The emerging role of interferon in human systemic lupus erythematosus

https://doi.org/10.1016/j.coi.2004.09.014Get rights and content

Recent studies of patients with systemic lupus erythematosus, together with data from lupus-prone mice, suggest that inappropriate activation of type I interferon might have a role in disease pathogenesis. Serum levels of IFN-α are elevated in SLE patients, and gene expression profiling of peripheral blood cells shows that most lupus cases demonstrate an upregulation of IFN-responsive genes. Of interest, the IFN gene ‘signature’ correlates with more severe disease. The available data support a model whereby chromatin-containing immune complexes circulating in the blood of lupus patients stimulate leukocytes to produce IFN, which perpetuates disease. These emerging insights into the connection between IFN and lupus provide a host of new diagnostic and therapeutic opportunities.

Introduction

Systemic lupus erythematosus (SLE) (Mendelian inheritance in man [MIM]; 152700) is a chronic systemic autoimmune disease that affects about 0.1% of the US population, and results in inflammation and damage to a range of organ systems. About a third of lupus cases have a milder form of the disease characterized by elevated titers of antinuclear antibodies (ANAs), arthritis, and skin and/or mucosal membrane involvement; however, the majority of patients will suffer additional and more severe clinical manifestations, such as renal inflammation (nephritis), central nervous system (CNS) vasculitis (cerebritis), pleuritis, pericarditis, hemolytic anemia, clotting and thrombocytopenia. The disease aggregates in families, suggesting an important role for genetic predisposition, and women are about 10 times more likely to develop SLE than men. Autoantibodies directed against nuclear antigens (e.g. histones, ssDNA, dsDNA, Ro, La) are found in virtually all cases.

Several lines of evidence have linked innate immune responses with the pathogenesis of SLE. These include genetic associations of SLE with complement deficiencies (C2, C4 and C1q), Fcγ receptors (FCGR2A, FCGR3A, FCGR2B), and C-reactive protein (see [1] for review). Dendritic cells (DCs) are key mediators of innate immune responses, particularly via their ability to secrete cytokines [2]. They are also the primary source of type I interferon (IFN), a molecule important in the front-line defense against viral infection, and recent data suggest that IFN produced by DCs might be important for SLE pathogenesis. Although there is some evidence that type II IFN (IFN-γ) could be involved in lupus, particularly in the mouse [3], here we will focus on data implicating type I IFN, with an emphasis on data in humans.

Section snippets

Type I interferon

Type I IFNs were first identified due to their ability to enhance mammalian anti-viral defense. The type I IFN gene cluster at human chromosome 9p22 consists of 13 distinct IFN-α genes, together with the IFN-β, -ω, -κ, and -τ genes. All type I IFN family members bind a common receptor complex (IFNAR1 and IFNAR2). Viral infection rapidly induces leukocyte production of IFN-α and -β, which initiates a JAK/STAT signaling cascade leading to transcription of target genes that promote host protection

A link between type I interferon and lupus in mice

New Zealand black (NZB) × New Zealand white (NZW) F1 female mice develop a disease closely resembling human SLE, characterized by the production of ANAs, severe glomerulonephritis and early mortality. In the NZB parental strain, which also develops a lupus-like syndrome, homozygous deletion of the type I IFN receptor resulted in reduced autoantibody production and mortality [10•]. Fas-defective lpr mice exhibit a lymphoproliferative disorder that evolves into severe systemic autoimmunity on a

Establishing a connection between interferon and lupus in man

Elevated levels of serum IFN in lupus were first reported 25 years ago 14., 15., 16., and this finding has been confirmed recently [17]. These elevations are generally quite modest, although they are sufficient to induce the maturation of normal monocytes into activated DCs, which then become extremely efficient antigen-presenting cells for CD4+ T cells [6].

An important clue that IFN might contribute to lupus is a series of studies in humans who received IFN-α as a therapeutic agent for viral

SLE peripheral blood expression profiles carry the mark of interferon pathway activation

To identify pathways that might be dysregulated in blood cells of lupus patients, we studied gene expression microarray profiles in 48 SLE patients and 42 matched controls [35••]. Of the many genes differentially expressed between the groups, we found a striking pattern of upregulated IFN-inducible genes in a subset of patients. Figure 1 shows the pattern of IFN-inducible genes in both patient and control PBMC samples, compared with the response of these same genes to stimulation of normal

Potential mechanisms of interferon pathway activation in systemic lupus erythmatosus

It is attractive to consider the possibility that infections might trigger the onset and progression of SLE in genetically susceptible individuals. Microbial components unique to pathogens, such as viral dsRNA, ssRNA or bacterial CpG motifs, signal through TLRs on pDCs and can lead to IFN production [40]. To date, however, a convincing candidate pathogen remains to be identified.

