Interferon alpha-1
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Interferon alpha 1
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Interferon alpha-1 is a protein that in humans is encoded by the IFNA1 gene.[3][4]
Leukocyte interferon is produced predominantly by B lymphocytes. Immune interferon (IFN-gamma; MIM 147570) is produced by mitogen- or antigen-stimulated T lymphocytes.[supplied by OMIM][4]
The type I interferon gene family
The
immunomodulatory properties.[5][6] IFNs were originally discovered as molecules that could reduce the ability of a normal virus to infect cells, a process called viral 'interference'.[7][8]
IFNs have been classified into two major types of IFNs,
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 sequence homology, and about 35% identity with IFNB.[12] The high degree of amino-acid sequence similarity within the IFNA genes suggests a common ancestor gene. It seems likely that the IFNA gene cluster has been generated by gene conversion or recent duplication events.
There are 12 functional human IFNA gene products. All of these IFN-α proteins exhibit high homology in their primary, secondary, and tertiary structures.[9] IFNA and IFNB are produced by a wide range of cells such as macrophages, fibroblasts and endothelial cells, but plasmacytoid dendritic cells (pDCs) are considered the main producers of IFNA in response to RNA or DNA viruses or nucleic acid-containing immune complexes.[13]
Type I IFN Signaling
The type I IFNs bind to the
homodimers that bind to interferon-gamma-activating factor (GAF), which also translocates to the nucleus and activates transcription of IFN-stimulated genes.[16]
Inducers of type I IFN
The virus-induced
TLR9) after binding to Fc receptors and induce IFN-α production by activation of the IRFs.[17][18] Signaling through TLRs can broadly be categorized into two pathways the MyD88 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 as IRAK1/4 and tumor necrosis factor receptor-associated factor 6 (TRAF6).[19] These molecules are linked to at least three major downstream pathways: the NF-κB pathway, the pathway involving mitogen-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 via cytosolic viral sensors can also activate similar pathways and result in transcription of IFN-α/β.[20]
Disease relevance
Emerging evidence suggests that abnormal IFN production contributes to
idiopathic inflammatory myopathies (IIM), Sjogren's syndrome (SS) and multiple sclerosis
(MS).
Increased antinuclear 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-associated autoantibody formation.[26][27]
Several observations suggest that type I IFN is involved in the pathogenesis of inflammatory myopathies. Patients with dermatomyositis and polymyositis 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 the Neuromyelitis optica, another autoimmune disorder similar to MS which does not respond to IFN therapy, is associated with higher baseline circulating IFN levels.[37]
Current and future therapeutic options
Several IFN-blocking strategies are currently being evaluated in clinical trials. For instance, a phase I clinical trial of the anti-IFN-α monoclonal 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 both peripheral blood and skin 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 to immunotherapy in RA.[40][41]
Notes
Wikidata Q36338717 . |
References
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