Mechanisms of immune tolerance breakdown in inborn errors of immunity

Autoimmunity and immunodeficiency have long been considered as two extreme opposites of the immune response spectrum. Accumulating evidence suggests that these conditions may coexist in the same patient. Up to 25% of patients with inborn errors of immunity (IEI) also present immunodysregulatory features. Different mechanisms may explain the association between immune dysregulation and immunodeficiency. In particular, this association may be due to alterations in genes that are crucial for both immune response and tolerance toward the self. The inability of the immune system to clear infections may also predispose individuals to the development of chronic inflammation that may cause autoimmunity through different mechanisms. The understanding of the mechanisms underlying immune dysregulation in IEI has paved the way for the development of targeted treatments. In this chapter, we will summarize the mechanisms of immune tolerance breakdown and the targeted therapeutic approaches to immunodysregulation in IEI.