Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

High serum IFN-α activity is a heritable risk factor for systemic lupus erythematosus

Abstract

Interferon α (IFN-α) levels are elevated in many patients with systemic lupus erythematosus (SLE); however it is not known whether high serum IFN-α activity is a cause or a result of the disease. We studied 266 SLE patients and 405 of their healthy relatives, and frequently found high serum IFN-α activity in both patients and healthy relatives as compared to healthy unrelated individuals. High IFN-α activity was clustered in specific families in both SLE patients and their healthy first-degree relatives, suggesting a heritable trait. Heritability was also supported by quantitative familial correlation of IFN-α activity, concordance in affected sib pairs and frequent transmission of the high IFN-α activity trait from parents to offspring. Autoantibodies to RNA-binding proteins and double-stranded DNA were associated with high IFN-α activity in SLE patients; however these autoantibodies were very uncommon in healthy family members and did not explain the observed familial correlations. The frequency of high IFN-α activity was similar across all studied ethnic backgrounds. These data suggest that high serum IFN-α activity is a complex heritable trait, which plays a primary role in SLE pathogenesis.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Blanco P, Palucka AK, Gill M, Pascual V, Banchereau J . Induction of dendritic cell differentiation by IFN-α in systemic lupus erythematosus. Science 2001; 294: 1540–1543.

    Article  CAS  Google Scholar 

  2. Kim T, Kanayama Y, Negoro N, Okamura M, Takeda T, Inoue T . Serum levels of interferons in patients with systemic lupus erythematosus. Clin Exp Immunol 1987; 70: 562–569.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Kirou KA, Lee C, George S, Louca K, Peterson MG, Crow MK . Activation of the interferon-α pathway identifies a subgroup of systemic lupus erythematosus patients with distinct serologic features and active disease. Arthritis Rheum 2005; 52: 1491–1503.

    Article  CAS  Google Scholar 

  4. Ronnblom LE, Alm GV, Oberg KE . Possible induction of systemic lupus erythematosus by interferon-α treatment in a patient with a malignant carcinoid tumour. J Intern Med 1990; 227: 207–210.

    Article  CAS  Google Scholar 

  5. Niewold TB, Swedler WI . Systemic lupus erythematosus arising during interferon-α therapy for cryoglobulinemic vasculitis associated with hepatitis C. Clin Rheumatol 2005; 24: 178–181.

    Article  Google Scholar 

  6. Bennett L, Palucka AK, Arce E, Cantrell V, Borvak J, Banchereau J et al. Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J Exp Med 2003; 197: 711–723.

    Article  CAS  Google Scholar 

  7. Kirou KA, Lee C, George S, Louca K, Papagiannis IG, Peterson MG et al. Coordinate overexpression of interferon-α-induced genes in systemic lupus erythematosus. Arthritis Rheum 2004; 50: 3958–3967.

    Article  CAS  Google Scholar 

  8. Baechler EC, Batliwalla FM, Karypis G, Gaffney PM, Ortmann WA, Espe KJ et al. Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci USA 2003; 100: 2610–2615.

    Article  CAS  Google Scholar 

  9. Tsao BP, Grossman JM, Riemekasten G, Strong N, Kalsi J, Wallace DJ et al. Familiality and co-occurrence of clinical features of systemic lupus erythematosus. Arthritis Rheum 2002; 46: 2678–2685.

    Article  Google Scholar 

  10. Scofield RH, Bruner GR, Harley JB, Namjou B . Autoimmune thyroid disease is associated with a diagnosis of secondary Sjogren's syndrome in familial systemic lupus. Ann Rheum Dis 2007; 66: 410–413.

    Article  Google Scholar 

  11. Ioannou Y, Isenberg DA . Current evidence for the induction of autoimmune rheumatic manifestations by cytokine therapy. Arthritis Rheum 2000; 43: 1431–1442.

    Article  CAS  Google Scholar 

  12. Sigurdsson S, Nordmark G, Goring HH, Lindroos K, Wiman AC, Sturfelt G et al. Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus. Am J Hum Genet 2005; 76: 528–537.

    Article  CAS  Google Scholar 

  13. Graham RR, Kozyrev SV, Baechler EC, Reddy MV, Plenge RM, Bauer JW et al. A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus. Nat Genet 2006; 38: 550–555.

    Article  CAS  Google Scholar 

  14. Hua J, Kirou K, Lee C, Crow MK . Functional assay of type I interferon in systemic lupus erythematosus plasma and association with anti-RNA binding protein autoantibodies. Arthritis Rheum 2006; 54: 1906–1916.

    Article  CAS  Google Scholar 

  15. Jabs WJ, Hennig C, Zawatzky R, Kirchner H . Failure to detect antiviral activity in serum and plasma of healthy individuals displaying high activity in ELISA for IFN-α and IFN-beta. J Interferon Cytokine Res 1999; 19: 463–469.

    Article  CAS  Google Scholar 

  16. Risch N . Linkage strategies for genetically complex traits. I. Multilocus models. Am J Hum Genet 1990; 46: 222–228.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Rybicki BA, Elston RC . The relationship between the sibling recurrence-risk ratio and genotype relative risk. Am J Hum Genet 2000; 66: 593–604.

    Article  CAS  Google Scholar 

  18. Lovgren T, Eloranta ML, Bave U, Alm GV, Ronnblom L . Induction of interferon-α production in plasmacytoid dendritic cells by immune complexes containing nucleic acid released by necrotic or late apoptotic cells and lupus IgG. Arthritis Rheum 2004; 50: 1861–1872.

