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Review
. 2018 Aug;38(6):646-655.
doi: 10.1007/s10875-018-0537-4. Epub 2018 Jul 25.

RAG Deficiency: Two Genes, Many Diseases

Ottavia M Delmonte  1 , Catharina Schuetz  2 , Luigi D Notarangelo  3
Affiliations
Review

RAG Deficiency: Two Genes, Many Diseases

Ottavia M Delmonte et al. J Clin Immunol. 2018 Aug.

Abstract

Purpose: To review the clinical and laboratory spectrum of RAG gene defects in humans, and discuss the mechanisms underlying phenotypic heterogeneity, the basis of immune dysregulation, and the current and perspective treatment modalities.

Methods: Literature review and analysis of medical records RESULTS: RAG gene defects in humans are associated with a surprisingly broad spectrum of clinical and immunological phenotypes. Correlation between in vitro recombination activity of the mutant RAG proteins and the clinical phenotype has been observed. Altered T and B cell development in this disease is associated with defects of immune tolerance. Hematopoietic cell transplantation is the treatment of choice for the most severe forms of the disease, but a high rate of graft failure has been observed.

Conclusions: Phenotypic heterogeneity of RAG gene defects in humans may represent a diagnostic challenge. There is a need to improve treatment for severe, early-onset forms of the disease. Optimal treatment modalities for patients with delayed-onset disease presenting with autoimmunity and/or inflammation remain to be defined.

Keywords: Recombinase-activating genes; autoimmunity; hematopoietic stem cell transplantation; immunodeficiency; immunological tolerance.

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Conflict of interest statement

Conflict of Interest The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Location of granulomas in 68 patients with combined immune deficiency with granulomas and/or autoimmunity (CID-G/AI)
Fig. 2
Fig. 2
Absolute count of lymphocyte subsets in patients with RAG gene defects presenting as combined immune deficiency with granulomas and/or autoimmunity (CID-G/AI), atypical SCID (AS), Omenn syndrome (OS), and severe combined immune deficiency (SCID). Shown are mean values ± SEM
Fig. 3
Fig. 3
Immunoglobulin serum levels in patients with RAG gene defects presenting as combined immune deficiency with granulomas and/or autoimmunity (CID-G/AI, n = 44), atypical SCID (AS, n = 49), Omenn syndrome (OS, n = 32), and severe combined immune deficiency (SCID, n = 82). Shown are mean values ± SEM
Fig. 4
Fig. 4
Recombination activity of mutant RAG proteins in patients with combined immune deficiency with granulomas and/or autoimmunity (CID-G/AI; n = 44), atypical SCID (AS, n = 44), Omenn syndrome (OS, n = 103), and severe combined immune deficiency (SCID, n = 68). Shown are mean values (as percentage of wild-type RAG protein) with 95% confidence interval (CI). In each patient, recombination activity was expressed as mean in vitro activity level of the two mutant alleles
See this image and copyright information in PMC

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