Table 2. Mechanisms of autoimmunity in RAG deficiency.

Lymphocyte population	Mechanism of autoimmunity
T-lymphocyte receptor development	Restriction in T cell receptor (TCR) repertoire
	Reduction in TCRβ diversity
	Distorted use of V, D, and J gene segments
	Restriction in CDR3 length diversity
	Reduction in VDJ junctional diversity
	Bias in TCRα use towards more proximal TRAV/TRAJ associations
	Enhanced use of hydrophobic amino acids in the CDR3 region
T-lymphocytes – central tolerance	Impaired T-lymphocyte development leading to disordered thymic architecture
	Impaired positive and negative thymocyte selection
	Failure of apoptosis of autoreactive T-lymphocytes due to diminished Autoimmune Regulator (AIRE) expression
T-lymphocytes – peripheral tolerance	Diminished regulatory T-lymphocyte numbers
	Impaired regulatory T-lymphocyte function
B-lymphocyte receptor development	Distorted use of V, D, and J gene segments
	Reduction in antigen receptor diversity
	B-lymphocyte-activating factor (BAFF)-associated survival of immature auto-reactive B-lymphocytes
	Production of auto-antibodies
	Production of neutralizing anti-cytokine antibodies
Environmental factors	Viral-driven clonal T-lymphocyte expansion
	Viral-driven clonal T-lymphocyte anti-cytokine antibody production
	Intestinal microbiota-driven expansion of gut-trophic T-lymphocytes