syndrome, severe combined immunodeficiency (SCID). Other severe and less-severe clinical phenotypes due to mutations in RAG genes are now recognized. The degree of residual protein function may permit some lymphocyte receptor formation, which confers a less-severe clinical phenotype. Many of the non-SCID phenotypes are associated with autoimmunity. New findings into the effect of mutations in RAG1/2 on the developing T- and B-lymphocyte receptor give insight into the development of autoimmunity. This article summarizes recent findings and places the genetic and molecular findings in a clinical context.

Highlights

Recombination-activating genes (RAG)[1] and RAG2 encode endonuclease proteins, which are critical to initiate the molecular processes that lead to lymphocyte receptor formation
Clinical phenotypes of RAG deficiency The recombination activity retained by RAG mutants correlates with the severity of clinical presentation, in that the least recombination activity is associated with the most-severe phenotype
Severe combined immunodeficiency Nonsense mutations in RAG1 or RAG2 abolish the initiation of antigen receptor recombination, which prevents the progression of T- and B-lymphocyte progenitors beyond the DN3 and pre-B-1 stage of development, giving rise to a T-B-natural killer cell (NK)+ severe combined immunodeficiency (SCID) phenotype[1]

Summary

Introduction

Recombination-activating genes (RAG)[1] and RAG2 encode endonuclease proteins, which are critical to initiate the molecular processes that lead to lymphocyte receptor formation. Role of RAG deficiency on B-lymphocyte-mediated clinical features As well as a raised IgE, IgM and IgG autoantibodies have been detected in patients with hypomorphic RAG mutations, including those with Omenn syndrome, and especially those with autoimmune manifestations with combined immunodeficiency or granulomas, against a wide range of auto-antigens[56]. Amongst these autoantibodies are neutralizing anti-cytokine antibodies directed against anti-IFN-α or anti-IFN-ω, which may be precipitated by environmental triggers such as viral infection[28,57]. The very best outcomes may be possible when patients are treated infection-free as newborns using a gene therapy protocol with chemotherapy-free antibody-based conditioning regimens[81,82]

Conclusion

Findings

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