Type I interferon as a biomarker in autoimmunity and viral infection: a leukocyte subset-specific analysis unveils hidden diagnostic options

Abstract

Interferon alpha and its surrogates, including IP-10 and SIGLEC1, paralleled changes of disease activity in systemic lupus erythematosus (SLE). However, the whole blood interferon signature (WBIFNS)—the current standard for type I IFN assessment in SLE—does not correlate with SLE disease activity in individual patients over time. The underlying causes for this apparent contradiction have not been convincingly demonstrated. Using a multicenter dataset of gene expression data from leukocyte subsets in SLE, we identify distinctive subset-specific contributions to the WBIFNS. In a subsequent analysis, the effects of type I interferon on cellular blood composition in patients with SLE and hepatitis B were also studied over time. We found that type I interferon mediates significant alterations in whole blood composition, including a neutropenia and relative lymphocytosis. Given different effects of type 1 interferon on different leukocyte subsets, these shifts confound measurement of a type 1 interferon signature in whole blood. To minimize and overcome these limitations of the WBIFNS, we suggest to measure IFN-induced transcripts or proteins in a specific leukocyte subset to improve clinical impact of interferon biomarkers.

Key messages

  • Myeloid cells contribute more to the WBIFNS in SLE than their lymphocytic counterpart.

  • Very similar leukocyte subsets reveal distinctive IFN signatures.

  • IFN alpha mixes up composition of blood and leads to a preferential neutropenia, yielding relative lymphocytosis.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  1. 1.

    Baechler EC, Batliwalla FM, Karypis G, Gaffney PM, Ortmann WA, Espe KJ, Shark KB, Grande WJ, Hughes KM, Kapur V et al (2003) Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci U S A 100:2610–2615

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

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

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Feng X, Wu H, Grossman JM, Hanvivadhanakul P, FitzGerald JD, Park GS, Dong X, Chen W, Kim MH, Weng HH et al (2006) Association of increased interferon-inducible gene expression with disease activity and lupus nephritis in patients with systemic lupus erythematosus. Arthritis Rheum 54:2951–2962

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Landolt-Marticorena C, Bonventi G, Lubovich A, Ferguson C, Unnithan T, Su J, Gladman DD, Urowitz M, Fortin PR, Wither J (2009) Lack of association between the interferon-alpha signature and longitudinal changes in disease activity in systemic lupus erythematosus. Ann Rheum Dis 68:1440–1446

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Petri M, Singh S, Tesfasyone H, Dedrick R, Fry K, Lal P, Williams G, Bauer J, Gregersen P, Behrens T et al (2009) Longitudinal expression of type I interferon responsive genes in systemic lupus erythematosus. Lupus 18:980–989

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Yao Y, Higgs BW, Richman L, White B, Jallal B (2010) Use of type I interferon-inducible mRNAs as pharmacodynamic markers and potential diagnostic markers in trials with sifalimumab, an anti-IFNalpha antibody, in systemic lupus erythematosus. Arthritis Res Ther 12(Suppl 1):S6

    Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    McBride JM, Jiang J, Abbas AR, Morimoto A, Li J, Maciuca R, Townsend M, Wallace DJ, Kennedy WP, Drappa J (2012) Safety and pharmacodynamics of rontalizumab in patients with systemic lupus erythematosus: results of a phase I, placebo-controlled, double-blind, dose-escalation study. Arthritis Rheum 64:3666–3676

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Petri M, Wallace DJ, Spindler A, Chindalore V, Kalunian K, Mysler E, Neuwelt CM, Robbie G, White WI, Higgs BW et al (2013) Sifalimumab, a human anti-interferon-a monoclonal antibody, in systemic lupus erythematosus: a phase 1 randomized controlled, dose-escalation study. Arthritis Rheum. doi:10.1002/art.37824

    Google Scholar 

  10. 10.

