Skip to main content
SpringerLink
Log in

Advances in Translational Science to Identify New Therapies for Systemic Lupus Erythematosus

  • Chapter
  • First Online:
Pathogenesis of Systemic Lupus Erythematosus

Abstract

The scope of this textbook is to provide an overview of the latest translational research in the field of lupus pathogenesis, with particular emphasis on how these discoveries progress in parallel with therapeutic drug development. Systemic lupus erythematosus (SLE) is a multifaceted disease with a number of well-defined immune pathways that are dysregulated, resulting in an immune-mediated chronic inflammatory injury at target organs. As knowledge of these pathways evolves to provide opportunities for targeted drug therapy and lays the foundation for personalized medicine, clinicians and researchers need to keep up with the ever-expanding medical and scientific literature.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Kaul A, Gordon C, Crow MK, Touma Z, Urowitz MB, van Vollenhoven R et al (2016) Systemic lupus erythematosus. Nat Rev Dis Primers 2:16039

    Article  PubMed  Google Scholar 

  2. Liu Y, Kaplan MJ (2018) Cardiovascular disease in systemic lupus erythematosus: an update. Curr Opin Rheumatol 30(5):441–448

    Article  PubMed  Google Scholar 

  3. Davidson A (2016) What is damaging the kidney in lupus nephritis? Nat Rev Rheumatol 12(3):143–153

    Article  PubMed  CAS  Google Scholar 

  4. Song K, Liu L, Zhang X, Chen X (2020) An update on genetic susceptibility in lupus nephritis. Clin Immunol 210:108272. https://doi.org/10.1016/j.clim.2019.108272

  5. Chung SA, Brown EE, Williams AH, Ramos PS, Berthier CC, Bhangale T et al (2014) Lupus nephritis susceptibility loci in women with systemic lupus erythematosus. J Am Soc Nephrol 25(12):2859–2870

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Niu Z, Zhang P, Tong Y (2015) Value of HLA-DR genotype in systemic lupus erythematosus and lupus nephritis: a meta-analysis. Int J Rheum Dis 18(1):17–28

    Article  PubMed  CAS  Google Scholar 

  7. Xu R, Li Q, Liu R, Shen J, Li M, Zhao M et al (2017) Association analysis of the MHC in lupus nephritis. J Am Soc Nephrol 28(11):3383–3394

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Salmon JE, Millard S, Schachter LA, Arnett FC, Ginzler EM, Gourley MF et al (1996) Fc gamma RIIA alleles are heritable risk factors for lupus nephritis in African Americans. J Clin Invest 97(5):1348–1354

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Tsang ASMW, Nagelkerke SQ, Bultink IE, Geissler J, Tanck MW, Tacke CE et al (2016) Fc-gamma receptor polymorphisms differentially influence susceptibility to systemic lupus erythematosus and lupus nephritis. Rheumatology (Oxford) 55(5):939–948

    Article  Google Scholar 

  10. Sanchez E, Nadig A, Richardson BC, Freedman BI, Kaufman KM, Kelly JA et al (2011) Phenotypic associations of genetic susceptibility loci in systemic lupus erythematosus. Ann Rheum Dis 70(10):1752–1757

    Article  PubMed  CAS  Google Scholar 

  11. Khan SQ, Khan I, Gupta V (2018) CD11b activity modulates pathogenesis of lupus nephritis. Front Med (Lausanne). 5:52

    Article  PubMed  PubMed Central  Google Scholar 

  12. Taylor KE, Remmers EF, Lee AT, Ortmann WA, Plenge RM, Tian C, et al (2008) Specificity of the STAT4 genetic association for severe disease manifestations of systemic lupus erythematosus. PLoS Genet 4(5):e1000084. https://doi.org/10.1371/journal.pgen.1000084

  13. Bolin K, Sandling JK, Zickert A, Jonsen A, Sjowall C, Svenungsson E, et al (2013) Association of STAT4 polymorphism with severe renal insufficiency in lupus nephritis. PLoS One 8(12):e84450. https://doi.org/10.1371/journal.pone.0084450

