Elsevier

Human Immunology

Volume 63, Issue 12, December 2002, Pages 1181-1193
Human Immunology

Original contribution
The natural interferon-α producing cells in systemic lupus erythematosus

https://doi.org/10.1016/S0198-8859(02)00757-7Get rights and content

Abstract

Prolonged exposure of the immune system to type I interferons (IFN-α/β/ω) in patients receiving IFN-α therapy frequently results in development of autoantibodies and autoimmune disease. This is attributed to the many immunostimulatory effects of these cytokines. Patients with the autoimmune disease systemic lupus erythematosus (SLE) have an ongoing IFN-α production. Recent studies of SLE demonstrated the presence of endogenous IFN-α inducers, acting specifically on natural IFN-α producing cells (NIPC), often termed plasmacytoid dendritic cells (PDC). These IFN-α inducers were potent, present at the blood level, and characterized as immune complexes that contained DNA and IgG as essential components. They were considered a likely reason for the activated IFN-α production in SLE, which, in turn, might be an important etiopathogenic factor. Here, we briefly review the biology of the type I IFN system, with emphasis on inducers, producing cells (especially NIPC/PDC), IFN-α actions, and target immune cells, which might be relevant in SLE. Based on such information and results from studies in SLE patients, we propose a hypothesis that explains how NIPC/PDC become activated and play a pivotal etiopathogenic role in SLE and perhaps also other autoimmune diseases. This hypothesis furthermore indicates new therapeutic targets.

Section snippets

Abbreviations

    ANA

    antinuclear antibody

    BCR

    B-cell receptor

    CFA

    Freund’s complete adjuvant

    CpG

    cytosine-guanine dinucleotide

    DC

    dendritic cell

    dsDNA

    double-stranded DNA

    FcγRII

    Fcγ-receptor II

    HSV

    herpes simplex virus

    IDDM

    insulin dependent diabetes mellitus

    IFN

    interferon

    IFNAR

    interferon-α receptor

    IL

    interleukin

    IRF

    interferon regulatory factor

    mAb

    monoclonal antibody

    NIPC

    natural interferon-α producing cell

    ODN

    oligodeoxyribonucleotide

    PBMC

    peripheral blood mononuclear cells

    PDC

    plasmacytoid DC

    RNP

    ribonucleoprotein

    SLE

    systemic lupus

Conclusion

The type I IFN system may play a pivotal role in the initiation and maintenance of the autoimmune process in SLE. Production of endogenous IFN-α inducers and continuous stimulation of NIPC to IFN-α secretion are key events in this process, leading to a vicious circle where autoimmune T and B cells are activated to sustained autoantibody production and generation of more IFN-α inducers. An important goal in search for better therapy of SLE patients is to learn how the production and action of

Acknowledgements

We thank all our colleagues who have greatly contributed to own data on which this review is based, especially Brita Cederblad, Maija-Leena Eloranta, Helena Vallin, Stina Blomberg, Ullvi Båve, Anders Bengtsson, Gunnar Sturfelt, Anders Perers, Anne Riesenfeld, Tanja Lovgren, Mattias Magnusson, and Lotta Sjöberg. Financial support was provided by the Swedish Medical Research Council, The Swedish Rheumatism Foundation, the 80-years foundation of King Gustaf V, Åke Wiberg foundation, Nanna Svartz

References (105)

  • F. Sinigaglia et al.

    Type I interferons and the Th1/Th2 paradigm

    Dev Comp Immunol

    (1999)
  • K. Ruuth et al.

    Interferon-α promotes survival of human primary B-lymphocytes via phosphatidylinositol 3-kinase

    Biochem Biophys Res Commun

    (2001)
  • X. Zhang et al.

    Potent and selective stimulation of memory-phenotype CD8+ T cells in vivo by IL-15

    Immunity

    (1998)
  • P. Fitzgerald-Bocarsly

    Human natural interferon-α producing cells

    Pharmacol Ther

    (1993)
  • B. Cederblad et al.

    Patients with systemic lupus erythematosus have reduced numbers of circulating natural interferon-α-producing cells

    J Autoimmun

    (1998)
  • L. Farkas et al.

    Plasmacytoid dendritic cells (natural interferon-α/β-producing cells) accumulate in cutaneous lupus erythematosus lesions

    Am J Pathol

    (2001)
  • U. Båve et al.

    Activation of natural interferon-α producing cells by apoptotic U937 cells combined with lupus IgG and its regulation by cytokines

    J Autoimmun

    (2001)
  • M. Herrmann et al.

    Etiopathogenesis of systemic lupus erythematosus

    Immunol Today

    (2000)
  • H. Wagner

    Interactions between bacterial CpG-DNA and TLR9 bridge innate and adaptive immunity

    Curr Opin Microbiol

    (2002)
  • H.M. Dijstelbloem et al.