    Lauwerys BR, Hachulla E, Spertini F, Lazaro E, Jorgensen C, Mariette X, Haelterman E, Grouard-Vogel G, Fanget B, Dhellin O et al (2013) Down-regulation of interferon signature in systemic lupus erythematosus patients by active immunization with interferon alpha-kinoid. Arthritis Rheum 65:447–456

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Kalunian KC, Merrill JT, Maciuca R, McBride JM, Townsend MJ, Wei X, Davis JC Jr, Kennedy WP (2016) A phase II study of the efficacy and safety of rontalizumab (rhuMAb interferon-alpha) in patients with systemic lupus erythematosus (ROSE). Ann Rheum Dis 75:196–202

    Article  PubMed  Google Scholar 

  12. 12.

    Preble OT, Rothko K, Klippel JH, Friedman RM, Johnston MI (1983) Interferon-induced 2′-5′ adenylate synthetase in vivo and interferon production in vitro by lymphocytes from systemic lupus erythematosus patients with and without circulating interferon. J Exp Med 157:2140–2146

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    von Wussow P, Jakschies D, Hochkeppel H, Horisberger M, Hartung K, Deicher H (1989) MX homologous protein in mononuclear cells from patients with systemic lupus erythematosus. Arthritis Rheum 32:914–918

    Google Scholar 

  14. 14.

    Rose T, Grutzkau A, Hirseland H, Huscher D, Dahnrich C, Dzionek A, Ozimkowski T, Schlumberger W, Enghard P, Radbruch A et al (2013) IFNalpha and its response proteins, IP-10 and SIGLEC-1, are biomarkers of disease activity in systemic lupus erythematosus. Ann Rheum Dis 72:1639–1645

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Hooks JJ, Jordan GW, Cupps T, Moutsopoulos HM, Fauci AS, Notkins AL (1982) Multiple interferons in the circulation of patients with systemic lupus erythematosus and vasculitis. Arthritis Rheum 25:396–400

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Yao Y, Higgs BW, Morehouse C, de Los RM, Trigona W, Brohawn P, White W, Zhang J, White B, Coyle AJ et al (2009) Development of potential pharmacodynamic and diagnostic markers for anti-IFN-alpha monoclonal antibody trials in systemic lupus erythematosus. Hum Genomics Proteomics 1:374312

    Google Scholar 

  17. 17.

    Morimoto AM, Flesher DT, Yang J, Wolslegel K, Wang X, Brady A, Abbas AR, Quarmby V, Wakshull E, Richardson B et al (2011) Association of endogenous anti-interferon-alpha autoantibodies with decreased interferon-pathway and disease activity in patients with systemic lupus erythematosus. Arthritis Rheum 63:2407–2415

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Hooks JJ, Moutsopoulos HM, Geis SA, Stahl NI, Decker JL, Notkins AL (1979) Immune interferon in the circulation of patients with autoimmune disease. N Engl J Med 301:5–8

    CAS  Article  PubMed  Google Scholar 

  19. 19.

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

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Kong KO, Tan AW, Thong BY, Lian TY, Cheng YK, Teh CL, Koh ET, Chng HH, Law WG, Lau TC et al (2009) Enhanced expression of interferon-inducible protein-10 correlates with disease activity and clinical manifestations in systemic lupus erythematosus. Clin Exp Immunol 156:134–140

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Bauer JW, Petri M, Batliwalla FM, Koeuth T, Wilson J, Slattery C, Panoskaltsis-Mortari A, Gregersen PK, Behrens TW, Baechler EC (2009) Interferon-regulated chemokines as biomarkers of systemic lupus erythematosus disease activity: a validation study. Arthritis Rheum 60:3098–3107

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Waddell SJ, Popper SJ, Rubins KH, Griffiths MJ, Brown PO, Levin M, Relman DA (2010) Dissecting interferon-induced transcriptional programs in human peripheral blood cells. PLoS One 5:e9753

    Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Merrill JT, Wallace DJ, Petri M, Kirou KA, Yao Y, White WI, Robbie G, Levin R, Berney SM, Chindalore V et al (2011) Safety profile and clinical activity of sifalimumab, a fully human anti-interferon alpha monoclonal antibody, in systemic lupus erythematosus: a phase I, multicentre, double-blind randomised study. Ann Rheum Dis 70:1905–1913