  14. Conti F, Spinelli FR, Alessandri C, Valesini G (2011) Toll-like receptors and lupus nephritis. Clin Rev Allergy Immunol 40(3):192–198

    Article  PubMed  CAS  Google Scholar 

  15. Soliman S, Mohan C (2017) Lupus nephritis biomarkers. Clin Immunol 185:10–20

    Article  PubMed  CAS  Google Scholar 

  16. Arazi A, Rao DA, Berthier CC, Davidson A, Liu Y, Hoover PJ et al (2019) The immune cell landscape in kidneys of patients with lupus nephritis. Nat Immunol 20(7):902–914

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Der E, Suryawanshi H, Morozov P, Kustagi M, Goilav B, Ranabothu S et al (2019) Tubular cell and keratinocyte single-cell transcriptomics applied to lupus nephritis reveal type I IFN and fibrosis relevant pathways. Nat Immunol 20(7):915–927

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Hanly JG (2014) Diagnosis and management of neuropsychiatric SLE. Nat Rev Rheumatol 10(6):338–347

    Article  PubMed  CAS  Google Scholar 

  19. Schwartz N, Stock AD, Putterman C (2019) Neuropsychiatric lupus: new mechanistic insights and future treatment directions. Nat Rev Rheumatol 15(3):137–152

    Article  PubMed  PubMed Central  Google Scholar 

  20. Cohen D, Rijnink EC, Nabuurs RJ, Steup-Beekman GM, Versluis MJ, Emmer BJ et al (2017) Brain histopathology in patients with systemic lupus erythematosus: identification of lesions associated with clinical neuropsychiatric lupus syndromes and the role of complement. Rheumatology (Oxford) 56(1):77–86

    Article  CAS  Google Scholar 

  21. Hirohata S, Miyamoto T (1990) Elevated levels of interleukin-6 in cerebrospinal fluid from patients with systemic lupus erythematosus and central nervous system involvement. Arthritis Rheum 33(5):644–649

    Article  PubMed  CAS  Google Scholar 

  22. Trysberg E, Carlsten H, Tarkowski A (2000) Intrathecal cytokines in systemic lupus erythematosus with central nervous system involvement. Lupus 9(7):498–503

    Article  PubMed  CAS  Google Scholar 

  23. Okamoto H, Katsumata Y, Nishimura K, Kamatani N (2004) Interferon-inducible protein 10/CXCL10 is increased in the cerebrospinal fluid of patients with central nervous system lupus. Arthritis Rheum 50(11):3731–3732

    Article  PubMed  CAS  Google Scholar 

  24. Iikuni N, Okamoto H, Yoshio T, Sato E, Kamitsuji S, Iwamoto T et al (2006) Raised monocyte chemotactic protein-1 (MCP-1)/CCL2 in cerebrospinal fluid of patients with neuropsychiatric lupus. Ann Rheum Dis 65(2):253–256

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Fragoso-Loyo H, Richaud-Patin Y, Orozco-Narvaez A, Davila-Maldonado L, Atisha-Fregoso Y, Llorente L et al (2007) Interleukin-6 and chemokines in the neuropsychiatric manifestations of systemic lupus erythematosus. Arthritis Rheum 56(4):1242–1250

    Article  PubMed  CAS  Google Scholar 

  26. Fragoso-Loyo H, Atisha-Fregoso Y, Llorente L, Sanchez-Guerrero J (2013) Inflammatory profile in cerebrospinal fluid of patients with headache as a manifestation of neuropsychiatric systemic lupus erythematosus. Rheumatology (Oxford) 52(12):2218–2222

    Article  CAS  Google Scholar 

  27. Yoshio T, Okamoto H, Kurasawa K, Dei Y, Hirohata S, Minota S (2016) IL-6, IL-8, IP-10, MCP-1 and G-CSF are significantly increased in cerebrospinal fluid but not in sera of patients with central neuropsychiatric lupus erythematosus. Lupus 25(9):997–1003