    Inflammation in autoimmunityreceptors for IgG revisited

    Trends Immunol

    (2001)
  • N. Shakoor et al.

    Drug-induced systemic lupus erythematosus associated with etanercept therapy

    Lancet

    (2002)
  • L. Rönnblom et al.

    An etiopathogenic role for the type I IFN system in SLE

    Trends Immunol

    (2001)
  • S. Gallucci et al.

    Danger signalsSOS to the immune system

    Curr Opin Immunol

    (2001)
  • A.K. Foulis et al.

    Immunoreactive alpha-interferon in insulin-secreting beta cells in type 1 diabetes mellitus

    Lancet

    (1987)
  • X. Huang et al.

    Islet expression of interferon-α precedes diabetes in both the BB rat and streptozotocin-treated mice

    Immunity

    (1994)
  • A. Isaacs et al.

    Virus interference. I. The interferon

    Proc R Soc B

    (1957)
  • M.A. Farrar et al.

    The molecular cell biology of interferon-gamma and its receptor

    Annu Rev Immunol

    (1993)
  • S. Pestka

    The human interferon α species and receptors

    Biopolymers

    (2000)
  • C.A. Biron et al.

    Innate immune responses to LCMV infectionsnatural killer cells and cytokines

    Curr Top Microbiol Immunol

    (2002)
  • C.A. Biron

    Initial and innate responses to viral infections—pattern setting in immunity or disease

    Curr Opin Microbiol

    (1999)
  • F. Belardelli

    Role of interferons and other cytokines in the regulation of the immune response

    APMIS

    (1995)
  • K. Shortman et al.

    Mouse and human dendritic cell subtypes

    Nature Rev Immunol

    (2002)
  • Y.J. Liu et al.

    Dendritic cell lineage, plasticity and cross-regulation

    Nat Immunol

    (2001)
  • D.L. Brassard et al.

    Interferon-α as an immunotherapeutic protein

    J Leukoc Biol

    (2002)
  • M.H. Nguyen et al.

    Therapeutic advances in the management of hepatitis B and hepatitis C

    Curr Opin Infect Dis

    (2001)
  • K. Öberg

    Interferon in the management of neuroendocrine GEP-tumorsa review

    Digestion

    (2000)
  • E.A. Abdi et al.

    Auto-immune thrombocytopenia related to interferon therapy

    Scand J Haematol

    (1986)
  • L.E. Rönnblom et al.

    Autoimmunity after alpha-interferon therapy for malignant carcinoid tumors

    Ann Intern Med

    (1991)
  • Y. Ioannou et al.

    Current evidence for the induction of autoimmune rheumatic manifestations by cytokine therapy

    Arthritis Rheum

    (2000)
  • P. Raanani et al.

    Immune-mediated complications during interferon therapy in hematological patients

    Acta Haematol

    (2002)
  • L.E. Rönnblom et al.

    Possible induction of systemic lupus erythematosus by interferon-α treatment in a patient with a malignant carcinoid tumour

    J Intern Med

    (1990)
  • K.M. Kälkner et al.

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

    Q J M

    (1998)
  • D. Braun et al.

    IFN-α/β enhances BCR-dependent B cell responses

    Int Immunol

    (2002)
  • F. Mattei et al.

    IL-15 is expressed by dendritic cells in response to type I IFN, double-stranded RNA, or lipopolysaccharide and promotes dendritic cell activation

    J Immunol

    (2001)
  • C. Stahl-Hallengren et al.

    Incidence studies of systemic lupus erythematosus in Southern Swedenincreasing age, decreasing frequency of renal manifestations and good prognosis

    J Rheumatol

    (2000)
  • D.J. Wallace et al.

    Dubois’ lupus erythematosus

    (1997)
  • R.G. Lahita

    Systemic lupus erythematosus

    (1999)
  • M.J. Fritzler

    Clinical relevance of autoantibodies in systemic rheumatic diseases

    Mol Biol Rep

    (1996)
  • O.T. Preble et al.

    Systemic lupus erythematosuspresence in human serum of an unusual acid-labile leukocyte interferon

    Science

    (1982)
  • O. Strannegård et al.

    Interferon and natural killer cells in systemic lupus erythematosus

    Clin Exp Immunol

    (1982)
  • Cited by (99)

    • Overview of microbial therapeutics in immunological disorders

      2023, Microbiome Therapeutics: Personalized Therapy Beyond Conventional Approaches
    • The contribution of the programmed cell death machinery in innate immune cells to lupus nephritis

      2017, Clinical Immunology
      Citation Excerpt :

      A clear type I interferon signature is detected in nephritic kidneys [43,44]. This finding potentially implicates plasmacytoid dendritic cells in LN pathogenesis, as this population is a major producer of type I interferon [45,46]. However, studies also suggest that resident renal cells are capable of producing type I interferon and can thus contribute to the observed type I interferon signature [47].

    View all citing articles on Scopus
    View full text