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Potential role of viral infection and B cells as a linker between innate and adaptive immune response in systemic lupus erythematosus

Immunologic Research volume 69, pages 196–204 (2021)Cite this article

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease that involves several organ systems. Although B cells play a key role in SLE pathogenesis, the mechanisms behind B cell dysregulation in SLE development remained controversial. Finding the modules containing highly co-expressed genes in B cells could explain biological pathways involved in the pathogenesis of SLE, which may further support the reasons for the altered function of B cells in SLE disease. A total of three microarray gene expression datasets were downloaded from Gene Expression Omnibus. SLE samples were prepared from the purified B lymphocyte cells of the patients who have not received immunosuppressive drugs as well as high dose immunocytotoxic therapies or steroids. A weighted gene co-expression network was then constructed to find the relevant modules implicated in the SLE progression. Among 17 identified modules, 3 modules were selected through mapping to STRING and finding the ones that had highly connection at the protein level. These modules clearly indicate the involvement of several pathways in the pathogenesis of SLE including viral infection, adaptive immune response, and innate immune response in B lymphocytes. The WGCN analysis further revealed the co-expressed genes involved in both innate and adaptive immune systems. Mix infections and primary immunodeficiency might also dysregulate B lymphocytes, which may facilitate SLE development. As such, identifying novel biomarkers and pathways in lupus would be of importance.

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Data availability

All data generated or analyzed during this study are included in this published article.

References

  1. Jakes RW, Bae SC, Louthrenoo W, Mok CC, Navarra SV, Kwon N. Systematic review of the epidemiology of systemic lupus erythematosus in the Asia-Pacific region: prevalence, incidence, clinical features, and mortality. Arthritis Care Res. 2012;64(2):159–68.

    Article  Google Scholar 

  2. Wakeland EK, Liu K, Graham RR, Behrens TW. Delineating the genetic basis of systemic lupus erythematosus. Immunity. 2001;15(3):397–408. https://doi.org/10.1016/s1074-7613(01)00201-1.

    Article  PubMed  CAS  Google Scholar 

  3. Maidhof W, Hilas O. Lupus: an overview of the disease and management options. Pharm Ther. 2012;37(4):240.

    Google Scholar 

  4. Pan L, Lu M-P, Wang J-H, Xu M, Yang S-R. Immunological pathogenesis and treatment of systemic lupus erythematosus. World J Pediatr. 2020;16(1):19–30.

  5. Shlomchik MJ. Sites and stages of autoreactive B cell activation and regulation. Immunity. 2008;28(1):18–28.

    Article  CAS  Google Scholar 

  6. Lund FE. Cytokine-producing B lymphocytes—key regulators of immunity. Curr Opin Immunol. 2008;20(3):332–8.

    Article  CAS  Google Scholar 

  7. Hampe CS. B cells in autoimmune diseases. Scientifica. 2012;2012:215308.

  8. Harvey PR, Gordon C. B-cell targeted therapies in systemic lupus erythematosus. BioDrugs. 2013;27(2):85–95.

    Article  CAS  Google Scholar 

  9. Sherer Y, Gorstein A, Fritzler MJ, Shoenfeld Y. Autoantibody explosion in systemic lupus erythematosus: more than 100 different antibodies found in SLE patients. Seminars in arthritis and rheumatism. 2004; 34(2):501–37.

  10. Dema B, Charles N. Autoantibodies in SLE: specificities, isotypes and receptors. Antibodies. 2016;5(1):2.

    Article  CAS  Google Scholar 

  11. Thurman JM, Yapa R. Complement therapeutics in autoimmune disease. Front Immunol. 2019;10:672.

  12. Yurasov S, Tiller T, Tsuiji M, Velinzon K, Pascual V, Wardemann H, et al. Persistent expression of autoantibodies in SLE patients in remission. J Exp Med. 2006;203(10):2255–61.

    Article  CAS  Google Scholar 

  13. Liu R, Zhang W, Liu Z-Q, Zhou H-H. Associating transcriptional modules with colon cancer survival through weighted gene co-expression network analysis. BMC Genomics. 2017;18(1):361. https://doi.org/10.1186/s12864-017-3761-z.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Miller JA, Cai C, Langfelder P, Geschwind DH, Kurian SM, Salomon DR, et al. Strategies for aggregating gene expression data: The collapseRows R function. BMC Bioinformatics. 2011;12(1):322. https://doi.org/10.1186/1471-2105-12-322.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Holtman IR, Raj DD, Miller JA, Schaafsma W, Yin Z, Brouwer N, et al. Induction of a common microglia gene expression signature by aging and neurodegenerative conditions: a co-expression meta-analysis. Acta Neuropathol Commun. 2015;3(1):31.

