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Interferon in Inflammatory Diseases Meeting report Lupus Sci Med: first published as 10.1136/lupus-2018-000276 on 15 June 2018. Downloaded from Report of the inaugural Interferon Research Summit: interferon in inflammatory diseases Mary K Crow,1 Lars Rönnblom2 To cite: Crow MK, ABSTRACT responses to distinct classes of therapeutic Rönnblom L. Report of An international summit agents. the inaugural Interferon on interferon (IFN) in inflammatory diseases, held in The inaugural International Summit on Research Summit: interferon Gaithersburg, Maryland, USA (4–5 May 2017), united 22 in inflammatory diseases. IFN in Inflammatory Diseases united 22 inter- internationally renowned clinicians and scientists with Lupus Science & Medicine nationally renowned clinicians and scientists backgrounds in basic science, translational science and 2018;5:e000276. doi:10.1136/ with backgrounds in basic science, transla- lupus-2018-000276 clinical medicine. The objectives of the summit were to assess the current knowledge of the role of type I IFN in tional science and clinical medicine. Goals inflammatory diseases and other conditions, discuss the of the summit included assessing the current ► Additional material is available clinical trial data of anti-IFN therapeutic agents knowledge of the role type I IFN plays in published online only. To view and identify key clinical and therapeutic knowledge gaps inflammatory diseases and other conditions, please visit the journal online (http:// dx. doi. org/ 10. 1136/ 10. and future directions to advance the treatment landscape discussing available clinical data examining 1136/ lupus- 2018- 000276) of diseases involving the type I IFN pathway. A discussion- anti-IFN therapies and identifying current key based consensus process was used to assess three main clinical and therapeutic knowledge gaps. This Protected by copyright. clinical areas: the role of type I IFN in innate immunity, report summarises the key findings of the the role of type I IFN in autoimmune diseases and rational Received 18 May 2018 meeting and includes the advisors’ recom- Revised 23 May 2018 therapeutic targets in the IFN pathway. These are described Accepted 24 May 2018 here, along with current knowledge gaps and resulting mendations for future efforts to advance the recommendations. The advisors unanimously agreed that, therapeutic landscape of diseases involving despite significant obstacles, the field should transition the type I IFN pathway. from an organ-based model to a pathophysiology-based http://lupus.bmj.com/ model. A better understanding of the molecular pathways could help inform potential therapeutic targets, thus BASIC FUNCTION OF THE TYPE I IFN SYSTEM progressing towards personalised medicine by tailoring the Role of IFN in immune responses therapy to each patient. IFNs (types I–III) are a highly complex family of cytokines (type I IFN subtypes (IFN-α; 13 IFN-α genes, 12 IFN-α proteins in humans), INTRODUCTION IFN-β, IFN-ω, IFN-κ, and IFN-ε) with diverse Type I interferon (IFN) is involved in the effects on immune function. The type I IFN on December 5, 2019 at Uppsala Universitet BIBSAM Consortia. pathogenesis of systemic autoimmune system serves as the major line of defence diseases and several organ-targeted inflam- against viruses and microorganisms by matory diseases. Although its primary path- promoting both innate and adaptive immune ogenic role is well established for systemic responses.6–8 The IFN concentrations lupus erythematosus (SLE), the role of type required for antiviral and immunomodula- I IFNs in other autoimmune diseases is less tory effects may be distinct, and our under- clear. Evidence from analyses of peripheral standing of how different type I IFNs and 1Department of Medicine, blood of patients with rheumatoid arthritis receptors generate diverse immune functions Mary Kirkland Center for Lupus demonstrating an IFN signature and is still evolving. Research, Hospital for Special evidence from murine models of diabetes Type I IFNs are particularly important in Surgery, Weill Cornell Medical mellitus strongly suggest a pathogenic role antivirus host defence,6 and the complexity College, New York, USA 1 2Department of Medical of type I IFN in a subset of these diseases. A of the pathway may be necessary to defend Sciences, Section of more prominent type I IFN signature can be against the variety of viruses that are encoun- Rheumatology, Science for Life seen in Sjögrens syndrome, dermatomyositis tered. The innate immune response to viral Laboratory, Uppsala University, (DM) and systemic sclerosis.2–5 Although we infection initiates intense but transient type Uppsala, Sweden have gained a better understanding of the I IFN expression (figure 1).9 10 Although Correspondence to role of type I IFN in autoimmune