Signaling pathways regulating RAG expression in B lymphocytes

Development of B-cell lymphopoiesis is dependent on the presence of recombination activating genes RAG1 and RAG2 enzymes. They control the rearrangements of immunoglobulin variable, diversity and joining region segments, and allow progression of the cellular maturation. RAG1 and RAG2 are successively up- and down-regulated at each B-cell stage to progressively generate a B-cell receptor for which unforeseeable antigenic specificity results from a stochastic process. Therefore, in autoreactive immature B cells, new round of RAG re-expression can be observed to eliminate self-reactivity. In some circumstances, RAG up-regulation can also be found in peripheral mature B lymphocytes, specifically in autoimmune diseases. It is therefore of utmost importance to unravel signaling pathways that trigger RAG induction in normal and pathological conditions. Therapeutic modulation of cytokines or intracellular contacts involved in RAG expression might restrict the development of inappropriate autoimmune repertoire.