    Article  CAS  Google Scholar 

  16. Langfelder P, Horvath S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics. 2008;9(1):559.

    Article  CAS  Google Scholar 

  17. Giulietti M, Occhipinti G, Principato G, Piva F. Weighted gene co-expression network analysis reveals key genes involved in pancreatic ductal adenocarcinoma development. Cell Oncol. 2016;39(4):379–88.

    Article  CAS  Google Scholar 

  18. Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, et al. STRING v11: protein–protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2018;47(D1):D607–13.

    Article  CAS  Google Scholar 

  19. Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J, et al. STRING v10: protein–protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 2014;43(D1):D447–52.

    Article  CAS  Google Scholar 

  20. Bastian M, Heymann S, Jacomy M. Gephi: an open source software for exploring and manipulating networks. Third international AAAI conference on weblogs and social media2009.

  21. Reimand J, Arak T, Adler P, Kolberg L, Reisberg S, Peterson H, et al. g: Profiler—a web server for functional interpretation of gene lists (2016 update). Nucleic Acids Res. 2016;44(W1):W83–9.

    Article  CAS  Google Scholar 

  22. Clark MR, Mandal M, Ochiai K, Singh H. Orchestrating B cell lymphopoiesis through interplay of IL-7 receptor and pre-B cell receptor signalling. Nat Rev Immunol. 2014;14(2):69–80. https://doi.org/10.1038/nri3570.

    Article  PubMed  CAS  Google Scholar 

  23. Dorner T, Giesecke C, Lipsky PE. Mechanisms of B cell autoimmunity in SLE. Arthritis Res Ther. 2011;13(5):243. https://doi.org/10.1186/ar3433.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Frances R, Tumang JR, Rothstein TL. B-1 cells are deficient in Lck: defective B cell receptor signal transduction in B-1 cells occurs in the absence of elevated Lck expression. J Immunol. 2005;175(1):27–31. https://doi.org/10.4049/jimmunol.175.1.27.

    Article  PubMed  CAS  Google Scholar 

  25. Poole BD, Templeton AK, Guthridge JM, Brown EJ, Harley JB, James JA. Aberrant Epstein-Barr viral infection in systemic lupus erythematosus. Autoimmun Rev. 2009;8(4):337–42. https://doi.org/10.1016/j.autrev.2008.12.008.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Moon UY, Park SJ, Oh ST, Kim WU, Park SH, Lee SH, et al. Patients with systemic lupus erythematosus have abnormally elevated Epstein-Barr virus load in blood. Arthritis Res Ther. 2004;6(4):R295-302. https://doi.org/10.1186/ar1181.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. McChesney MB, Kehrl JH, Valsamakis A, Fauci AS, Oldstone MB. Measles virus infection of B lymphocytes permits cellular activation but blocks progression through the cell cycle. J Virol. 1987;61(11):3441–7.

    Article  CAS  Google Scholar 

  28. Zhdanov V. Integration of viral genomes. Nature. 1975;256(5517):471–3.

    Article  CAS  Google Scholar 

  29. Viola MV, Gann K, Scott C, Rothfield N. Absence of measles proviral DNA in systemic lupus erythematosus. Nature. 1978;275(5681):667–9. https://doi.org/10.1038/275667a0.

    Article  PubMed  CAS  Google Scholar 

  30. Cunninghame Graham DS. Genome-wide association studies in systemic lupus erythematosus: a perspective. Arthritis Res Ther. 2009;11(4):119. https://doi.org/10.1186/ar2739.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Grammatikos AP, Tsokos GC. Immunodeficiency and autoimmunity: lessons from systemic lupus erythematosus. Trends Mol Med. 2012;18(2):101–8. https://doi.org/10.1016/j.molmed.2011.10.005.

    Article  PubMed  CAS  Google Scholar 

  32. Odendahl M, Jacobi A, Hansen A, Feist E, Hiepe F, Burmester GR, et al. Disturbed peripheral B lymphocyte homeostasis in systemic lupus erythematosus. J Immunol. 2000;165(10):5970–9. https://doi.org/10.4049/jimmunol.165.10.5970.

    Article  PubMed  CAS  Google Scholar 

  33. Chen L, Widhopf G, Huynh L, Rassenti L, Rai KR, Weiss A, et al. Expression of ZAP-70 is associated with increased B-cell receptor signaling in chronic lymphocytic leukemia. Blood. 2002;100(13):4609–14.

