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Review
. 2011 Nov;116(4):227-37.
doi: 10.3109/03009734.2011.624649.

The type I interferon system in the etiopathogenesis of autoimmune diseases

Lars Rönnblom  1
Affiliations
Review

The type I interferon system in the etiopathogenesis of autoimmune diseases

Lars Rönnblom. Ups J Med Sci. 2011 Nov.

Abstract

Many patients with systemic autoimmune diseases have signs of a continuous production of type I interferon (IFN) and display an increased expression of IFN-α-regulated genes. The reason for the on-going IFN-α synthesis in these patients seems to be an activation of plasmacytoid dendritic cells (pDCs) by immune complexes (ICs), consisting of autoantibodies in combination with DNA or RNA-containing autoantigens. Such interferogenic ICs are internalized via the FcγRIIa expressed on pDCs, reach the endosome, and stimulate Toll-like receptor (TLR)-7 or -9, which subsequently leads to IFN-α gene transcription. Variants of genes involved in both the IFN-α synthesis and response have been linked to an increased risk to develop systemic lupus erythematosus (SLE) and other autoimmune diseases. Among these autoimmunity risk genes are IFN regulatory factor 5 (IRF5), which is involved in TLR signaling, and the signal transducer and activator of transcription 4 (STAT4) that interacts with the type I IFN receptor. Several other gene variants in the IFN signaling pathway also confer an increased risk to develop an autoimmune disease. The observations that IFN-α therapy can induce autoimmunity and that many autoimmune conditions have an on-going type I IFN production suggest that the type I IFN system has a pivotal role in the etiopathogenesis of these diseases. Possible mechanisms behind the dysregulated type IFNsystem in autoimmune diseases and how the IFN-α produced can contribute to the development of an autoimmune process will be reviewed.

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Figures

Figure 1.
Figure 1.
Genes connected to the type I interferon production and response in pDC. Left: Genes involved in the response to viral RNA/DNA by the cytosolic pattern recognition receptors leading to transcription of type I IFN genes. Via NF-kB activation, genes for several inflammatory cytokines are also activated. TNAIP3 is involved in the down-regulation of a pro-inflammatory response. Middle: Induction of IFN production by interferogenic DNA/RNA-containing immune complexes (IC) as outlined in the text. TLR3 is expressed by many different cell types and can be activated by viral RNA, while bacterial LPS is recognized via TLR4 that signals via two different pathways. Right: IFN signaling via the type I IFN receptor (IFNAR). The interferon-stimulated response elements (ISREs) induce expression of several hundreds of IFN-induced genes, including IRF5 and IRF7. The pDC response is modulated by several chemokines. Variants of genes in red circles are associated to an increased risk for SLE.
Figure 2.
Figure 2.
The role of the type I interferon system in the etiopathogenesis of systemic autoimmune diseases. A viral infection induces IFN-α production in pDC and the release of autoantigens from dying cells. The produced IFN-α activates both the innate and adaptive immune system as described in the text. In individuals with a genetic set-up that causes a strong IFN-α production and/or a marked IFN-α response, tolerance is broken, and antibodies against nucleic acid-containing autoantigens are produced. These antibodies together with the autoantigens form interferogenic ICs that stimulate the pDC to IFN-α synthesis and the B cells to increased autoantibody production, which causes a vicious circle with a continuous IFN-α production and an on-going autoimmune reaction. NK cells promote the IFN-α production and activated monocytes down-regulate the NK cells, but this latter function seems to be deficient in lupus. Figure modified from (101). (DC = dendritic cell; IC = immune complex; IFN = interferon; Mo = monocyte; NK = natural killer; pDC = plasmacytoid dendritic cell; TCR = T cell receptor).
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