Other groups have proposed very plausible models for the potential role of IFN in SLE 41., 42., 43.. We have little

Conclusions

In summary, there is abundant evidence that IFN contributes to the pathogenesis of human lupus. However, the precise role of IFN remains to be elucidated, and many important questions remain. Is the induction of IFN-responsive genes primary to disease pathogenesis or secondary to ongoing immune activation? Why do we observe only a subset of the genes that have the potential to respond to IFN (as measured by in vitro experiments) upregulated in the blood of patients? Is the IFN signature unique

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We are grateful to the patients and their referring physicians for participation in these studies. We apologize to colleagues whose work we were unable to cite due to page limitations. This work was supported by grants and contracts from National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institute of Allergy and Infectious Diseases (NIAID), the Alliance for Lupus Research, the Mary Kirkland Center for Lupus Research, and the Minnesota Lupus Foundation.

References (49)

  • M. Carroll

    Innate immunity in the etiopathology of autoimmunity

    Nat Immunol

    (2001)
  • C.O. Jacob et al.

    In vivo treatment of (NZBxNZW)F1 lupus-like nephritis with monoclonal antibody to gamma interferon

    J Exp Med

    (1987)
  • D.S. Aaronson et al.

    A road map for those who don’t know JAK-STAT

    Science

    (2002)
  • L. Ronnblom et al.

    Properties of human natural interferon-producing cells stimulated by tumor cell lines

    Eur J Immunol

    (1983)
  • P. Blanco et al.

    Induction of dendritic cell differentiation by IFN-alpha in systemic lupus erythematosus

    Science

    (2001)
  • S. Blomberg et al.

    Presence of cutaneous interferon-alpha producing cells in patients with systemic lupus erythematosus

    Lupus

    (2001)
  • M.L. Santiago-Raber et al.

    Type-I interferon receptor deficiency reduces lupus-like disease in NZB mice

    J Exp Med

    (2003)
  • D. Braun et al.

    Type I Interferon controls the onset and severity of autoimmune manifestations in lpr mice

    J Autoimmun

    (2003)
  • J.J. Hooks et al.

    Immune interferon in the circulation of patients with autoimmune disease

    N Engl J Med

    (1979)
  • S.R. Ytterberg et al.

    Serum interferon levels in patients with systemic lupus erythematosus

    Arthritis Rheum

    (1982)
  • O.T. Preble et al.

    Systemic lupus erythematosus: presence in human serum of an unusual acid-labile leukocyte interferon

    Science

    (1982)
  • A.A. Bengtsson et al.

    Activation of type I interferon system in systemic lupus erythematosus correlates with disease activity but not with antiretroviral antibodies

    Lupus

    (2000)
  • K.M. Kalkner et al.

    Antibodies against double-stranded DNA and development of polymyositis during treatment with interferon

    QJM

    (1998)
  • L.E. Ronnblom et al.

    Autoimmune phenomena in patients with malignant carcinoid tumors during interferon-alpha treatment

    Acta Oncol

    (1991)

    • Cited by (205)

    • Impact of Siglecs on autoimmune diseases

      2023, Molecular Aspects of Medicine

    • Abnormalities of the type I interferon signaling pathway in lupus autoimmunity

      2021, Cytokine

    • Development of antigen sandwich ELISA to detect interferon-alpha (IFN-α) using monoclonal antibodies in chicken

      2020, Veterinary Immunology and Immunopathology

    • Environmental agents, oxidative stress and autoimmunity

      2018, Current Opinion in Toxicology

    • SnapshotDx Quiz: December 2017

      2017, Journal of Investigative Dermatology

    • Sirtuin 3 is required for the dexmedetomidine-mediated alleviation of inflammation and oxidative stress in nephritis

      2024, Immunity, Inflammation and Disease
    View all citing articles on Scopus
    View full text
    Copyright © 2004 Elsevier Ltd. All rights reserved.