Primary immune deficiencies have been traditionally defined based on increased susceptibility to recurrent and/or severe infections. However, immune dysregulation, manifesting with autoimmunity or hyperinflammatory disease, has emerged as a common feature. This is especially the case in patients affected with combined immune deficiency (CID), a group of disorders caused by genetic defects that impair, but do not completely abolish T cell function. Hypomorphic mutations in the Recombination Activating Genes RAG1and RAG2represent the prototype of the broad spectrum of clinical and immunological phenotypes associated with CID. The study of patients with RAG deficiency and with other forms of CID has disclosed distinct abnormalities in central and peripheral T and B cell tolerance as the key mechanisms involved in immune dysregulation. Understanding the pathophysiology of autoimmunity and hyperinflammation in these disorders may also permit more targeted therapeutic interventions.

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