Interferons

Interferon was first described in 1957 by A. Isaacs and J. Lindenmann and was considered an antiviral substance. The mechanism by which interferon acts against viruses is by stimulating the production of cytokines and the upregulation of antiviral effector proteins.

Interferon (short form: IFN) is a group of signaling proteins that are part of the immune response to viral infections as well as to some other diseases, including certain cancers and autoimmune diseases. Interferons are produced by various cells in the body, particularly in response to the presence of pathogens such as viruses. When interferons bind to their specific receptors on target cells, they trigger intracellular signaling pathways that lead to the activation of genes that help to establish an antiviral state, enhance the immune response and regulate other aspects of the immune system.

A distinction is made between:

Type I interferons:

• Interferon-alfa (formerly known as leukocyte interferons; this is a group of subtypes consisting of a total of 13 different subtypes (IFN-α1 to IFN-α13). These subtypes can be produced in different cells and tissues and have similar but also different biological activities.
• Interferon-beta (fibroblast interferon (IFN-β): This is a single type of interferon produced primarily by fibroblastic cells and certain other cell types. IFN-β has an important role in the immune response and is often used in the treatment of multiple sclerosis.
• Interferon-kappa (IFN-κ): IFN-κ is expressed in certain immune cells, especially in keratinocytes of the skin.
• Interferon-omega (IFN-ω): IFN-ω is a type I interferon that is mainly produced by leukocytes and plays a role in antiviral immunity.
• Interferon-tau (IFN-τ): This interferon is mainly produced by the placenta of cattle and other animals and has an important role in early pregnancy and the immune response during pregnancy.

Type II interferon:

• Interferon-gamma (immune interferon)

Type III interferon:

• IFN-lambda: Interferon λ (IFN-λ) is crucial for viral defense at mucosal surfaces and stimulates immunomodulatory signals acting on epithelial cells and few other cell types due to restricted IFN-λ receptor expression (Wallace JW et al. 2021).

The term type II interferon was introduced for IFN-gamma to distinguish it from the acid-stable type I interferons. The interferons were discovered due to their ability to interfere with virus replication. Later, the antiproliferative activity of interferons was also discovered. In addition, there is a growing number of biological activities.

Type I IFNs, including IFN-α, IFN-β, IFN-ω, IFN-ϵ, IFN-κ, IFN-δ and IFN-τ, are potent antiviral molecules that act both in innate immunity (particularly via their secretion by plasmacytoid dendritic cells) and in cellular immunity (in most, if not all, cell types). All the IFNs mentioned bind to the IFN-alpha receptor(IFNAR), which consists of two subunits R1 and R2 (see IFNAR1 gene and IFNAR2 gene below). Once the type I IFNs bind to the receptor, the binding causes the phosphorylation of TYK2 and JAK1, which are associated with IFNalphaR1 and IFNalphaR2 separately. Phosphorylation of TYK2 and JAK1 leads coselectively to phosphorylation of STAT1/STAT2. Activated STATs dimerize, migrate to the nucleus and regulate type I IFN-induced gene expression to stimulate cytokine production and upregulation of antiviral effector proteins.

Type II interferons: IFN-gamma further induces MHCII antigens and activates macrophages. Type II IFNs, also called IFN-γ, are mainly produced by natural killer (NK) cells, and NKT cells are one of the most important cytokines for host defense against intracellular pathogens related to antigen presentation, macrophage differentiation and activation, production of proinflammatory cytokines, cell death, tumor immunity and autoimmunity (44). Cytokine-induced NK cell activation is controlled by IL-12. In the early stages of infection, phagocytes secrete IL-12 upon binding to its receptor on NK cells, leading to STAT4 activation and eventually IFN-γ production. NK cell-mediated IFN-γ production promotes phagocyte activation, leads to increased secretion of IL-12 by phagocytes and ultimately forms a positive feedback loop (Meager A et al. 2003). The IFN-gamma receptor (IFNgammaR) is present in almost all cell types except mature erythrocytes. The receptor consists of IFNR1 and IFNR2 and belongs to the class II cytokine receptor family. Similar to type I IFNs, IFN-γ activates the JAK-STAT signaling pathway after binding to IFNγR and mediates various biological responses.

