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Characterization of virus-mediated autoimmunity and the consequences for pathological process in patients with systemic lupus erythematosus

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Abstract

Introduction/Objectives

This study aimed to identify differentially expressed genes (DEGs) of systemic lupus erythematosus (SLE) using gene expression-based computational methodologies to analyze disease-immune interactions, which affect the development and progression of SLE.

Method

Twenty-six patients with SLE and 46 healthy controls were selected from the Gene Expression Omnibus (GEO) database. The significantly enriched immune and virus-related gene lists were computed and visualized by using the DEGs from the gene set enrichment analysis (GSEA). Quantification of 38 immune cells was performed in determining the impact of immune cells on the virus mediated immunity in SLE by using ImmQuant algorithm.

Results

Thirty-nine upregulated and 57 downregulated were identified in SLE patient compared to the healthy controls. Upregulated genes were significantly implicated in Gene Ontology gene sets as cytokine mediated signaling, secretion, and exocytosis in immune response pathways in 26 female SLE patients. In addition, these genes were enriched in hepatitis C, influenza A, measles, Epstein–Barr virus, and herpes simplex virus 1 infection in Kyoto Encyclopedia of Genes and Genomes pathways. Especially, FCGR1A, IRF7, OAS2, CAMP, MX1, OAS3, OAS1, DEFA3, ISG15, and RSAD2 were involved in virus mediated SLE mechanism, and the expression for OAS1, OAS2, and IRF7 was closely associated with the quantities of colony forming unit-monocyte and colony forming unit-granulocyte.

Conclusions

Identifying virus-mediated SLE genes and quantifies of immune cells were used to understand the pathological process and perform early diagnosis of female SLE, and will lead to clinical tools for treating SLE in patients.

Key Points

• Using gene expression-based computational methodologies, the 57 immune and viral genes were significantly upregulated in 26 SLE patients.

• The identified three key  viral genes such as OAS1, OAS2, and IF7 were closely associated with colony-forming unit-monocytes and colony-forming unit-granulocytes, which affect the virus mediated immunity in SLE.

• The viral genes and quantifies of immune cells are useful in understanding pathogenesis of SLE, and this will provide clinical strategies of potential treatment choices in SLE patients.

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Data Availability

This data can be directly accessed from the Gene Expression Omnibus (GEO) database.

References

  1. Ghodke-Puranik Y, Niewold TB (2015) Immunogenetics of systemic lupus erythematosus: A comprehensive review. J Autoimmunity 64:125–136. https://doi.org/10.1016/j.jaut.2015.08.004

    Article  CAS  Google Scholar 

  2. Chi M, Ma K, Li Y, Quan M, Han Z, Ding Z, Liang X, Zhang Q, Song L, Liu C (2021) Immunological involvement of microRNAs in the key events of systemic lupus erythematosus. Front Immunol 12:699684. https://doi.org/10.3389/fimmu.2021.699684

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Mok CC, Lau CS (2003) Pathogenesis of systemic lupus erythematosus. J Clin Pathol 56(7):481–490. https://doi.org/10.1136/jcp.56.7.481

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Gergianaki I, Bortoluzzi A, Bertsias G (2018) Update on the epidemiology, risk factors, and disease outcomes of systemic lupus erythematosus. Best Pract Res Clin Rheumatol 32(2):188–205. https://doi.org/10.1016/j.berh.2018.09.004

    Article  PubMed  Google Scholar 

  5. Ceccarelli F, Perricone C, Borgiani P, Ciccacci C, Rufini S, Cipriano E, Alessandri C, Spinelli FR, SiliScavalli A, Novelli G, Valesini G, Conti F (2015) Genetic factors in systemic lupus erythematosus: contribution to disease phenotype. J Immunol Res 2015:745647. https://doi.org/10.1155/2015/745647

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Teruel M, Alarcón-Riquelme ME (2016) The genetic basis of systemic lupus erythematosus: what are the risk factors and what have we learned. J Autoimmun 74:161–175. https://doi.org/10.1016/j.jaut.2016.08.001

    Article  CAS  PubMed  Google Scholar 

  7. Ramos PS, Brown EE, Kimberly RP, Langefeld CD (2010) Genetic factors predisposing to systemic lupus erythematosus and lupus nephritis. Semin Nephrol 30(2):164–176. https://doi.org/10.1016/j.semnephrol.2010.01.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Crow MK, Kirou KA, Wohlgemuth J (2003) Microarray analysis of interferon-regulated genes in SLE. Autoimmunity 36(8):481–490. https://doi.org/10.1080/08916930310001625952

    Article  CAS  PubMed  Google Scholar 

  9. Catalina MD, Bachali P, Geraci NS, Grammer AC, Lipsky PE (2019) Gene expression analysis delineates the potential roles of multiple interferons in systemic lupus erythematosus. Commun Biol 2:140. https://doi.org/10.1038/s42003-019-0382-x

    Article  PubMed  PubMed Central  Google Scholar 

  10. Wu C, Zhao Y, Lin Y, Yang X, Yan M, Min Y, Pan Z, Xia S, Shao Q (2018) Bioinformatics analysis of differentially expressed gene profiles associated with systemic lupus erythematosus. Mol Med Rep 17(3):3591–3598. https://doi.org/10.3892/mmr.2017.8293