    Article  CAS  Google Scholar 

  34. Chen L, Apgar J, Huynh L, Dicker F, Giago-McGahan T, Rassenti L, et al. ZAP-70 directly enhances IgM signaling in chronic lymphocytic leukemia. Blood. 2005;105(5):2036–41.

    Article  CAS  Google Scholar 

  35. Dörner T, Giesecke C, Lipsky PE. Mechanisms of B cell autoimmunity in SLE. Arthritis Res Ther. 2011;13(5):243. https://doi.org/10.1186/ar3433.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Majolini MB, D’elios MM, Galieni P, Boncristiano M, Lauria F, Del Prete G, et al. Expression of the T-cell–specific tyrosine kinase Lck in normal B-1 cells and in chronic lymphocytic leukemia B cells. Blood. 1998;91(9):3390–6.

    Article  CAS  Google Scholar 

  37. Isaák A, Gergely P Jr, Szekeres Z, Prechl J, Poór G, Erdei A, et al. Physiological up-regulation of inhibitory receptors FcγRII and CR1 on memory B cells is lacking in SLE patients. Int Immunol. 2008;20(2):185–92.

    Article  CAS  Google Scholar 

  38. Dommett RM, Klein N, Turner MW. Mannose-binding lectin in innate immunity: past, present and future. Tissue Antigens. 2006;68(3):193–209. https://doi.org/10.1111/j.1399-0039.2006.00649.x.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Carroll MC. The role of complement in B cell activation and tolerance. Adv Immunol. 2000;74:61–88. https://doi.org/10.1016/s0065-2776(08)60908-6.

    Article  PubMed  CAS  Google Scholar 

  40. Feng X, Wu H, Grossman JM, Hanvivadhanakul P, FitzGerald JD, Park GS, 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):2951–62. https://doi.org/10.1002/art.22044.

    Article  PubMed  CAS  Google Scholar 

  41. Unterholzner L. The interferon response to intracellular DNA: why so many receptors? Immunobiology. 2013;218(11):1312–21. https://doi.org/10.1016/j.imbio.2013.07.007.

    Article  PubMed  CAS  Google Scholar 

  42. Bentz GL, Shackelford J, Pagano JS. Epstein-Barr virus latent membrane protein 1 regulates the function of interferon regulatory factor 7 by inducing its sumoylation. J Virol. 2012;86(22):12251–61. https://doi.org/10.1128/JVI.01407-12.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Wang JH, Wu Q, Yang P, Li H, Li J, Mountz JD, et al. Type I interferon-dependent CD86(high) marginal zone precursor B cells are potent T cell costimulators in mice. Arthritis Rheum. 2011;63(4):1054–64. https://doi.org/10.1002/art.30231.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Pau E, Cheung YH, Loh C, Lajoie G, Wither JE. TLR tolerance reduces IFN-alpha production despite plasmacytoid dendritic cell expansion and anti-nuclear antibodies in NZB bicongenic mice. PLoS ONE. 2012;7(5):e36761. https://doi.org/10.1371/journal.pone.0036761.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Hamilton JA, Hsu HC, Mountz JD. Role of production of type I interferons by B cells in the mechanisms and pathogenesis of systemic lupus erythematosus. Discov Med. 2018;25(135):21–9.

    PubMed  Google Scholar 

  46. Applequist SE, Wallin RP, Ljunggren HG. Variable expression of Toll-like receptor in murine innate and adaptive immune cell lines. Int Immunol. 2002;14(9):1065–74. https://doi.org/10.1093/intimm/dxf069.

    Article  PubMed  CAS  Google Scholar 

  47. Kenny EF, Quinn SR, Doyle SL, Vink PM, van Eenennaam H, O’Neill LAJ. Bruton’s tyrosine kinase mediates the synergistic signalling between TLR9 and the B cell receptor by regulating calcium and calmodulin. PLoS ONE. 2013;8(8):e74103. https://doi.org/10.1371/journal.pone.0074103.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Gao W, Xiong Y, Li Q, Yang H. Inhibition of toll-like receptor signaling as a promising therapy for inflammatory diseases: a journey from molecular to nano therapeutics. Front Physiol. 2017;8(508). https://doi.org/10.3389/fphys.2017.00508.

  49. Ziegler-Heitbrock HW, Pechumer H, Petersmann I, Durieux JJ, Vita N, Labeta MO, et al. CD14 is expressed and functional in human B cells. Eur J Immunol. 1994;24(8):1937–40. https://doi.org/10.1002/eji.1830240835.