The type III interferon (refers to IFN-λ), which was first described in 2003. IFN-λ is the most recently recognized type of IFN. IFN-λ is secreted by most cells but mainly acts on epithelial surfaces due to limited receptor expression (Sommereyns C et al. 2008).

Anti-IFN-I autoantibodies can be found in patients treated with IFN-alpha or IFN-beta and are present in almost all patients with autoimmune polyendocrine syndrome type-1 (APS-1). They are also observed in patients with systemic lupus erythematosus (SLE). They can also affect people infected with COVID-19 (Bastard P et al. 2020). In addition, congenital defects are reported to be more common in patients under 60 years of age, while autoantibodies in COVID-19 are more common in patients over 70 years of age.

In simple terms, anti-IFN autoantibodies with high titers in serum, regardless of the type of interferons, interrupt the activation of the downstream response pathway by blocking the connection between IFNs and their receptor, leading to an increased infection rate.

The induction of transcription of the IFN alpha gene and the IFN beta gene in virus-infected cells is an essential component of innate immunity. Virus-stimulated leukocytes mainly produce IFN-α. Fibroblasts produce mainly or even exclusively IFN-beta. Although almost every cell type can produce IFN-alfa or IFN-beta after a viral infection, there are cells that secrete up to a thousand times the amount of IFN.

These so-called "natural interferon-producing cells", also known as NIPCs, have been described as cells with a plasmacytoid morphology. Apparently, they play an important role in the innate immune defense. Toll-like receptors are of particular importance in the recognition of pathogenic processes and the subsequent type I IFN induction. Glucocorticoids and catecholamines, on the other hand, the most important stress hormones, inhibit the synthesis of pro-inflammatory cytokines such as interleukin-2, tumor necrosis factor-alfa and IFN-gamma. This is linked to an increased susceptibility to bacterial and viral infections in acute stress phases.

Myxovirus resistance protein a marker for interferon activity: Myxovirus resistance protein (Mx protein, MxA in humans) is an antiviral protein that plays a central role in the innate immune response - specifically in response to interferon stimulation. MxA is considered a marker for interferon activity, e.g. in viral infections or autoimmune diseases such as SLE. In diagnostic tests, MxA expression is also used as an indicator for a viral infection (e.g. to distinguish viral infections from bacterial infections).

1. Bastard P et al. (2021) Autoantibodies Neutralizing Type I Ifns are Present in ~4% of Uninfected Individuals Over 70 Years Old and Account for ~20% of COVID-19 Deaths. Sci Immunol 6, 4340.
2. Ealy AD et al. (2017) The evolution of interferon-tau. Reproduction 154:F1-F10.
3. El-Raziky MS et al. (2015) Natural history and response to treatment of HCV infection among Egyptian survivors of childhood malignancy. Pediatr Hematol Oncol 32:138-145.
4. He X et al. (2014) Anti-lyssaviral activity of Interferons kappa and omega from the serotine bat, Eptesicus serotinus. J Virol 88:5444-5454.
5. Imakawa K et al. (2017) Thirty years of interferon-tau research; Past, present and future perspective. Anim Sci J 88: 927-936.
6. Isaacs A, Lindenmann J (1957). Virus Interference. I. The interferon. Proc R Soc Lond B Biol Sci 147(927):258-267.
7. Li SF et al. (2017) Interferon-omega: Current status in clinical applications. Int Immunopharmacol 52:253-260.
8. Meager A et al. (2003) Anti-Cytokine Autoantibodies in Autoimmunity: Preponderance of Neutralizing Autoantibodies Against Interferon-alpha, Interferon-omega and Interleukin-12 in Patients With Thymoma and/or Myasthenia Gravis. Clin Exp Immunol132:128-136.
9. Pan YY et al. (2023) Interferon-lambda: New role in intestinal symptoms of COVID-19. World J Gastroenterol 29: 1942-1954.
10. Sommereyns C et al. (2008) IFN-Lambda (IFN-Lambda) Is Expressed in a Tissue-Dependent Fashion and Primarily Acts on Epithelial Cells In Vivo. PloS Pathog 4:e1000017.
11. Wallace JW et al. (2021) Interferon Lambda in the Pathogenesis of Inflammatory Bowel Diseases. Front Immunol 12:767505.
12. Wolf SJ et al. (2022) IFN-κ is critical for normal wound repair and is decreased in diabetic wounds. JCI Insight 7:e152765.