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Biesen R, Demir C, Barkhudarova F, Grun JR, Steinbrich-Zollner M, Backhaus M, Haupl T, Rudwaleit M, Riemekasten G, Radbruch A et al (2008) Sialic acid-binding Ig-like lectin 1 expression in inflammatory and resident monocytes is a potential biomarker for monitoring disease activity and success of therapy in systemic lupus erythematosus. Arthritis Rheum 58:1136–1145

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Kyogoku C, Smiljanovic B, Grun JR, Biesen R, Schulte-Wrede U, Haupl T, Hiepe F, Alexander T, Radbruch A, Grutzkau A (2013) Cell-specific type I IFN signatures in autoimmunity and viral infection: what makes the difference? PLoS One 8:e83776

    Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Lyons PA, McKinney EF, Rayner TF, Hatton A, Woffendin HB, Koukoulaki M, Freeman TC, Jayne DR, Chaudhry AN, Smith KG (2010) Novel expression signatures identified by transcriptional analysis of separated leucocyte subsets in systemic lupus erythematosus and vasculitis. Ann Rheum Dis 69:1208–1213

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Becker AM, Dao KH, Han BK, Kornu R, Lakhanpal S, Mobley AB, Li QZ, Lian Y, Wu T, Reimold AM et al (2013) SLE peripheral blood B cell, T cell and myeloid cell transcriptomes display unique profiles and each subset contributes to the interferon signature. PLoS One 8:e67003

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Yoshida T, Mei H, Dorner T, Hiepe F, Radbruch A, Fillatreau S, Hoyer BF (2010) Memory B and memory plasma cells. Immunol Rev 237:117–139

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Hepburn AL, Narat S, Mason JC (2010) The management of peripheral blood cytopenias in systemic lupus erythematosus. Rheumatology (Oxford) 49:2243–2254

    CAS  Article  Google Scholar 

  30. 30.

    Peck-Radosavljevic M, Wichlas M, Homoncik-Kraml M, Kreil A, Hofer H, Jessner W, Gangl A, Ferenci P (2002) Rapid suppression of hematopoiesis by standard or pegylated interferon-alpha. Gastroenterology 123:141–151

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Soza A, Everhart JE, Ghany MG, Doo E, Heller T, Promrat K, Park Y, Liang TJ, Hoofnagle JH (2002) Neutropenia during combination therapy of interferon alfa and ribavirin for chronic hepatitis C. Hepatology 36:1273–1279

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, Schaller JG, Talal N, Winchester RJ (1982) The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 25:1271–1277

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Kabanova S, Kleinbongard P, Volkmer J, Andree B, Kelm M, Jax TW (2009) Gene expression analysis of human red blood cells. Int J Med Sci 6:156–159

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Lood C, Amisten S, Gullstrand B, Jonsen A, Allhorn M, Truedsson L, Sturfelt G, Erlinge D, Bengtsson AA (2010) Platelet transcriptional profile and protein expression in patients with systemic lupus erythematosus: up-regulation of the type I interferon system is strongly associated with vascular disease. Blood 116:1951–1957

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Courtney PA, Crockard AD, Williamson K, Irvine AE, Kennedy RJ, Bell AL (1999) Increased apoptotic peripheral blood neutrophils in systemic lupus erythematosus: relations with disease activity, antibodies to double stranded DNA, and neutropenia. Ann Rheum Dis 58:309–314

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Samarajiwa SA, Forster S, Auchettl K, Hertzog PJ (2009) INTERFEROME: the database of interferon regulated genes. Nucleic Acids Res 37:D852–D857

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Hacbarth E, Kajdacsy-Balla A (1986) Low density neutrophils in patients with systemic lupus erythematosus, rheumatoid arthritis, and acute rheumatic fever. Arthritis Rheum 29:1334–1342

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Tochizawa S, Akamatsu S, Sugiyama Y, Muraguchi M, Ohmoto Y, Ono Y, Ishikawa H, Tanigami A, Sumida T, Mori T (2004) A flow cytometric method for determination of the interferon receptor IFNAR2 subunit in peripheral blood leukocyte subsets. J Pharmacol Toxicol Methods 50:59–66

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Shoshan Y, Shapira I, Toubi E, Frolkis I, Yaron M, Mevorach D (2001) Accelerated Fas-mediated apoptosis of monocytes and maturing macrophages from patients with systemic lupus erythematosus: relevance to in vitro impairment of interaction with iC3b-opsonized apoptotic cells. J Immunol 167:5963–5969

