Fueling autoimmunity: type I interferon in autoimmune diseases

Abstract

Summary In recent years, active research using genomic, cellular and animal modeling approaches has revealed the fundamental forces driving the development of autoimmune diseases. Type I IFN (IFN) imprints unique molecular signatures in a list of autoimmune diseases. IFN is induced by diverse nucleic acid-containing complexes, which trigger innate immune activation of plasmacytoid dendritic cells (pDCs). IFN primes, activates or differentiates various leukocyte populations to promote autoimmunity. Accordingly, IFN signaling is essential for the initiation and/or progression of lupus in several experimental models. However, the heterogeneous nature of SLE requires better characterization on how IFN pathways are activated and subsequently promote the advancement of autoimmune diseases. Given the central role of type I IFN, various strategies are devised to target these cytokines or related pathways to curtail the progression of autoimmune diseases.

TLRs and interferons: a central paradigm in autoimmunity

“…It is now widely accepted that IFN-I are a driving pathogenic force in the majority of SLE patients based on substantial clinical, epidemiologic, and genetic data (reviewed in [1•,2,3,4]) as well as direct evidence from animal models using IFN-I receptor-deficient lupus mice or anti-IFN-α/βR antibody treatment [5,6•]. Additional studies in these models have also documented: (a) the existence of IFN-I-independent lupus in MRL- Fas lpr mice due to background genes and not Fas deficiency [7,8]; (b) a requirement for IFN-I in mouse lupus models despite the absence of elevated IFN-α or interferon-stimulated genes (ISGs, so called ‘IFN-I signature’) [5], consistent with the recent finding that IFN-I expression even at very low concentrations modulates immune homeostasis by affecting tonic signaling [9]; (c) IFN-α induction of clinically-significant lupus required genetic susceptibility [10], which could explain the infrequent occurrence of lupus in patients treated with high dose IFN-I; and (d) inhibition of lupus was most effective when IFN-I signaling was blocked in early disease stages, implying IFN-I is mainly important at this innate stage, but not after the pathogenic adaptive autoimmune response has been established [6•].…”

Pivotal Functions of Plasmacytoid Dendritic Cells in Systemic Autoimmune Pathogenesis

“…The discoveries of predominant involvement of type I IFN and nucleic acid sensing mechanisms have driven the development of therapies targeting IFNα/β or TLRs, many of which are currently under clinical evaluation [160,161]. Needless to say, the success of new therapies relies on a deep understanding of the participation of specific cellular and molecular pathways in the disease progression.…”

A Rare Case of Aicardi-Goutières Syndrome Who Showed a Positive Evolution after Being Treated with Growth Hormone, High Doses of Melatonin and Neurorehabilitation

“…Type 1 interferons regulate the transcription of a number of genes belonging to the immune system, by multiple and different signaling pathways (JAK/STATS, MAPK p38, Pi3K/Akt) [40]. Therefore it is logic that the existence of interferon signature has been linked to the development of a number of autoinmune diseases, such as systemic lupus erythematosus, Sjögren's syndrome, myositis, psoriasis, systemic sclerosis, rheumatoid arthritis and even it has been considered as a risk factor for developing type I diabetes in children with a genetic predisposition for this disease [41][42][43].…”