Fueling autoimmunity: type I interferon in autoimmune diseases

Abstract

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 interferon imprints unique molecular signatures in a list of autoimmune diseases. Interferon is induced by diverse nucleic acid-containing complexes, which trigger innate immune activation of plasmacytoid dendritic cells. Interferon primes, activates or differentiates various leukocyte populations to promote autoimmunity. Accordingly, interferon signaling is essential for the initiation and/or progression of lupus in several experimental models. However, the heterogeneous nature of systemic lupus erythematosus requires better characterization on how interferon pathways are activated and subsequently promote the advancement of autoimmune diseases. Given the central role of type I interferon, various strategies are devised to target these cytokines or related pathways to curtail the progression of autoimmune diseases.

Figure 1. Human pDCs are activated by nucleic acid-containing complexes to produce type I IFN

SLE ICs containing chromatin or ribonucleoprotein (RNP) are internalized by pDCs via binding to Fc receptor and activating TLR9 or TLR7, respectively, to induce IFN production. Other nucleic acid-containing complexes, such as LL-37 or amyloid fibrils, also activate pDCs to trigger IFN secretion. SLE Neutrophils, which are primed by pDC-produced IFN and stimulated by autoantibodies, undergo NETosis. Nucleic acids-containing NET then prompts IFN production from pDCs.

Figure 2. Induction of type I IFN initiates systemic autoimmunity in vivo

Murine experimental lupus models illustrate that activation of different innate immune pathways induce type I IFN and cause systemic lupus-like autoimmunity.