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.

The role of interleukin-18 and interleukin-18 binding protein in K/BxN serum transfer-induced arthritis.

Background: Interleukin-18 is a proinflammatory cytokine, the activity of which is regulated by its natural inhibitor, IL-18 binding protein (IL-18BP). Elevated circulating levels of IL-18 have been observed in patients with systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease (AOSD), two conditions associated with dysregulated innate immune responses. This study examines the expression and function of IL-18 and IL-18BP in K/BxN serum transfer arthritis (STA), a model that is uniquely dependent on innate immune responses. Methods: Naïve and serum transfer-induced arthritis (STA) wild-type (WT) mice were used to examine the articular levels of IL-18 and IL-18BP mRNA by RT-qPCR. The cellular sources of IL-18BP in the joints were determined by using Il18bp-tdTomato reporter knock-in mice. The incidence and severity of arthritis, including mRNA levels of different cytokines, were compared in IL-18BP or IL-18 knock-out (KO) mice and their WT littermates. Results: IL-18 and IL-18BP mRNA levels were significantly increased in arthritic as compared to normal joints. Synovial neutrophils, macrophages, and endothelial cells represented the cellular sources of IL-18BP in arthritic joints, whereas IL-18BP production was limited to endothelial cells in non-inflamed joints. The incidence and severity of arthritis were similar in IL-18BP KO and IL-18 KO compared to their WT littermates. Transcript levels of different inflammatory cytokines were not different in the two KO mouse lines compared to WT mice. Conclusion: Although IL-18 and IL-18BP levels were increased in arthritic joints, our results show that the IL-18/IL-18BP balance is not involved in the regulation of STA.