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Interferons in Lupus
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Interferons in Lupus

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 21893

Special Issue Editor

Dr. Trine N. Jorgensen

E-Mail Website
Guest Editor
Department of Inflammation and Immunity, Cleveland Clinic, Lerner Research Institute, Cleveland, OH, USA
Interests: systemic lupus erythematosus; type I interferons; B cells; dendritic cells; myeloid-derived suppressor cells; sex hormones

Special Issue Information

Dear Colleagues,

Systemic lupus erythematosus (SLE) is a debilitating autoimmune disorder affecting millions of people world-wide. The pathogenesis of SLE is diverse among patients driven by dysregulated immune cells, cytokines, and hormones, resulting in a variety of symptoms such as nephritis, vasculitis, myocarditis, pleuritis, etc. Over the past several decades, the identification of elevated levels of type I interferons in a significant proportion of SLE patients has aided in the enrichment of our understanding of the pathogenesis of SLE. In addition, other interferons such as interferon-lambda, interferon-kappa, and interferon-gamma have also been suggested to play important roles in disease pathogenesis in both animal models and SLE patients.

This Special Issue, “Interferons in Lupus”, welcomes original research and review articles with a focus on cellular, molecular ,and mechanistic inducers, modulators, and responders of interferons in SLE, LE, and animal models of lupus.

Small-molecule inhibitors or specific antibodies targeting interferon induction, production, and/or effector functions offer new therapeutic strategies that may aid in controlling SLE pathogenesis. However, an understanding of the widespread immunological effects attributed to interferons is imperative for such agents to become available to SLE patients. What types of interferons are involved in disease pathogenesis at different times? What signal(s) induces interferon production in SLE patients and animal models of lupus? When does the induction of interferons take place, and when are these best targeted? Is it feasible to target the inducer(s) therapeutically? What cell subsets are involved in the production of interferons, and how do these relate to disease symptoms? What cell subsets respond to interferons, and how?

Dr. Trine N. Jorgensen
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • lupus
  • nephritis
  • myocarditis
  • vasculitis
  • type I interferons
  • interferon-γ
  • regulation
  • interference
  • treatment
  • immune cells

Published Papers (5 papers)

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Research

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13 pages, 2454 KiB  
Article
Spontaneous CD4+ T Cell Activation and Differentiation in Lupus-Prone B6.Nba2 Mice Is IFNAR-Independent
by Emma J. Keller, Nina Dvorina and Trine N. Jørgensen
Int. J. Mol. Sci. 2022, 23(2), 874; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23020874 - 14 Jan 2022
Viewed by 2013
Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by dysregulated T and B lymphocytes. Type I interferons (IFN-I) have been shown to play important pathogenic roles in both SLE patients and mouse models of lupus. Recent studies have shown that B cell [...] Read more.
Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by dysregulated T and B lymphocytes. Type I interferons (IFN-I) have been shown to play important pathogenic roles in both SLE patients and mouse models of lupus. Recent studies have shown that B cell intrinsic responses to IFN-I are enough to drive B cell differentiation into autoantibody-secreting memory B cells and plasma cells, although lower levels of residual auto-reactive cells remain present. We speculated that IFN-I stimulation of T cells would similarly drive specific T-cell associated lupus phenotypes including the upregulation of T follicular helper cells and Th17, thereby affecting autoantibody production and the development of glomerulonephritis. Using the B6.Nba2 mouse model of lupus, we evaluated disease parameters in T cell specific IFN-I receptor (IFNAR)-deficient mice (cKO). Surprisingly, all measured CD4+ T cell abnormalities and associated intra-splenic cytokine levels (IFNγ, IL-6, IL-10, IL-17, IL-21) were unchanged and thus independent of IFN-I. In contrast B6.Nba2 cKO mice displayed reduced levels of effector CD8+ T cells and increased levels of Foxp3+ CD8+ regulatory T cells, suggesting that IFN-I induced signaling specifically affecting CD8+ T cells. These data suggest a role for both pathogenic and immunosuppressive CD8+ T cells in Nba2-driven autoimmunity, providing a model to further evaluate the role of these cell subsets during lupus-like disease development in vivo. Full article
(This article belongs to the Special Issue Interferons in Lupus)
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Review

