Genetic and epigenetic dysregulation of innate immune mechanisms in autoinflammatory diseases

Dysregulation and hyperactivation of innate immune responses can lead to the onset of systemic autoinflammatory diseases. Monogenic autoinflammatory diseases are caused by inborn genetic errors and based on molecular mechanisms at play, can be divided into inflammasomopathies, interferonopathies, relopathies, protein misfolding, and endogenous antagonist deficiencies. On the other hand, more common autoinflammatory diseases are multifactorial, with both genetic and non-genetic factors playing an important role. During the last decade, long-term memory characteristics of innate immune responses have been described (also called trained immunity) that in physiological conditions provide enhanced host protection from pathogenic re-infection. However, if dysregulated, induction of trained immunity can become maladaptive, perpetuating chronic inflammatory activation. Here, we describe the mechanisms of genetic and epigenetic dysregulation of the innate immune system and maladaptive trained immunity that leads to the onset and perpetuation of the most common and recently described systemic autoinflammatory diseases. Dysregulation and hyperactivation of innate immune responses can lead to the onset of systemic autoinflammatory diseases, caused by inborn genetic errors alone, or in combination with non-genetic factors. Innate immune memory (trained immunity) is physiologically beneficial, but can become maladaptive, perpetuating chronic inflammatory activation. Here, we describe the mechanisms of genetic and epigenetic dysregulation of the innate immune system and maladaptive trained immunity leading to the onset of systemic autoinflammatory diseases. image