    Article  PubMed  CAS  Google Scholar 

  28. Raison CL, Demetrashvili M, Capuron L, Miller AH (2005) Neuropsychiatric adverse effects of interferon-alpha: recognition and management. CNS Drugs 19(2):105–123

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Winfield JB, Shaw M, Silverman LM, Eisenberg RA, Wilson HA 3rd, Koffler D (1983) Intrathecal IgG synthesis and blood-brain barrier impairment in patients with systemic lupus erythematosus and central nervous system dysfunction. Am J Med 74(5):837–844

    Article  PubMed  CAS  Google Scholar 

  30. Shiozawa S, Kuroki Y, Kim M, Hirohata S, Ogino T (1992) Interferon-alpha in lupus psychosis. Arthritis Rheum 35(4):417–422

    Article  PubMed  CAS  Google Scholar 

  31. Fragoso-Loyo H, Atisha-Fregoso Y, Nunez-Alvarez CA, Llorente L, Sanchez-Guerrero J (2012) Utility of interferon-alpha as a biomarker in central neuropsychiatric involvement in systemic lupus erythematosus. J Rheumatol 39(3):504–509

    Article  PubMed  CAS  Google Scholar 

  32. Santer DM, Yoshio T, Minota S, Moller T, Elkon KB (2009) Potent induction of IFN-alpha and chemokines by autoantibodies in the cerebrospinal fluid of patients with neuropsychiatric lupus. J Immunol 182(2):1192–1201

    Article  PubMed  CAS  Google Scholar 

  33. Trysberg E, Nylen K, Rosengren LE, Tarkowski A (2003) Neuronal and astrocytic damage in systemic lupus erythematosus patients with central nervous system involvement. Arthritis Rheum 48(10):2881–2887

    Article  PubMed  Google Scholar 

  34. DeGiorgio LA, Konstantinov KN, Lee SC, Hardin JA, Volpe BT, Diamond B (2001) A subset of lupus anti-DNA antibodies cross-reacts with the NR2 glutamate receptor in systemic lupus erythematosus. Nat Med 7(11):1189–1193

    Article  PubMed  CAS  Google Scholar 

  35. Matus S, Burgos PV, Bravo-Zehnder M, Kraft R, Porras OH, Farias P et al (2007) Antiribosomal-P autoantibodies from psychiatric lupus target a novel neuronal surface protein causing calcium influx and apoptosis. J Exp Med 204(13):3221–3234

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Hanly JG, Urowitz MB, Su L, Bae SC, Gordon C, Clarke A et al (2011) Autoantibodies as biomarkers for the prediction of neuropsychiatric events in systemic lupus erythematosus. Ann Rheum Dis 70(10):1726–1732

    Article  PubMed  CAS  Google Scholar 

  37. Bonfa E, Golombek SJ, Kaufman LD, Skelly S, Weissbach H, Brot N et al (1987) Association between lupus psychosis and anti-ribosomal P protein antibodies. N Engl J Med 317(5):265–271

    Article  PubMed  CAS  Google Scholar 

  38. Yoshio T, Hirata D, Onda K, Nara H, Minota S (2005) Antiribosomal P protein antibodies in cerebrospinal fluid are associated with neuropsychiatric systemic lupus erythematosus. J Rheumatol 32(1):34–39

    PubMed  CAS  Google Scholar 

  39. Bialas AR, Presumey J, Das A, van der Poel CE, Lapchak PH, Mesin L et al (2017) Microglia-dependent synapse loss in type I interferon-mediated lupus. Nature 546(7659):539–543

    Article  PubMed  CAS  Google Scholar 

  40. Chalmers SA, Wen J, Shum J, Doerner J, Herlitz L, Putterman C (2017) CSF-1R inhibition attenuates renal and neuropsychiatric disease in murine lupus. Clin Immunol 185:100–108

    Article  PubMed  CAS  Google Scholar 

  41. Huang MW, Stock AD, Mike EV, Herlitz L, Kolbeck R, Putterman C (2019) Anti-IFNAR treatment does not reverse neuropsychiatric disease in MRL/lpr lupus mice. Lupus 28(13):1510–1523

