Interferon at the crossroads of allergy and viral infections

Abstract

IFN-α/β was first described as a potent inhibitor of viral replication, but it is now appreciated that IFN signaling plays a pleiotropic role in regulating peripheral T cell functions. Recently, IFN-α/β was shown to block human Th2 development by suppressing the transcription factor GATA3. This effect is consistent with the role for IFN-α/β in suppressing allergic inflammatory processes by blocking granulocyte activation and IL-4-mediated B cell isotype switching to IgE. With the consideration of recent studies demonstrating a defect in IFN-α/β secretion in DCs and epithelial cells from individuals with severe atopic diseases, there is an apparent reciprocal negative regulatory loop in atopic individuals, whereby the lack of IFN-α/β secretion by innate cells contributes to the development of allergic Th2 cells. Is it possible to overcome these events by treating with IFN-α/β or by inducing its secretion in vivo? In support of this approach, case studies have documented the therapeutic potential of IFN-α/β in treating steroid-resistant allergic asthma and other atopic diseases. Additionally, individuals with asthma who are infected with HCV and respond to IFN therapy showed a reduction in symptoms and severity of asthma attacks. These findings support a model, whereby allergic and antiviral responses are able to cross-regulate each other, as IgER cross-linking of pDCs prevents IFN-α/β production in response to viral infection. The clinical importance of upper-respiratory viruses in the context of allergic asthma supports the need to understand how these pathways intersect and to identify potential therapeutic targets.

Keywords: IgE-mediated regulation; Th2 cell regulation; atopic asthma; atopic disease.

Figure 1.. The classic IFN signaling pathways.

IFN-α/β and IFN-λ signaling induces the activation of STAT2, leading to the formation of the INF-stimulated gene factor 3, which consists of STAT2, STAT1, and IRF9. This complex binds to the promoters ISGs that contain the ISRE DNA motif. IFN-α/β and IFN-λ signaling can also induce the formation of STAT1 homodimers, binding the canonical GAS elements, which promotes of hundreds of cytokine-sensitive genes. IFN-γ signaling predominantly signals through STAT1 homodimer activation and does not activate STAT2. TYK2, Tyrosine kinase 2; IFNAR, IFN-α/β receptor; IFNLR, IFN-λ receptor; IFNGR, IFN-γ receptor; p, tyrosine phosphorylation.

Figure 2.. Reciprocal regulation of allergic stimulation and IFN-α/β-mediated Th2 suppression.

IFN-α/β produced by activated pDCs potently suppresses Th2 development and function. IgER cross-linking potently suppresses IFN-α/β production, thereby preventing downstream regulation of Th2 development and B cell (B) class-switching. IFN-α/β signaling destabilizes Th2 development through the suppression of GATA3 expression and over-rides IL-4-mediated epigenetic modifications of the GATA3 gene locus, making it inaccessible to transcription factor-mediated expression. IFN-α/β therapy would reduce the Th2 bias and IgE expression by suppressing these specific cell types, and the pairing of IFN-α/β therapy with Omalizumab could be sufficient to induce a more permanent tolerance in severe allergic asthma patients.