    Article  Google Scholar 

  19. Ramos PS, Kelly JA, Gray-McGuire C, Bruner GR, Leiran AN, Meyer CM et al. Familial aggregation and linkage analysis of autoantibody traits in pedigrees multiplex for systemic lupus erythematosus. Genes Immun 2006; 7: 417–432.

    Article  CAS  Google Scholar 

  20. Bengtsson AA, Sturfelt G, Truedsson L, Blomberg J, Alm G, Vallin H et al. Activation of type I interferon system in systemic lupus erythematosus correlates with disease activity but not with antiretroviral antibodies. Lupus 2000; 9: 664–671.

    Article  CAS  Google Scholar 

  21. Arbuckle MR, McClain MT, Rubertone MV, Scofield RH, Dennis GJ, James JA et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med 2003; 349: 1526–1533.

    Article  CAS  Google Scholar 

  22. Bave U, Nordmark G, Lovgren T, Ronnelid J, Cajander S, Eloranta ML et al. Activation of the type I interferon system in primary Sjogren's syndrome: a possible etiopathogenic mechanism. Arthritis Rheum 2005; 52: 1185–1195.

    Article  CAS  Google Scholar 

  23. Lovgren T, Eloranta ML, Kastner B, Wahren-Herlenius M, Alm GV, Ronnblom L . Induction of interferon-α by immune complexes or liposomes containing systemic lupus erythematosus autoantigen- and Sjogren's syndrome autoantigen-associated RNA. Arthritis Rheum 2006; 54: 1917–1927.

    Article  Google Scholar 

  24. Consortium. Initial sequence of the chimpanzee genome and comparison with the human genome. Nature 2005; 437: 69–87.

    Article  Google Scholar 

  25. Wang ET, Kodama G, Baldi P, Moyzis RK . Global landscape of recent inferred Darwinian selection for Homo sapiens. Proc Natl Acad Sci USA 2006; 103: 135–140.

    Article  CAS  Google Scholar 

  26. Taniguchi T, Takaoka A . A weak signal for strong responses: interferon-α/beta revisited. Nat Rev Mol Cell Biol 2001; 2: 378–386.

    Article  CAS  Google Scholar 

  27. Whitney AR, Diehn M, Popper SJ, Alizadeh AA, Boldrick JC, Relman DA et al. Individuality and variation in gene expression patterns in human blood. Proc Natl Acad Sci USA 2003; 100: 1896–1901.

    Article  CAS  Google Scholar 

  28. Graham RR, Kyogoku C, Sigurdsson S, Vlasova IA, Davies LR, Baechler EC et al. Three functional variants of IFN regulatory factor 5 (IRF5) define risk and protective haplotypes for human lupus. Proc Natl Acad Sci USA 2007; 104: 6758–6763.

    Article  CAS  Google Scholar 

  29. Kozyrev SV, Lewen S, Reddy PM, Pons-Estel B, Witte T, Junker P et al. Structural insertion/deletion variation in IRF5 is associated with a risk haplotype and defines the precise IRF5 isoforms expressed in systemic lupus erythematosus. Arthritis Rheum 2007; 56: 1234–1241.

    Article  CAS  Google Scholar 

  30. von Wussow P, Jakschies D, Hartung K, Deicher H . Presence of interferon and anti-interferon in patients with systemic lupus erythematosus. Rheumatol Int 1988; 8: 225–230.

    Article  CAS  Google Scholar 

  31. Griffiths AJF, Gelbart WM, Miller JH, Lewontin RC . Modern Genetic Analysis, 7th edn. WH Freeman Publishers: New York, NY, 1999.

    Google Scholar 

  32. Olson JM, Witte JS, Elston RC . Association within twin pairs for a dichotomous trait. Genet Epidemiol 1996; 13: 489–499.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We acknowledge Karen Onel and Kenan Onel for their contribution in establishing the Hospital for Special Surgery Family Lupus registry, and Marie Flesch for her assistance in obtaining materials from the Lupus Multiplex Registry and Repository at Oklahoma Medical Research Foundation. The Hospital for Special Surgery Family Lupus Registry was established with support from the S.L.E. Foundation, Inc. and the Toys-R-Us Foundation. The Lupus Multiplex Registry and Repository is supported by NIH NIAMS AR-5-2221 to JBH TBN received salary support from NIH T32 AR07517 and NIAID Clinical Research Loan Repayment grants. This work was supported by the NIH (AI059893) and research grants from the Alliance for Lupus Research, the Lupus Research Institute and the Mary Kirkland Center for Lupus Research to MKC.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to T B Niewold.

Additional information

Disclosures and Support

TB Niewold – NIH T32 AR07517, NIAID Clinical Research Loan Repayment; J Hua – patent pending for interferon assay; TJA Lehman – none; JB Harley – Lupus Multiplex Registry and Repository – NIH NIAMS AR-5-2221; MK Crow – patent pending for interferon assay, NIH R01 AI05983-01, Research Grants from Alliance for Lupus Research, Mary Kirkland Center for Lupus Research and Lupus Research Institute; Support for HSS Family Lupus Registry – Toys ‘R Us Foundation and SLE Foundation.

Supplementary Information accompanies the paper on Genes and Immunity web site (http://www.nature.com/gene)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Niewold, T., Hua, J., Lehman, T. et al. High serum IFN-α activity is a heritable risk factor for systemic lupus erythematosus. Genes Immun 8, 492–502 (2007). https://doi.org/10.1038/sj.gene.6364408

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gene.6364408

Keywords

This article is cited by

Search

Quick links