    Article  CAS  PubMed  Google Scholar 

  11. Lauwerys BR, Hachulla E, Spertini F, Lazaro E, Jorgensen C, Mariette X, Haelterman E, Grouard-Vogel G, Fanget B, Dhellin O, Vandepapelière P, Houssiau FA (2013) Down-regulation of interferon signature in systemic lupus erythematosus patients by active immunization with interferon α-kinoid. Arthritis Rheum 65(2):447–456. https://doi.org/10.1002/art.37785

    Article  CAS  PubMed  Google Scholar 

  12. Wither JE, Prokopec SD, Noamani B, Chang NH, Bonilla D, Touma Z, Avila-Casado C, Reich HN, Scholey J, Fortin PR, Boutros PC, Landolt-Marticorena c, (2018) Identification of a neutrophil-related gene expression signature that is enriched in adult systemic lupus erythematosus patients with active nephritis: Clinical/pathologic associations and etiologic mechanisms. PLoS One 13(5):e0196117. https://doi.org/10.1371/journal.pone.0196117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Gautier L, Cope L, Bolstad BM, Irizarry RA (2004) affy—analysis of Affymetrix GeneChip data at the probe level. Bioinformatics 20(3):307–315. https://doi.org/10.1093/bioinformatics/btg405

    Article  CAS  PubMed  Google Scholar 

  14. Kim A, Lim SM, Kim JH, Seo JS (2021) Integrative genomic and transcriptomic analyses of tumor suppressor genes and their role on tumor microenvironment and immunity in lung squamous cell carcinoma. Front Immunol 12:598671. https://doi.org/10.3389/fimmu.2021.598671

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 102(43):15545–15550. https://doi.org/10.1073/pnas.0506580102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Seo JS, Lee JW, Kim A, Shin JY, Jung YJ, Lee SB, Kim YH, Park S, Lee HJ, Park IK, Kang CH, Yun JY, Kim J, Kim YT (2018) Whole exome and transcriptome analyses integrated with microenvironmental immune signatures of lung squamous cell carcinoma. Cancer Immunol Res 6(7):848–859. https://doi.org/10.1158/2326-6066.CIR-17-0453

    Article  CAS  PubMed  Google Scholar 

  17. Love MI, Anders S, Kim V, Huber W (2015) RNA-Seq workflow: gene-level exploratory analysis and differential expression. F1000Res 4:1070. https://doi.org/10.12688/f1000research.7035.1

    Article  PubMed  PubMed Central  Google Scholar 

  18. Frishberg A, Brodt A, Steuerman Y, Gat-Viks I (2016) ImmQuant: a user-friendly tool for inferring immune cell-type composition from gene-expression data. Bioinformatics 32(24):3842–3843. https://doi.org/10.1093/bioinformatics/btw535

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Almaani S, Meara A, Rovin BH (2017) Update on lupus nephritis. Clin J Am Soc Nephrol 12(5):825–835. https://doi.org/10.2215/CJN.05780616

    Article  PubMed  Google Scholar 

  20. Nelson P, Rylance P, Roden D, Trela M, Tugnet N (2014) Viruses as potential pathogenic agents in systemic lupus erythematosus. Lupus 23(6):596–605. https://doi.org/10.1177/0961203314531637

    Article  CAS  PubMed  Google Scholar 

  21. Jog NR, James JA (2020) Epstein Barr virus and autoimmune responses in systemic lupus erythematosus. Front Immunol 11:623944. https://doi.org/10.3389/fimmu.2020.623944

    Article  CAS  PubMed  Google Scholar 

  22. Spihlman AP, Gadi N, Wu SC, Moulton VR (2020) COVID-19 and systemic lupus erythematosus: focus on immune response and therapeutics. Front Immunol 11:589474. https://doi.org/10.3389/fimmu.2020.589474

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Mok CC, Tse SM, Chan KL, Ho LY (2018) Effect of immunosuppressive therapies on survival of systemic lupus erythematosus: a propensity score analysis of a longitudinal cohort. Lupus 27(5):722–727. https://doi.org/10.1177/0961203317739129

    Article  CAS  PubMed  Google Scholar 

  24. Herrada AA, Escobedo N, Iruretagoyena M, Valenzuela RA, Burgos PI, Cuitino L (2019) Llanos C (2019) Innate immune cells’ contribution to systemic lupus erythematosus. Front Immunol 10:772. https://doi.org/10.3389/fimmu.2019.00772

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Navarra SV, Guzmán RM, Gallacher AE, Hall S, Levy RA, Jimenez RE, Li EK, Thomas M, Kim HY, León MG, Tanasescu C, Nasonov E, Lan JL, Pineda L, Zhong ZJ, Freimuth W, Petri MA (2011) Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet 377(9767):721–731. https://doi.org/10.1016/S0140-6736(10)61354-2