    Article  PubMed  CAS  Google Scholar 

  50. Duhlin A. The regulation of B cell responses in systemic autoimmunity. Thesis, 2017

  51. McGaha TL, Sorrentino B, Ravetch JV. Restoration of tolerance in lupus by targeted inhibitory receptor expression. Science. 2005;307(5709):590–3.

    Article  CAS  Google Scholar 

  52. Kyogoku C, Dijstelbloem HM, Tsuchiya N, Hatta Y, Kato H, Yamaguchi A, et al. Fcγ receptor gene polymorphisms in Japanese patients with systemic lupus erythematosus: contribution of FCGR2B to genetic susceptibility. Arthritis Rheum. 2002;46(5):1242–54.

    Article  CAS  Google Scholar 

  53. Mkaddem SB, Murua A, Flament H, Titeca-Beauport D, Bounaix C, Danelli L, et al. Lyn and Fyn function as molecular switches that control immunoreceptors to direct homeostasis or inflammation. Nat Commun. 2017;8(1):1–13.

    Article  CAS  Google Scholar 

  54. Ben Mkaddem S, Benhamou M, Monteiro RC. Understanding Fc receptor involvement in inflammatory diseases: from mechanisms to new therapeutic tools. Front Immunol. 2019;10(811). https://doi.org/10.3389/fimmu.2019.00811.

  55. Hayden MS, West AP, Ghosh S. NF-kappaB and the immune response. Oncogene. 2006;25(51):6758–80. https://doi.org/10.1038/sj.onc.1209943.

    Article  PubMed  CAS  Google Scholar 

  56. Schulze-Luehrmann J, Ghosh S. Antigen-receptor signaling to nuclear factor kappa B. Immunity. 2006;25(5):701–15. https://doi.org/10.1016/j.immuni.2006.10.010.

    Article  PubMed  CAS  Google Scholar 

  57. Martin P, Moscat J. Th1/Th2 differentiation and B cell function by the atypical PKCs and their regulators. Front Immunol. 2012;3(241). https://doi.org/10.3389/fimmu.2012.00241.

  58. Yu S-L, Kuan W-P, Wong C-K, Li EK, Tam L-S. Immunopathological roles of cytokines, chemokines, signaling molecules, and pattern-recognition receptors in systemic lupus erythematosus. Clin Dev Immunol. 2012;2012:715190. https://doi.org/10.1155/2012/715190.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Hampe CS. B cells in autoimmune diseases. Scientifica. 2012;2012:215308. https://doi.org/10.6064/2012/215308.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Liu Q, Liu Z, Rozo CT, Hamed HA, Alem F, Urban JF Jr, et al. The role of B cells in the development of CD4 effector T cells during a polarized Th2 immune response. J Immunol. 2007;179(6):3821–30. https://doi.org/10.4049/jimmunol.179.6.3821.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Choi SC, Morel L. B cell contribution of the CD4(+) T cell inflammatory phenotypes in systemic lupus erythematosus. Autoimmunity. 2017;50(1):37–41. https://doi.org/10.1080/08916934.2017.1280028.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Harvey BP, Gee RJ, Haberman AM, Shlomchik MJ, Mamula MJ. Antigen presentation and transfer between B cells and macrophages. Eur J Immunol. 2007;37(7):1739–51.

    Article  CAS  Google Scholar 

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Funding

This study was supported by the Tehran University of Medical Sciences (Grant No: 96–01-27–32013).

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Affiliations

  1. Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran

    Mohadeseh Zarei Ghobadi

  2. Department of Virology, School of Public Health, Tehran University of Medical Sciences, 14155-6446, Tehran, Iran

    Mohadeseh Zarei Ghobadi, Shima Izadi, Majid Teymoori-Rad, Mohammad Farahmand, Negar Labbaf & Sayed Mahdi Marashi

  3. Department of Microbiology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran

    Sayed-Hamidreza Mozhgani

  4. Non‑Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran

    Sayed-Hamidreza Mozhgani

  5. Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran

    Fazel Shokri

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  1. Mohadeseh Zarei Ghobadi
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Ghobadi, M.Z., Izadi, S., Teymoori-Rad, M. et al. Potential role of viral infection and B cells as a linker between innate and adaptive immune response in systemic lupus erythematosus . Immunol Res 69, 196–204 (2021). https://doi.org/10.1007/s12026-021-09186-4

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  • DOI: https://doi.org/10.1007/s12026-021-09186-4

Keywords

  • Systemic lupus erythematosus (SLE)
  • B cells
  • Weighted gene co-expression network (WGCNA)
  • PPIN