Figure 4. The interaction of genetic, immunological and environmental factors in determining the phenotype of human RAG deficiency.

The recombination-activating gene (RAG) genotype determines the levels of recombination activity of the mutant RAG proteins. Mechanisms contributing to immune deficiency are shown on the left (blue) and those associated with autoimmunity are shown on the right (red), for both T cell- and B cell-dependent immune responses. RAG mutations with higher residual recombination activity are more likely to result in immune dysregulation. Ultimately, exposure to environmental triggers affects the immune deficiency and immune dysregulation status of the patient, thereby determining the clinical phenotype. AIRE, autoimmune regulator; BAFF, B cell-activating factor; D, diversity; EBV, Epstein–Barr virus; J, joining; T_Reg cell, regulatory T cell; V, variable.