Physical Address
304 North Cardinal St.
Dorchester Center, MA 02124
The interferon (IFN) system consists of three different families of proteins (i.e., type I, type II and type III IFNs), and their cell surface receptor complexes. IFNs constitute an essential part of our innate and adaptive immune system, as they have evolved to protect the body from viral infections and other pathogens. The initial observation that patients with systemic lupus erythematosus (SLE) have increased serum levels of IFN occurred four decades ago. Since then, numerous studies indicate a central role of IFNs in a number of other chronic inflammatory and autoimmune diseases. The association between IFNs and SLE pathogenesis is supported by the development of lupus-like symptoms during IFN-α therapy, the presence of endogenous IFN inducers in SLE patients, and gain-of-function gene variants in the IFN pathway that are linked to risk of SLE. High IFN levels in blood are also associated with SLE severity, autoantibody formation, and organ involvement. Therapies directly or indirectly targeting IFNs in SLE are currently at different phases of preclinical and clinical trials. Approximately half of SLE patients have persistently elevated type I IFN levels, and stratifying patients by this molecular characteristic may allow for more personalized therapy.
In this chapter, we will provide a general description of the biology of the IFN system, its regulatory mechanisms, and their role in SLE.
The interferons (IFNs) are a large group of functionally related cytokines that mediate host defense against microbes, especially viruses. Since their initial discovery several decades ago, and the reports of increased type I IFN levels in patients with SLE, additional essential roles in other autoimmune diseases, cancer, inflammation, and monogenic disorders have been identified. IFNs are divided into three families (I–III), based on the cell surface receptor complex they bind to ( Table 21.1 ).
IFN family | Genes | Producing cells | Receptors |
---|---|---|---|
Type I: IFN-α |
IFNA1, 2, 4, 5, 6, 7, 8, 10, 13, 14, 16, 17, 21 | pDCs, monocytes/macrophages, fibroblasts, keratinocytes | IFNAR-1 and IFNAR-2 |
IFN-β | IFNB1 | ||
IFN-δ, IFN-ɛ, IFN-κ, IFN-τ, IFN-ζ | IFNK (IFNE1) | ||
IFN-ω | IFNW1 | ||
Type II: IFN-γ |
IFNG | Activated T cells, NK and NKT cells | IFNGR-1 and IFNGR-2 |
Type III: IFN-λ1, IFN-λ2, IFN-λ3, IFN-λ4 |
IFNL1, 2, 3, 4 | Dendritic cells, epithelial cells | IFN-λR1 IL-10R2 |
Type I IFNs are the largest family and include IFN-α, a 13-member multigene family, as well as the IFN-β, IFN-δ, IFN-ɛ, IFN-κ, IFN-τ, IFN-ω, and IFN-ζ classes. Type I IFNs bind to a shared cell surface receptor, the IFN-α/β or type I IFN receptor (IFNAR). IFNAR is a heterodimeric transmembrane receptor composed of two subunits, IFNAR1 and IFNAR2. Interestingly, IFN-α and IFN-β induce different conformational changes in the receptor, which translates into differential signaling depending on which of the two cytokines binds to it. IFNAR mediates the canonical type I IFN downstream signals through the associated proteins Janus Kinase 1 (JAK1) and nonreceptor tyrosine kinase 2 (TYK2). Once JAK1 and TYK2 are activated, these proteins phosphorylate and allow translocation to the nucleus of the interferon-stimulated gene factor 3 (ISGF3) complex, which leads to activation of IFN-stimulated genes (ISGs), including classic antiviral genes. ISGF3 is composed of the signal transducer and activator of transcription (STAT) 1, STAT2, and IFN regulatory factor (IRF)-9. Nonetheless, other STATs and transcription factors such as mitogen-activated protein kinase, nuclear factor-κB (NF-κB) and protein kinase B, may also be involved in IFNAR signaling, in a cell type and context-dependent manner.
IFN-γ, the only molecule in the type II IFN family, binds to the IFN-γ receptor (IFNGR). IFNGR is a heterodimeric transmembrane receptor consisting of two subunits, IFNGR-1 and -2. Downstream effectors of IFNGR include STAT1 and STAT3, which in turn result in the induction of proinflammatory cytokines, apoptotic factors, and to a lesser degree, antiinflammatory cytokines such as interleukin (IL)-10.
Type III IFNs are the most recently described of the IFN families, comprising IFNλ-1 (IL-29), IFNλ-2 (IL-28A), IFNλ-3 (IL-28B), and IFNλ-4. Type III IFNs bind to the IFN-λ receptor, which consists of a high-affinity (IFN-λR1) chain and a low-affinity (IL-10R2) chain. Similar to type I IFNs, activation of the IFN-λ receptor leads to downstream events that allow recruitment of IRF-9 and increased transcription of ISGs.
While most nucleated cells can secrete type I IFNs in response to the activation of pattern recognition receptors (PRR) by microbial products, plasmacytoid dendritic cells (pDCs) are considered the main source of IFN-α. PRRs include membrane and endosomal Toll-like receptors (TLRs), as well as the cytosolic sensors retinoic acid-induced gene I (RIG-I), melanoma differentiation factor 5 (MDA5), and cyclic GMP-AMP synthase (cGAS). Endosomal TLRs, such as TLR3, TLR7, TLR8, and TLR9, recognize exogenous or endogenous nucleic acids from endocytosed viruses or immune complex (ICs), respectively. In pDCs, the activation of TLR7, TLR8 or TLR9, allows recruitment of the myeloid differentiation factor 88, which results in downstream phosphorylation of IRF-5 and IRF-7, ultimately leading to increased IFN-α production ( Fig. 21.1 ). In contrast, ligand binding to TLR3 (and TLR4) leads to the activation of IRF-3 in phagocytes and dendritic cells, with subsequent increased production of IFN-β by these cells. Additionally, estrogen may positively regulate the production of type I IFNs by pDCs through activation of the TLR7 pathway.