and inflam- we know many of the triggers that initiate Dr Mary K Crow; matory diseases in recent years, key knowl- a type I IFN response after an acute viral crowm@ hss. edu edge gaps remain, including those related to infection,8 the mechanisms by which this Crow MK, Rönnblom L. Lupus Science & Medicine 2018;5:e000276. doi:10.1136/lupus-2018-000276 1 Lupus Science & Medicine Lupus Sci Med: first published as 10.1136/lupus-2018-000276 on 15 June 2018. Downloaded from Figure 1 The role of IFN in viral infection over time. cDC, conventional dendritic cell; IFN, interferon; IL, interleukin; ISG, interferon-stimulating genes; pDC, plasmacytoid dendritic cells; PD-L1, programmed death ligand 1; PRR, pattern recognition receptor. Left panel adapted from Crouse et al9; right panel adapted from Zuniga et al10 (Reprinted by permission from Springer Customer Service Centre GmbH: Springer Nature, Nature Reviews Immunology; Regulation of antiviral T cell responses by type I interferons. Crouse J, Kalinke U, Oxenius A, © 2015. Republished with permission of Annual Reviews, from Innate and Adaptive Immune Regulation During Chronic Viral Infections, Zuniga EI, Macal M, Lewis GM, et al, Vol. 2, © 2015; permission conveyed through Copyright Clearance Center.). Protected by copyright. response is terminated are yet to be elucidated. The type nucleic acids in the form of immune complexes can acti- I IFN pathway is dysregulated in SLE,11 12 and the advi- vate endosomal nucleic acid–sensing TLRs and drive type sors agreed that a large research gap exists in our under- I IFN and IFN-induced gene expression, mimicking a standing of what drives overproduction of this cytokine. viral infection.21 Understanding the regulatory mechanisms that control Several nucleic acid sensors (eg, TLRs) within pDCs the innate immune response may yield information bene- trigger distinct signalling pathways, including canonical ficial to the autoimmune diseases community and may type I IFN signalling—IFN-dependent activation of Janus http://lupus.bmj.com/ uncover novel drug targets. kinase (JAK)–signal transducer and activator of tran- Although increased type I IFN expression is common scription (STAT) leading to transcription of IFN-stim- in several diseases, the link between IFN signatures and ulated genes (the type I IFN gene signature (IFNGS)). various clinical manifestations of disease remains unclear, Human pDCs express TLR7 and TLR9 nucleic acid suggesting that the role of type I IFN may differ among sensors, and TLR7/TLR9 signalling induces a morpho- diseases. The advisors discussed the potential utility of IFN logical change in pDCs, from an IFN-producing cell on December 5, 2019 at Uppsala Universitet BIBSAM Consortia. blockade in HIV infection, because studies have demon- with high IFN production and low antigen presentation strated that IFN may be detrimental in these patients, to an antigen-presenting cell with low IFN production potentially contributing to T-cell exhaustion.13 14 Many and high antigen presentation.2 pDCs do not express of the immune alterations that characterise patients with TLR8 under most circumstances,22 which distinguishes autoimmune diseases may be attributable to the immuno- them from monocytes, neutrophils and cDCs, although modulatory properties of type I IFN, epigenetic modifica- recent data from patients with systemic sclerosis suggest tions and irreversible autoimmune processes. that TLR8 can be expressed in pDCs.23 Interleukin receptor–associated kinase-4 (IRAK-4) is involved Sources of IFN: plasmacytoid dendritic cells and other cells in signalling innate immune responses from TLRs. Plasmacytoid dendritic cells (pDCs) have unique IRAK-4-deficient patients produce IFN-α in response biology, are the most active type I IFN-producing cells to viral infections but not to TLR7/TLR9 ligands; thus, and contribute to both innate and adaptive immunity these patients are susceptible to pyogenic bacterial 15 16 (figure 2). pDC type I IFN production is most evident infections (Gram+ bacteria) but appear to have normal at early time points after viral infection. Over time, other resistance to viral infections.24 These data demonstrate cells (eg, conventional dendritic cells (cDCs) and epithe- the presence of non-TLR nucleic acid sensors. lial cells) become more prominent producers of type I IFN.17–19 Exogenous (eg, viral) RNA and DNA elicit type Genetic contributors to the type I IFN system: SLE I IFN production via toll-like receptor (TLR)–dependent heterogeneity and interferonopathies and TLR-independent (cytosolic) mechanisms in pDCs Understanding the molecular basis of diseases will help us and other cells.20 In autoimmune diseases, endogenous progress towards personalised medicine by tailoring the 2 Crow MK, Rönnblom L. Lupus Science
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