    Article  CAS  PubMed  Google Scholar 

  26. Khamashta M, Merrill JT, Werth VP, Furie R, Kalunian K, Illei GG, Drappa J, Wang L, Greth W (2016) Sifalimumab, an anti-interferon-α monoclonal antibody, in moderate to severe systemic lupus erythematosus: a randomised, double-blind, placebo-controlled study. Ann Rheum Dis 75(11):1909–1916. https://doi.org/10.1136/annrheumdis-2015-208562

    Article  CAS  PubMed  Google Scholar 

  27. Morand EF, Furie R, Tanaka Y, Bruce IN, Askanase AD, Richez C, Bae SC, Brohawn PZ, Pineda L, Berglind A, Tummala R (2020) Trial of anifrolumab in active systemic lupus erythematosus. N Engl J Med 382(3):211–221. https://doi.org/10.1056/NEJMoa1912196

    Article  CAS  PubMed  Google Scholar 

  28. Weckerle CE, Niewold TB (2011) The unexplained female predominance of systemic lupus erythematosus: clues from genetic and cytokine studies. Clin Rev Allergy Immunol 40(1):42–49. https://doi.org/10.1007/s12016-009-8192-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Pan Q, Liu Z, Liao S, Ye L, Lu X, Chen X, Li Z, Li X, Xu YZ, Liu H (2019) Current mechanistic insights into the role of infection in systemic lupus erythematosus. Biomed Pharmacother 117:109122. https://doi.org/10.1016/j.biopha.2019.109122

    Article  CAS  PubMed  Google Scholar 

  30. Quaglia M, Merlotti G, De Andrea M, Borgogna C, Cantaluppi V (2021) Viral infections and systemic lupus erythematosus: new players in an old story. Viruses 13(2):277. https://doi.org/10.3390/v13020277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Dreyfus DH (2011) Autoimmune disease: a role for new anti-viral therapies? Autoimmun Rev 11(2):88–97. https://doi.org/10.1016/j.autrev.2011.08.005

    Article  CAS  PubMed  Google Scholar 

  32. Gies V, Bekaddour N, Dieudonné Y, Guffroy A, Frenger Q, Gros F, Rodero MP, Herbeuval JP, Korganow AS (2020) Beyond anti-viral effects of chloroquine/hydroxychloroquine. Front Immunol 11:1409. https://doi.org/10.3389/fimmu.2020.01409

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Ahmed M (2018) Era of direct acting anti-viral agents for the treatment of hepatitis C. World J Hepatol 10(10):670–684. https://doi.org/10.4254/wjh.v10.i10.670

    Article  PubMed  PubMed Central  Google Scholar 

  34. Francis L, Perl A (2010) Infection in systemic lupus erythematosus: friend or foe? Int J Clin Rheumtol 5(1):59–74. https://doi.org/10.2217/ijr.09.72

    Article  PubMed  PubMed Central  Google Scholar 

  35. Migliorini A, Anders HJ (2012) A novel pathogenetic concept-antiviral immunity in lupus nephritis. Nat Rev Nephrol 8(3):183–189. https://doi.org/10.1038/nrneph.2011.197

    Article  CAS  PubMed  Google Scholar 

  36. Leisching G, Wiid I, Baker B (2018) OAS1, 2, and 3: Significance during active tuberculosis? J Infect Dis 217(10):1517–1521. https://doi.org/10.1093/infdis/jiy084

    Article  CAS  PubMed  Google Scholar 

  37. Feng X, Huang J, Liu Y, Xiao L, Wang D, Hua B, Tsao BP, Sun L (2015) Identification of interferon-inducible genes as diagnostic biomarker for systemic lupus erythematosus. Clin Rheumatol 34(1):71–79. https://doi.org/10.1007/s10067-014-2799-4

    Article  PubMed  Google Scholar 

  38. Xu WD, Zhang YJ, Xu K, Zhai Y, Li BZ, Pan HF, Ye DQ (2012) IRF7, a functional factor associates with systemic lupus erythematosus. Cytokine 58(3):317–320. https://doi.org/10.1016/j.cyto.2012.03.003

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the ArrayExpress(E-GEOD-39088; Lauwerys et al. 11) for using their data.

Funding

This work was supported by Il-Yang Pharm. [grant number I2200061].

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Authors and Affiliations

  1. Department of Education and Training, CHA Bundang Medical Center, Seongnam, Republic of Korea

    Ahreum Kim & Joo-Hang Kim

  2. Department of Medicine, Korea University College of Medicine, Seoul, Republic of Korea

    Sung Jae Choi, Gwan Gyu Song & Jae Hyun Jung

  3. Division of Rheumatology, Department of Internal Medicine, Korea University Ansan Hospital, Ansan, Republic of Korea

    Sung Jae Choi & Jae Hyun Jung

  4. Division of Rheumatology, Department of Internal Medicine, Korea University Guro Hospital, Seoul, Republic of Korea

    Gwan Gyu Song

  5. Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea

    Joo-Hang Kim

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Kim, A., Choi, S.J., Song, G.G. et al. Characterization of virus-mediated autoimmunity and the consequences for pathological process in patients with systemic lupus erythematosus. Clin Rheumatol 42, 2799–2809 (2023). https://doi.org/10.1007/s10067-023-06597-6

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