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Maria NI, Brkic Z, Waris M, van Helden-Meeuwsen CG, Heezen K, van de Merwe JP, van Daele PL, Dalm VA, Drexhage HA, Versnel MA (2014) MxA as a clinically applicable biomarker for identifying systemic interferon type I in primary Sjogren’s syndrome. Ann Rheum Dis 73:1052–1059

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Sehgal K, Guo X, Koduru S, Shah A, Lin A, Yan X, Dhodapkar KM (2013) Plasmacytoid dendritic cells, interferon signaling, and FcgammaR contribute to pathogenesis and therapeutic response in childhood immune thrombocytopenia. Sci Transl Med 5:193ra189

    Article  Google Scholar 

  42. 42.

    Crow YJ (2011) Type I interferonopathies: a novel set of inborn errors of immunity. Ann N Y Acad Sci 1238:91–98

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    Crow YJ, Casanova JL (2014) STING-associated vasculopathy with onset in infancy—a new interferonopathy. N Engl J Med 371:568–571

    Article  PubMed  Google Scholar 

  44. 44.

    Ramilo O, Allman W, Chung W, Mejias A, Ardura M, Glaser C, Wittkowski KM, Piqueras B, Banchereau J, Palucka AK et al (2007) Gene expression patterns in blood leukocytes discriminate patients with acute infections. Blood 109:2066–2077

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Zaas AK, Chen M, Varkey J, Veldman T, Hero AO 3rd, Lucas J, Huang Y, Turner R, Gilbert A, Lambkin-Williams R et al (2009) Gene expression signatures diagnose influenza and other symptomatic respiratory viral infections in humans. Cell Host Microbe 6:207–217

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Abbas AR, Wolslegel K, Seshasayee D, Modrusan Z, Clark HF (2009) Deconvolution of blood microarray data identifies cellular activation patterns in systemic lupus erythematosus. PLoS One 4:e6098

    Article  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Li Y, Lee PY, Kellner ES, Paulus M, Switanek J, Xu Y, Zhuang H, Sobel ES, Segal MS, Satoh M et al (2010) Monocyte surface expression of Fcgamma receptor RI (CD64), a biomarker reflecting type-I interferon levels in systemic lupus erythematosus. Arthritis Res Ther 12:R90

    Article  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Kikuchi-Taura A, Yura A, Tsuji S, Ohshima S, Kitatoube A, Shimizu T, Nii T, Katayama M, Teshigawara S, Yoshimura M et al (2015) Monocyte CD64 expression as a novel biomarker for the disease activity of systemic lupus erythematosus. Lupus. doi:10.1177/0961203315579093

    PubMed  Google Scholar 

  49. 49.

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

    CAS  Article  PubMed  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Robert Biesen.

Ethics declarations

Funding

The work was supported by the Sixth Framework Programme (project AutoCure; LSHB-CT-2006-018861), the German Research Foundation (grant number SFB650 TP12), the IMI JU-funded project BeTheCure (contract number 115142-29), and the Zukunftsfond Berlin (contract number 101399339). PAL and SMF were funded by project grants from the Medical Research Council (G0400929) and the Wellcome Trust (094227/Z/10/Z). SMF was supported by a Wellcome Trust Translational Medicine and Therapeutics PhD Studentship. Cambridge Institute for Medical Research is in receipt of a Wellcome Trust Strategic Award (079895). LSD was supported by an Alliance for Lupus Research (ALR) Award #257549 and National Institutes of Health grants AR067625 (PI, Satterthwaite) and AI122720 (PI, Satterthwaite).

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

.

ESM 1

(PDF 238 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Strauß, R., Rose, T., Flint, S.M. et al. Type I interferon as a biomarker in autoimmunity and viral infection: a leukocyte subset-specific analysis unveils hidden diagnostic options. J Mol Med 95, 753–765 (2017). https://doi.org/10.1007/s00109-017-1515-7

Download citation

Keywords

  • Disease activity
  • Type I interferon
  • Biomarker
  • Systemic lupus erythematosus