An additional mechanism of type I IFN production involves the cytosolic nucleic acid sensors such as RIG-I and cGAS, and their adaptor proteins mitochondrial antiviral-signaling protein (MAVS) and stimulator of interferon genes, respectively. These proteins are phosphorylated by the TANK Binding Kinase 1 (TBK1) and the IκB kinase, leading to recruitment and phosphorylation/activation of IRF-3. These pathways primarily stimulate the transcription of IFN-β in dendritic cells, epithelial cells, and macrophages. The interferon-induced with helicase domain 1 (IFIH1) gene, which encodes the RNA sensor MDA5, also promotes IRF-3 and IRF-7 phosphorylation, the activating transcription of antiviral genes and type I IFN production.
Activation of tumor necrosis factor (TNF)-associated pathways can also increase IFN-β production by an IRF1-dependent induction of an autocrine loop, stimulating a sustained expression of proinflammatory genes and ISGs. In macrophages, this synergy can prime these cells for increased responses to subsequent challenges. Similarly, type I IFN exerts positive feedback by enhancing type I IFN production in dendritic cells via upregulation of IRF-7 and TLR7 expression.
Neutrophil extracellular traps (NETs) in patients with SLE contain self-nucleic acids in complex with RNA- or DNA-binding proteins, such as high mobility group box chromosomal protein 1 (HMGB1) and LL-37. These NETs can activate pDCs to produce high levels of IFN-α by a TLR9-dependent mechanism. Moreover, neutrophils have also been shown to produce IFN-α in response to circulating chromatin, in a TLR9-independent manner.
IFN-κ is constitutively synthesized in keratinocytes, and its expression is upregulated by UV light exposure. Additionally, IFN-κ can prime keratinocytes for the production of proinflammatory cytokines like IL-6.
Type I IFNs are also produced under physiological conditions. For instance, IFN-β is synthesized by macrophage progenitors in response to the macrophage colony-stimulating factor, and the receptor activator of nuclear factor kappa-B ligand during osteoclast differentiation. In both cases, IFN-β has antiproliferative effects. In contrast to other type I IFNs, IFN-ɛ is constitutively expressed by epithelial cells of the female reproductive tract, where it plays a key role in protecting against viral and bacterial infections. Instead of being induced by PRRs, IFN-ɛ expression is upregulated by estrogen and downregulated by progesterone.
Type I IFN production is tightly controlled at multiple stages. This ensures a robust and temporally appropriate response to infections, while limiting the toxicity to the host by preventing tissue damage and autoimmunity. Hence, it is not surprising that there is a complex network of negative regulators of IFN production and signaling that help fine-tuning the immune response. For instance, some mediators of the inflammatory response inhibit type I IFN production, including reactive oxygen species, TNF-α and prostaglandin E2. C1q, a component of the classical complement pathway, is also a negative regulator of type I IFN production, which may at least partially explain the exceedingly high prevalence of SLE in patients with homozygous deficiency of C1q.
Several IFN inducible proteins provide negative feedback by modifying PRR function, IFN receptors, and their signaling pathways. The ring finger protein 125 (RNF 125) stimulates ubiquitin ligation to RIG-I, MDA5, and MAVS, which targets these proteins for proteasomal degradation. IFN-induced protein also suppresses RIG-I by ubiquitin-mediated and ubiquitin-independent mechanisms. SMAD 2/3, signal transducers for the transforming growth factor-β receptor superfamily, have also been shown to inhibit IRF3 and STAT1, therefore affecting type I IFN production and signaling. The protein kinase D2, another IFN inducible protein, and TYK2 stimulate IFNAR1 ubiquitination and subsequent degradation. In contrast, USP18 binds to IFNAR2, displacing JAK1 and modifying the receptor-ligand binding properties.
Multiple protein tyrosine phosphatases negatively regulate the type I IFN-induced JAK-STAT signaling pathway, including Src homology phosphatase (SHP) 1, SHP2, protein phosphatase 1 B (PTPN1), and the T cell protein tyrosine phosphatase (PTPN2). Additionally, the suppressor of cytokine signaling (SOCS) proteins inhibits the tyrosine kinase function of JAKs.
IFN-γ is mainly produced by NK cells, CD8+ and CD+4 T cells, and in a lesser degree by NKT cells, B cells, and professional antigen-presenting cells. IFN-γ production is stimulated by exposure to intracellular bacteria, parasites, and certain viruses. Recent evidence suggests that there may be a role of IFN-γ in SLE pathogenesis.
Type III IFNs are also produced by many different cell types, in particular pDCs, myeloid dendritic cells (mDCs), monocytes, and epithelial cells. Despite using different receptors, both type I and III IFNs recruit IRF-9 and ultimately induce the transcription of ISGs (previously described in this chapter).
Become a Clinical Tree membership for Full access and enjoy Unlimited articles
If you are a member. Log in here