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16 pages, 826 KiB  
Review
Type I Interferons in Systemic Lupus Erythematosus: A Journey from Bench to Bedside
by Tao Ming Sim, Siying Jane Ong, Anselm Mak and Sen Hee Tay
Int. J. Mol. Sci. 2022, 23(5), 2505; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23052505 - 24 Feb 2022
Cited by 21 | Viewed by 4368
Abstract
Dysregulation of type I interferons (IFNs) has been implicated in the pathogenesis of systemic lupus erythematosus (SLE) since the late 1970s. The majority of SLE patients demonstrate evidence of type I IFN pathway activation; however, studies attempting to address the relationship between type [...] Read more.
Dysregulation of type I interferons (IFNs) has been implicated in the pathogenesis of systemic lupus erythematosus (SLE) since the late 1970s. The majority of SLE patients demonstrate evidence of type I IFN pathway activation; however, studies attempting to address the relationship between type I IFN signature and SLE disease activity have yielded conflicting results. In addition to type I IFNs, type II and III IFNs may overlap and also contribute to the IFN signature. Different genetic backgrounds lead to overproduction of type I IFNs in SLE and contribute to the breakdown of peripheral tolerance by activation of antigen-presenting myeloid dendritic cells, thus triggering the expansion and differentiation of autoreactive lymphocytes. The consequence of the continuous stimulation of the immune system is manifested in different organ systems typical of SLE (e.g., mucocutaneous and cardiovascular involvement). After the discovery of the type I IFN signature, a number of different strategies have been developed to downregulate the IFN system in SLE patients, finally leading to the successful trial of anifrolumab, the second biologic to be approved for the treatment of SLE in 10 years. In this review, we will discuss the bench to bedside translation of the type I IFN pathway and put forward some issues that remain unresolved when selecting SLE patients for treatment with biologics targeting type I IFNs. Full article
(This article belongs to the Special Issue Interferons in Lupus)
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15 pages, 770 KiB  
Review
Cytokines as Biomarkers in Systemic Lupus Erythematosus: Value for Diagnosis and Drug Therapy
by Helena Idborg and Vilija Oke
Int. J. Mol. Sci. 2021, 22(21), 11327; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111327 - 20 Oct 2021
Cited by 24 | Viewed by 3037
Abstract
Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease. The disease is characterized by activation and dysregulation of both the innate and the adaptive immune systems. The autoimmune response targets self-molecules including cell nuclei, double stranded DNA and other intra and extracellular structures. [...] Read more.
Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease. The disease is characterized by activation and dysregulation of both the innate and the adaptive immune systems. The autoimmune response targets self-molecules including cell nuclei, double stranded DNA and other intra and extracellular structures. Multiple susceptibility genes within the immune system have been identified, as well as disturbances in different immune pathways. SLE may affect different organs and organ systems, and organ involvement is diverse among individuals. A universal understanding of pathophysiological mechanism of the disease, as well as directed therapies, are still missing. Cytokines are immunomodulating molecules produced by cells of the immune system. Interferons (IFNs) are a broad group of cytokines, primarily produced by the innate immune system. The IFN system has been observed to be dysregulated in SLE, and therefore IFNs have been extensively studied with a hope to understand the disease mechanisms and identify novel targeted therapies. In several autoimmune diseases identification and subsequent blockade of specific cytokines has led to successful therapies, for example tumor necrosis factor-alpha (TNF-α) inhibition in rheumatoid arthritis. Authors of this review have sought corresponding developments in SLE. In the current review, we cover the actual knowledge on IFNs and other studied cytokines as biomarkers and treatment targets in SLE. Full article
(This article belongs to the Special Issue Interferons in Lupus)
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21 pages, 4688 KiB  
Review
The Pathogenesis, Molecular Mechanisms, and Therapeutic Potential of the Interferon Pathway in Systemic Lupus Erythematosus and Other Autoimmune Diseases
by Madhu Ramaswamy, Raj Tummala, Katie Streicher, Andre Nogueira da Costa and Philip Z. Brohawn
Int. J. Mol. Sci. 2021, 22(20), 11286; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011286 - 19 Oct 2021
Cited by 23 | Viewed by 8816
Abstract
Therapeutic success in treating patients with systemic lupus erythematosus (SLE) is limited by the multivariate disease etiology, multi-organ presentation, systemic involvement, and complex immunopathogenesis. Agents targeting B-cell differentiation and survival are not efficacious for all patients, indicating a need to target other inflammatory [...] Read more.
Therapeutic success in treating patients with systemic lupus erythematosus (SLE) is limited by the multivariate disease etiology, multi-organ presentation, systemic involvement, and complex immunopathogenesis. Agents targeting B-cell differentiation and survival are not efficacious for all patients, indicating a need to target other inflammatory mediators. One such target is the type I interferon pathway. Type I interferons upregulate interferon gene signatures and mediate critical antiviral responses. Dysregulated type I interferon signaling is detectable in many patients with SLE and other autoimmune diseases, and the extent of this dysregulation is associated with disease severity, making type I interferons therapeutically tangible targets. The recent approval of the type I interferon-blocking antibody, anifrolumab, by the US Food and Drug Administration for the treatment of patients with SLE demonstrates the value of targeting this pathway. Nevertheless, the interferon pathway has pleiotropic biology, with multiple cellular targets and signaling components that are incompletely understood. Deconvoluting the complexity of the type I interferon pathway and its intersection with lupus disease pathology will be valuable for further development of targeted SLE therapeutics. This review summarizes the immune mediators of the interferon pathway, its association with disease pathogenesis, and therapeutic modalities targeting the dysregulated interferon pathway. Full article
(This article belongs to the Special Issue Interferons in Lupus)
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16 pages, 1364 KiB  
Review
Regulation of B Cell Responses in SLE by Three Classes of Interferons
by Phillip P. Domeier and Ziaur S. M. Rahman
Int. J. Mol. Sci. 2021, 22(19), 10464; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910464 - 28 Sep 2021
Cited by 4 | Viewed by 2831
Abstract
There are three classes of interferons (type 1, 2, and 3) that can contribute to the development and maintenance of various autoimmune diseases, including systemic lupus erythematosus (SLE). Each class of interferons promotes the generation of autoreactive B cells and SLE-associated autoantibodies by [...] Read more.
There are three classes of interferons (type 1, 2, and 3) that can contribute to the development and maintenance of various autoimmune diseases, including systemic lupus erythematosus (SLE). Each class of interferons promotes the generation of autoreactive B cells and SLE-associated autoantibodies by distinct signaling mechanisms. SLE patients treated with various type 1 interferon-blocking biologics have diverse outcomes, suggesting that additional environmental and genetic factors may dictate how these cytokines contribute to the development of autoreactive B cells and SLE. Understanding how each class of interferons controls B cell responses in SLE is necessary for developing optimized B cell- and interferon-targeted therapeutics. In this review, we will discuss how each class of interferons differentially promotes the loss of peripheral B cell tolerance and leads to the development of autoreactive B cells, autoantibodies, and SLE. Full article
(This article belongs to the Special Issue Interferons in Lupus)
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