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. Host cell death is an intrinsic cell protection mechanism during infection. Several studies have conclusively shown that the pathways of necroptosis and pyroptotic cell death are crucial for the release and action of inflammatory cytokines.

Polypeptides with antiviral, antiproliferative and immunomodulatory properties. A distinction is made between:

Type I interferons:

• INF-alfa (formerly known as leukocyte interferons)
• IFN-beta (fibroblast interferon)

Type II interferon:

• IFN-gamma (immune interferon)

Type III interferon:

• IFN-lambda

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 viral 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; the phosphorylation of TYK2 and JAK1 subsequently leads to the 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.

Type III IFN (referring to IFN-λ), which was first described in 2003, 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.

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. Isaacs A, Lindenmann J (1957). Virus Interference. I. The interferon. Proc R Soc Lond B Biol Sci 147(927):258-267.

3. 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.

4. 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.