significance-of-ifn-1

60-80% of lupus patients exhibit an increased expression of ISGs in PBMCs (IFN signature).²

CENTRAL NERVOUS SYSTEM

Increased IFN-1 in CSF and high IFN-regulated gene expression are associated with neuropsychiatric manifestations.^8,9

SKIN:

IFNGS correlates with cutaneous disease activity.⁴

CARDIOVASCULAR:

IFN-1 is associated with increased risk of CVD, and IFNGS is associated with arterial hypertension.^{5, 6}

LIVER:

IFNGS is associated with elevated transaminases and liver disease.⁶

KIDNEY:

The patients affected by lupus nephritis showed local production of IFN-alpha associated with a type I IFN signature.⁷

JOINT:

Synovial tissue from patients with lupus and SLE arthritis has increased expression of IFN-inducible genes.⁸

ALT, alanine aminotransferase; AST, aspartate aminotransferase; CSF, cerebrospinal fluid; CVD, cardiovascular disease; IFN, interferon; IFN-1, type 1 interferon; IFNGS, interferon gene signature; SLE, systemic lupus erythematosus.

ALC, absolute lymphocyte count; C, complement; dsDNA, double-stranded DNA; ESR, erythrocyte sedimentation rate; IFN, interferon; RNP, ribonucleic protein; SLE, systemic lupus erythematosus; Sm, Smith; SSA, Sjögren syndrome antigen A; SSB, Sjögren syndrome antigen B.

Kirou et al. 2005: This retrospective study included patients with SLE (n=77), disease controls (n=20 patients with rheumatoid arthritis and n=2 patients with inflammatory uveitis), and healthy donors (n=28). Patients were recruited from October 2002 to March 2004. IFNα scores were determined by measuring the expression of PRKR, IFIT1, and IFI44 from peripheral blood mononuclear cells. Laboratory abnormalities associated with SLE, such as decreased complement proteins, haemoglobin, and albumin and increased autoantibodies (eg, anti-Ro, anti-U1 RNP, anti-Sm, anti-RBP, anti-dsDNA) were all associated with a high IFNα score.⁹
Kennedy et al. 2015: Patients were evaluated from the University of Michigan Observational Cohort, the EXPLORER, LUNAR, and ROSE trials, and the phase 1 rontalizumab trial. Healthy controls were recruited by the Genentech blood donation programme. All patients met the ACR criteria for SLE. Expression of HERC5, EPSTI1, and CMPK2 was measured to determine the IFN signature using quantitative PCR from whole blood samples. High IFN signature scores were associated with decreased complement proteins and increased anti-dsDNA, anti-SSA/Ro52, anti-RNP, anti-Sm, and BAFF.¹⁰

ACR, American College of Rheumatology; BAFF, B-cell–activating factor; CMPK2, cytidine/uridine monophosphate kinase 2; dsDNA, double-stranded DNA; EPSTI1, epithelial stromal interaction 1; HERC5, HECT and RLD domain containing E3 ubiquitin protein ligase 5; IFI44, interferon-induced protein 44; IFIT1, interferon-induced protein with tetratricopeptide repeats 1; IFN, interferon; PCR, polymerase chain reaction; PRKR, eukaryotic translation initiation factor 2 alpha kinase 2; RBP, RNA-binding protein; RNP, ribonucleic protein; SLE, systemic lupus erythematosus; Sm, Smith; SSA, Sjögren syndrome antigen A; SSB, Sjögren syndrome antigen B.

