Type I interferons: crucial participants in disease amplification in autoimmunity

Abstract

A significant body of data implicates the type I interferon (IFN) pathway in the pathogenesis of autoimmune rheumatic diseases. In these disorders, a self-reinforcing cycle of IFN production can contribute to immunopathology through multiple mechanisms. Type I IFN cytokines are pleiotropic in their effects, mediating antiviral and antitumor activities, and possess numerous immunomodulatory functions for both the innate and adaptive immune responses. A key principle of the type I IFN system is rapid induction and amplification of the signaling pathway, which generates a feed-forward loop of IFN production, ensuring that a vigorous antiviral immune response is mounted. Although such feed-forward pathways are highly adaptive when it comes to rapid and effective virus eradication, this amplification can be maladaptive in immune responses directed against host tissues. Such feed-forward loops, however, create special opportunities for therapy.

Figure 1. Steps in the induction of an anti-viral state

1. Endocytosis of viral particles leads to the release of viral nucleic acid into the cytoplasm. 2. Cytoplasmic nucleic acid sensing receptors (such as RIG-I, MDA5 and DAI) bind nucleic acid within the cytoplasm and initiate a signal transduction cascade which results in phosphorylation of IRF3. 3. Phosphorylated IRF3 dimerizes and translocates to the nucleus where it associates with additional transcription factors to induce transcription primarily at the IFNβ locus. 4. IFN-β is produced and secreted from the infected cell. 5. Secreted IFN-β functions in an autocrine and paracrine manner to trigger IFNAR expressed on the infected and neighboring cells. 6. IFNAR signaling leads to the formation of phosphorylated STAT1/STAT2 heterodimers which associate with IRF9 to form the ISGF3 complex. 7. ISGF3 translocates to the nucleus and initiates transcription at ISRE binding sites, inducing transcription of hundreds of ISGs. 8. Expression of ISGs leads to induction of anti-viral state through the expression of direct and indirect inhibitors of viral replication, increases expression of MHC class I molecules on cell surface, enhancing antigen presentation to cytotoxic lymphocytes, and increases sensitivity to cell-death-inducing stimuli. Abbreviations DAI, DNA-dependent activator of interferon regulatory factors; IFNAR, interferon-α receptor; INF-β, interferon β; ISG, IFN-stimulated genes; ISGF3, IFN-stimulated gene factor 3; ISRE, interferon-stimulated response element; IRF, interferon regulatory factor; JAK, Janus kinase; MDA5, melanoma differentiation-associated gene 5; MHC, major histocompatibility complex; PKR, RNA-activated protein kinase; RIG-I, retinoic acid inducible gene I; STAT, signal transducer and activator of transcription; TYK, tyrosine kinase; TRIM, tripartite motif.

Figure 2. The self-amplifying nature of type I IFN production and tissue damage in systemic autoimmunity

1. Recognition of viral nucleic acid in apoptotic debris by pDCs induces rapid production of large quantities of type I IFN. 2. Type I IFN induces self-amplification of the TLR pathway in pDCs and induces an anti-viral state in target cells. 3. Type I IFN influences monocyte differentiation and subsequent activation of dendritic cells, which, 4. process and present self and viral antigens derived from dying cells. 5. Autoreactive CD4 and CD8 T cells are activated by DCs expressing self antigens, and signaling through the type I IFN receptor promotes their survival and enhances the cytotoxic activity of CTLs. 6. CTLs kill uninfected host cells, which express high levels of autoantigens, via the granzyme B pathway. Debris from dying cells is taken up by dendritic cells and presented for recognition by T cells in a self-amplifying loop. 7. Type I IFN also induces the differentiation of autoreactive B cells into plasma cells and promotes antibody production. 8. Autoantibodies can form immune complexes with self molecules in cell debris, which 9. bind Fc receptors and TLRs on pDCs, further amplifying IFN production. Abbreviations BCR, B cell receptor; CTL, cytotoxic T lymphocytes; IFN, interferon; IFNAR, interferon-α receptor; MDA5, melanoma differentiation-associated gene 5; pDC, plasmacytoid dendritic cells; Ro52, Ro/SSA 52 kD; TLR, Toll-like receptors.