Theinterferons (IFN)s are a family ofcytokines with potentantiviral,antiproliferative andimmunomodulatory properties.[5][6] IFNs were originally discovered asmolecules that could reduce the ability of a normalvirus to infectcells, a process called viral 'interference'.[7][8] IFNs have been classified into two major types of IFNs,type I andtype II, based on their interactions to a specificcell surface receptor.[6][9] In recent years, a novel class of cytokines with IFN-like activities has been described and designated as type III IFNs (IFN-λ1-3).[10] In humans, there are 13 different IFN-alpha genes, designated as IFN-α1, -α2, - α4, - α5, - α6, - α7, - α8, - α10, - α13, - α14, - α16, - α17 and - α21, and one each of the IFN beta (IFNB), IFN-Epsilon, IFN-Kappa and IFN-Omega genes.[11] The human IFNA gene family shares 70-80%amino acid sequencehomology, and about 35% identity with IFNB.[12] The high degree of amino-acid sequence similarity within the IFNA genes suggests acommon ancestor gene. It seems likely that the IFNAgene cluster has been generated by gene conversion or recent duplication events. There are 12 functional human IFNA gene products. All of these IFN-αproteins exhibit high homology in their primary, secondary, and tertiary structures.[9] IFNA and IFNB are produced by a wide range of cells such asmacrophages,fibroblasts andendothelial cells, butplasmacytoid dendritic cells (pDCs) are considered the main producers of IFNA in response toRNA orDNA viruses or nucleic acid-containing immune complexes.[13]
The type I IFNs bind to theinterferon alpha receptor (IFNAR), which consists of two subunits, IFNAR1 (α-subunit) and IFNAR2 (β-subunit). Two cytoplasmictyrosine kinases provide downstream signaling after type I IFN binds to the IFNAR receptor,Janus kinase 1 (JAK1) andtyrosine kinase 2 (TYK2). The biological effects of IFNs are mediated through the Janus kinase/signal transducer and activator oftranscription (JAK/STAT) pathway.STAT1 andSTAT2 are activated by these tyrosine kinases, and STAT1 and STAT2 mediate the antiviral andinflammatory effects of IFN-α/IFN-β.[14] STAT1 and STAT2 form a complex with IFN-regulatory factor 9 (IRF) forming the transcription factor complex ISGF3,[15] which thentranslocates to thenucleus and binds to IFN-stimulatedresponse elements (ISREs) in the promoters of IFN-regulated genes (IRGs). In addition, canonical type I IFN signalling may activate STAT1homodimers that bind to interferon-gamma-activating factor (GAF), which also translocates to the nucleus and activatestranscription of IFN-stimulated genes.[16]
The virus-inducedexpression of IFNA/IFNB genes is primarily controlled at the gene transcription level, by theinterferon regulatory factors (IRFs) and IFN-stimulated genes.[17] Viruses andimmune complexes (ICs) containingnucleic acids can access intracellularTLRs (TLR3,TLR7/8 andTLR9) after binding toFc receptors and induce IFN-α production by activation of the IRFs.[17][18] Signaling through TLRs can broadly be categorized into two pathways theMyD88 and the Trip-dependent pathway. All TLRs except TLR3 signal through the MyD88-dependent pathway. Only TLR3 and TLR4 signal through the TRIF-dependent pathway.[18] The MyD88-dependent pathway recruits several effector molecules such asIRAK1/4 andtumor necrosis factor receptor-associated factor 6 (TRAF6).[19] These molecules are linked to at least three major downstream pathways: theNF-κB pathway, the pathway involvingmitogen-activated protein kinases (MAPKs) and IRF pathways, depending on the stimulus and the responding cell types activation of these pathways results in transcription of various cytokines including IFN-α/β.[18] Signaling viacytosolic viral sensors can also activate similar pathways and result in transcription of IFN-α/β.[20]
Emerging evidence suggests that abnormal IFN production contributes toimmune dysfunction and mediates tissue inflammation and organ damage in a number ofautoimmune diseases such assystemic lupus erythematosus (SLE),rheumatoid arthritis (RA),idiopathic inflammatory myopathies (IIM),Sjogren's syndrome (SS) andmultiple sclerosis (MS). Increasedserum IFN-α and IFN-α-induced gene expression are frequently observed in patients with SLE, and many of SLE clinical manifestations such as fever, fatigue andleukopenia are similar to those observed in patients withinfluenza or as a side effect of IFN-therapy, suggesting that type I IFNs are important in the molecularpathogenesis of SLE.[21][22][23][24] A heritable pattern of high circulating type I IFN has been observed in SLE families, suggesting that high IFN is a heritable risk factor for SLE.[25] Furthermore, patients with non-autoimmune diseases treated with IFN-α can develop a “lupus-like” syndrome, includingantinuclear antibodies (ANA) and anti-double stranded DNA (ds-DNA) which usually resolve after IFN-α therapy discontinuation.