Type I interferon in the pathogenesis of systemic lupus erythematosus
Introduction
Systemic lupus erythematosus (SLE) is a chronic, multisystem, autoimmune disease resulting from defects in both the innate and adaptive immune systems [1,2•]. Both genetic and environmental factors are important determinants of the different phenotypes observed in SLE [3]. Type I interferon (IFN) levels are chronically and persistently elevated in blood in approximately 50% of SLE patients [4]. An even greater percentage of patients demonstrate overexpression of type I IFN pathway genes in their peripheral blood cells [5•,6,7], referred to as the ‘IFN signature’. Type I and Type II IFN can induce many of the same genes, which may explain why more patients demonstrate the signature than have high functional circulating type I IFN in their blood [5•]. In addition, other pathways and downstream effectors can induce IFN signature genes [8, 9, 10]. Interestingly, a high type I IFN activity is associated with the presence of other cytokines, such as B-cell activating factor (BAFF) and type II IFN [11,12••], specific autoantibodies [13], and certain clinical manifestations, such as lupus nephritis [12••].
Despite the well-established association between type I IFN and SLE, the specific triggers of type I IFN production, the mechanisms by which IFNs help perpetuate the cycle of autoreactive cells and autoantibody production, and the clinical relevance of targeting type I IFN in SLE are less clear. In this review, we will provide an updated overview of recent evidence on mechanisms of type I IFN production, genetic associations, the relevance of impaired nucleic acid processing in animal models of lupus and human SLE, as well as the emergence of successful therapeutic agents targeting type I IFN pathways.
Section snippets
Mechanisms of Type I IFN production
Plasmacytoid dendritic cells (pDCs) have been a focus of interest in SLE ([14], reviewed in [15]). Each pDC can produce as many as 109 IFN-α molecules in 12 hours [16]. This striking feature, along with the skewing of blood type I IFNs toward IFN-α over IFN-β in SLE [17], suggest pDCs as the potential cellular IFN source in this disease. Accordingly, pDC deficiency has been shown to ameliorate murine lupus models [18,19]. However, isolating IFN-α-producing pDCs from SLE patients’ blood and
Type I IFNs in the initiation of SLE
Type I IFNs are implicated in SLE susceptibility by multiple lines of investigation, including genetics, family studies, and induction of SLE by type I IFN treatment [37]. Chronic elevation of type I IFN predisposing to SLE is thought to be due to overproduction, increased sensitivity, and impaired negative regulation (Figure 1). For example, genetic polymorphisms in the interferon regulatory factor (IRF)5 and IRF7 genes are associated with increased type I IFN in circulation [38,39]. Genes
Common and rare genetic influences on Type I IFN in SLE
SLE has been associated with over 100 genetic risk loci and many of these risk genes encode proteins with functions linked to type I IFN response [47]. Family members of patients with SLE are at higher risk of developing autoimmune diseases [48,49]. Type I IFN levels are heritable within SLE families [17], suggesting that genetic overactivity in this pathway predisposes to SLE and other IFN-related autoimmune conditions [49]. Polymorphisms in the type I IFN gene locus itself have not been
Clinical associations with high serum IFN levels in SLE patients
There is substantial evidence that type I IFNs are important in propagating ongoing disease activity in SLE, and not just an initial susceptibility factor. Previous studies have demonstrated that elevated type I IFN in blood is associated with increased disease activity in cross-sectional studies [5•,6,64]. Despite this robust association, longitudinal studies generally do not support the idea that IFN levels fluctuate predictably with changes in SLE disease activity [65,66]. These findings
Non-α/β type I IFNs in SLE
Although much of the research on IFNs in SLE has focused on IFN-α and IFN-β, recent studies have shown a role for IFN-κ, another member of the type I IFN family. IFN-κ is mainly expressed in keratinocytes after exposure to UV light, hence, it has been suggested as a key mediator involved in photosensitivity and other cutaneous manifestations of SLE in humans and murine models [72,73]. Additionally, the presence of genetic associations between IFNK gene variants and cutaneous phenotypes in SLE
Therapeutic strategies targeting type I IFN
Current standard of care treatment of SLE involves the use of corticosteroids and immunosuppressive agents that are associated with a wide range of potential adverse effects [75]. Type I IFN has been considered as a potential target to reduce chronic inflammation and end-organ damage in SLE [75]. Various therapeutics agents which target specific aspects of the type I interferon pathway are currently in different phases of clinical development [76]. For instance, IFN-α kinoid, a vaccine designed
Conclusion
As our understanding of SLE pathogenesis grows, our ability to directly target the underlying pathogenic mechanisms in clinical practice continues to improve. Ideally, our enhanced understanding of human disease biology and pathogenesis, including genetic susceptibility, clinical symptoms, and immunological dysfunction will allow for more specific and effective therapy, and eventually a personalized medicine approach in SLE [87].
Conflict of interest statement
TBN has received research grants from EMD Serono and Janssen, Inc., and has consulted for Thermo Fisher and Inova, all unrelated to the current manuscript. Other authors have no conflict of interest to declare.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as
• of special interest
•• of outstanding interest
Acknowledgements
Appenzeller S: Fundação de Amparo à Pesquisa do Estado São Paulo-Brasil (FAPESP 2008/02917-0 and 2016/23269-3), Conselho Nacional Pesquisa Desenvolvimento-Brasil CNPq (300447/2009-4 and 471343/2011-0 and 302205/2012-8 and 473328/2013-5 and 157534/2015-4). This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001. Niewold TB: Colton Center for Autoimmunity, NIH (AR060861, AR057781, AR065964, AI071651), the Lupus
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Authors have contributed equally and should be considered co-first authors. The authors have nothing to disclose.