References:

1. Crow MK. Type I interferon in the pathogenesis of lupus. J Immunol. 2014;192(12):5459-5468. 2. Lauwerys BR, Ducreux J, Houssiau FA. Type I interferon blockade in systemic lupus erythematosus: where do we stand? Rheumatology (Oxford). 2014;53(8):1369-1376. 3. Rönnblom L, Elkon KB. Cytokines as therapeutic targets in SLE. Nat Rev Rheumatol. 2010;6(6):339-347. 4. Yao Y, Higgs BW, Richman L, et al. Use of type I interferon inducible mRNAs as pharmacodynamic markers and potential diagnostic markers in trials with sifalimumab, an anti-IFNα antibody, in systemic lupus erythematosus. Arthritis Res Ther. 2010;12(suppl 1):S6. 5. Becker AM, Dao KH, Han BK, et al. SLE peripheral blood B cell, T cell and myeloid cell transcriptomes display unique profiles and each subset contributes to the interferon signature. PLoS One. 2013;8(6):e67003. 6. Jefferies CA. Regulating IRFs in IFN driven disease. Front Immunol. 2019;10:325. 7. Mai L, Asaduzzaman A, Noamani B, et al. The baseline interferon signature predicts disease severity over the subsequent 5 years in systemic lupus erythematosus. Arthritis Res Ther. 2021;23(1):29. 8. Baechler EC, Batliwalla FM, Karypis G, et al. Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci USA. 2003;100(5):2610-2615. 9. Shiozawa S, Kuroki Y, Kim M, et al. Interferon-alpha in lupus psychosis. Arthritis Rheum. 1992;35(4):417-422. 10. Braunstein I, Klein R, Okawa J, et al. The interferon-regulated gene signature is elevated in subacute cutaneous lupus erythematosus and discoid lupus erythematosus and correlates with the Cutaneous Lupus Area and Severity Index score. Br J Dermatol. 2012;166(5):971-975. 11. Sarkar MK, Hile GA, Tsoi LC, et al. Photosensitivity and type I IFN responses in cutaneous lupus are driven by epidermal-derived interferon kappa. Ann Rheum Dis. 2018;77(11):1653-1664. 12. Wenzel J. Cutaneous lupus erythematosus: new insights into pathogenesis and therapeutic strategies. Nat Rev Rheumatol. 2019;15(9):519-532. 13. Tumurkhuu G, Montano E, Jefferies C. Innate immune dysregulation in the development of cardiovascular disease in lupus. Curr Rheumatol Rep. 2019;21(9):46. 14. de Jesus AA, Hou Y, Brooks S, et al. Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases. J Clin Invest. 2020;130(4):1669-1682. 15. Watanabe S, Imaizumi T, Tsuruga K, et al. Glomerular expression of myxovirus resistance protein 1 in human mesangial cells: possible activation of innate immunity in the pathogenesis of lupus nephritis. Nephrology (Carlton). 2013;18(12):833-837. 16. Castellano G, Cafiero C, Divella C, et al. Local synthesis of interferon-alpha in lupus nephritis is associated with type I interferons signature and LMP7 induction in renal tubular epithelial cells. Arthritis Res Ther. 2015;17(1):72. 17. Peterson KS, Huang JF, Zhu J, et al. Characterization of heterogeneity in the molecular pathogenesis of lupus nephritis from transcriptional profiles of laser-captured glomeruli. J Clin Invest. 2004;113(12):1722-1733. 18. Kirou KA, Lee C, George S, et al. 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(5):1491-1503. 19. Feng X, Wu H, Grossman JM, et al. Association of increased interferon-inducible gene expression with disease activity and lupus nephritis in patients with systemic lupus erythematosus. Arthritis Rheum. 2006;54(9):2951-2962. 20. Toukap NA, Galant C, Theate I, et al. Identification of distinct gene expression profiles in the synovium of patients with systemic lupus erythematosus. Arthritis Rheum. 2007;56(5):1579-1588. 21. Kennedy WP, Maciuca R, Wolslegel K, et al. Association of the interferon signature metric with serological disease manifestations but not global activity scores in multiple cohorts of patients with SLE. Lupus Sci Med. 2015;2(1):e000080.

Burden of Disease

Pathophysiology of Disease

Learn More

Welcome to Unlocking-lupus Egypt

Clinical correlations between type I IFN and SLE1

60-80% of lupus patients exhibit an increased expression of ISGs in PBMCs (IFN signature).2