[24] As noted above, IRFs are proteins which regulate transcription of IFNs.Genetic variations in the IRF genes have been associated with risk of developing SLE, and these genetic variations have also been linked to increased IFN-α production and with SLE-associatedautoantibody formation.[26][27]Several observations suggest that type I IFN is involved in the pathogenesis ofinflammatory myopathies. Patients withdermatomyositis andpolymyositis have increased IFN serum levels which in some studies correlate with disease activity or myositis-specific autoantibodies.[28][29][30][31] Also, studies have suggested a genetic or heritable component to the high type I IFN observed in myositis patients, similar to SLE.[32][33]Multiple sclerosis (MS) is a disorder of thecentral nervous system characterized by inflammation,demyelination andneurodegeneration with presumed autoimmune origin. Whereas type I IFNs are thought to induce some autoimmune conditions such as SLE as noted above, MS is effectively treated by administering recombinant human IFN-β. MS patients have lower levels of circulating type I interferon compared to patients with other autoimmune diseases.[34][35] However, a number of patients withrelapsing-remitting MS have a high IFN signature as well as more clinical and MRI attacks before therapy and these patients often do not response to IFN-β therapy.[36]Neuromyelitis optica, another autoimmune disorder similar to MS which does not respond to IFN therapy, is associated with higher baseline circulating IFN levels.[37]
Several IFN-blocking strategies are currently being evaluated inclinical trials. For instance, a phase I clinical trial of the anti-IFN-αmonoclonal antibody MEDI-545 in SLE patients suggested possible disease activity improvement in SLE patients.[38] Another phase I clinical trial has reported a dose-dependent inhibition of IFN-α/β-inducible genes in bothperipheral blood andskin biopsies in SLE patients treated with anti-IFN monoclonal antibody therapy.[39] Also, some studies suggest that type I IFN in circulation may be useful to predict response toimmunotherapy in RA.[40][41]
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^Olopade OI, Bohlander SK, Pomykala H, Maltepe E, Van Melle E, Le Beau MM, et al. (October 1992). "Mapping of the shortest region of overlap of deletions of the short arm of chromosome 9 associated with human neoplasia".Genomics.14 (2):437–443.doi:10.1016/S0888-7543(05)80238-1.PMID1385305.
^Uzé G, Schreiber G, Piehler J, Pellegrini S (2007). "The Receptor of the Type I Interferon Family".Interferon: The 50th Anniversary. Current Topics in Microbiology and Immunology. Vol. 316. pp. 71–95.doi:10.1007/978-3-540-71329-6_5.ISBN978-3-540-71328-9.PMID17969444.
^Díaz MO, Pomykala HM, Bohlander SK, Maltepe E, Malik K, Brownstein B, et al. (August 1994). "Structure of the human type-I interferon gene cluster determined from a YAC clone contig".Genomics.22 (3):540–552.doi:10.1006/geno.1994.1427.PMID8001965.
^Rönnblom L, Eloranta ML, Alm GV (December 2003). "Role of natural interferon-alpha producing cells (plasmacytoid dendritic cells) in autoimmunity".Autoimmunity.36 (8):463–472.doi:10.1080/08916930310001602128.PMID14984023.S2CID84646255.
^Feng X, Wu H, Grossman JM, Hanvivadhanakul P, FitzGerald JD, Park GS, et al. (September 2006). "Association of increased interferon-inducible gene expression with disease activity and lupus nephritis in patients with systemic lupus erythematosus".Arthritis and Rheumatism.54 (9):2951–2962.doi:10.1002/art.22044.PMID16947629.
^Hertzog PJ, Wright A, Harris G, Linnane AW, Mackay IR (January 1991). "Intermittent interferonemia and interferon responses in multiple sclerosis".Clinical Immunology and Immunopathology.58 (1):18–32.doi:10.1016/0090-1229(91)90145-z.PMID1701372.
^Wallace DJ, Petri M, Olsen N, Kirou K, Dennis G, Yao Y, et al. (2007). "MEDI-545, an anti-interferon alpha monoclonal antibody, shows evidence of clinical activity in systemic lupus erythematosus".Arthritis Rheum.56:S526 –S527.
^Yao Y, Richman L, Higgs BW, Morehouse CA, de los Reyes M, Brohawn P, et al. (June 2009). "Neutralization of interferon-alpha/beta-inducible genes and downstream effect in a phase I trial of an anti-interferon-alpha monoclonal antibody in systemic lupus erythematosus".Arthritis and Rheumatism.60 (6):1785–1796.doi:10.1002/art.24557.PMID19479852.
^Thurlings RM, Boumans M, Tekstra J, van Roon JA, Vos K, van Westing DM, et al. (December 2010). "Relationship between the type I interferon signature and the response to rituximab in rheumatoid arthritis patients".Arthritis and Rheumatism.62 (12):3607–3614.doi:10.1002/art.27702.PMID20722020.