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Morand EF, Furie R, Tanaka Y, Bruce IN, Askanase AD, Richez C et al (2020) Trial of anifrolumab in active systemic lupus erythematosus. N Engl J Med 382(3):211–221

    Article  PubMed  CAS  Google Scholar 

  43. Wenzel J (2019) Cutaneous lupus erythematosus: new insights into pathogenesis and therapeutic strategies. Nat Rev Rheumatol 15(9):519–532

    Article  PubMed  Google Scholar 

  44. Vital EM, Wittmann M, Edward S, Md Yusof MY, MacIver H, Pease CT et al (2015) Brief report: responses to rituximab suggest B cell-independent inflammation in cutaneous systemic lupus erythematosus. Arthritis Rheumatol 67(6):1586–1591

    Article  PubMed  CAS  Google Scholar 

  45. Fleischmann M, Celerier P, Bernard P, Litoux P, Dreno B (1996) Long-term interferon-alpha therapy induces autoantibodies against epidermis. Dermatology 192(1):50–55

    Article  PubMed  CAS  Google Scholar 

  46. Farkas L, Beiske K, Lund-Johansen F, Brandtzaeg P, Jahnsen FL (2001) Plasmacytoid dendritic cells (natural interferon- alpha/beta-producing cells) accumulate in cutaneous lupus erythematosus lesions. Am J Pathol 159(1):237–243

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Blomberg S, Eloranta ML, Cederblad B, Nordlin K, Alm GV, Ronnblom L (2001) Presence of cutaneous interferon-alpha producing cells in patients with systemic lupus erythematosus. Lupus 10(7):484–490

    Article  PubMed  CAS  Google Scholar 

  48. Wenzel J, Worenkamper E, Freutel S, Henze S, Haller O, Bieber T et al (2005) Enhanced type I interferon signalling promotes Th1-biased inflammation in cutaneous lupus erythematosus. J Pathol 205(4):435–442

    Article  PubMed  CAS  Google Scholar 

  49. Meller S, Winterberg F, Gilliet M, Muller A, Lauceviciute I, Rieker J et al (2005) Ultraviolet radiation-induced injury, chemokines, and leukocyte recruitment: an amplification cycle triggering cutaneous lupus erythematosus. Arthritis Rheum 52(5):1504–1516

    Article  PubMed  CAS  Google Scholar 

  50. Guiducci C, Tripodo C, Gong M, Sangaletti S, Colombo MP, Coffman RL et al (2010) Autoimmune skin inflammation is dependent on plasmacytoid dendritic cell activation by nucleic acids via TLR7 and TLR9. J Exp Med 207(13):2931–2942

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Rheumatology Research Group, School of Clinical Sciences At Monash Health, Centre for Inflammatory Diseases, Monash University, Clayton, VIC, 3168, Australia

    Alberta Hoi & Fabien Vincent

  2. Department of Rheumatology, Monash Health, Clayton, VIC, 3168, Australia

    Alberta Hoi

  3. Department of Rheumatology, Austin Health, Heidelberg, VIC, 3084, Australia

    Alberta Hoi

  4. Department of Immunology and Pathology, Central Clinical School, Alfred Research Alliance, Monash University, Melbourne, VIC, 3004, Australia

    Margaret L. Hibbs

Authors
  1. Alberta Hoi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fabien Vincent
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Margaret L. Hibbs
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alberta Hoi .

Editor information

Editors and Affiliations

  1. Department of Medicine, Monash University, Clayton, VIC, Australia

    Alberta Hoi

Rights and permissions

Reprints and permissions

Copyright information

© 2021 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Hoi, A., Vincent, F., Hibbs, M.L. (2021). Advances in Translational Science to Identify New Therapies for Systemic Lupus Erythematosus. In: Hoi, A. (eds) Pathogenesis of Systemic Lupus Erythematosus. Springer, Cham. https://doi.org/10.1007/978-3-030-85161-3_1

Download citation

Publish with us

Policies and ethics

Search

Navigation