Skip to main content

Advertisement

Log in

New advances in measurement of complement activation: Lessons of systemic lupus erythematosus

  • Published:
Current Rheumatology Reports Aims and scope Submit manuscript

Abstract

Activation of the complement system plays a fundamental role in the pathogenesis of systemic lupus erythematosus (SLE). For the past several decades, quantifying this process has focused primarily on determination of serum C3 and C4, although the utility of these assays for diagnosis and monitoring disease activity is still debated. During this same timespan, knowledge of the complement system has exploded, with identification of more than 30 proteins, an abundance of newly recognized functions, and even a third pathway of activation. These advances suggest that it is appropriate to revisit the complement system as a potential source of biomarkers for SLE. This paper reviews briefly the role of complement in SLE and other inflammatory diseases, discusses conventional methods for complement measurement and their drawbacks, and focuses on recent advancements in harnessing the complement system for monitoring SLE. Specifically, novel assays that measure cell-bound complement activation products are introduced and their utility as biomarkers of SLE disease activity is discussed.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References and Recommended Reading

  1. Walport MJ: Complement. First of two parts. N Engl J Med 2001, 344:1058- 1066.

    Article  PubMed  CAS  Google Scholar 

  2. Walport MJ: Complement. Second of two parts. N Engl J Med 2001, 344:1140- 1144.

    Article  PubMed  CAS  Google Scholar 

  3. Jongen PJH, Doesburg WH, Ibrahim-Stappers JLM, et al.: Cerebrospinal fluid C3 and C4 indexes in immunological disorders of the central nervous system. Acta Neurol Scand 2000, 101:116- 121.

    Article  PubMed  CAS  Google Scholar 

  4. Sturfelt G, Sjoholm AG: Complement components, complement activation, and acute phase response in systemic lupus erythematosus. Int Arch Allerg Appl Immunol 1984, 75:75- 83.

    CAS  Google Scholar 

  5. Gabay C, Kushner I: Acute-phase proteins and other systemic responses to inflammation. N Engl J Med 1999, 340:448- 454.

    Article  PubMed  CAS  Google Scholar 

  6. Manderson AP, Botto M, Walport ML: The role of complement in the development of systemic lupus erythematosus. Ann Rev Immunol 2004, 431-456. An extensive review of the intricate roles of the complement system in the protection against and development of SLE.

  7. Liu C-C, Ahearn JM, Manzi S: Complement as a source of biomarkers in systemic lupus erythematosus: past, present, and future. Curr Rheumatol Reports 2004, 6:85- 88.

    Google Scholar 

  8. Valentijn RM, van Overhagen H, Hazevoet HM, et al.: The value of complement and immune complex determinations in monitoring disease activity in patients with systemic lupus erythematosus. Arthritis Rheum 1985, 28:904- 913.

    Article  PubMed  CAS  Google Scholar 

  9. Falk RJ, Agustin MD, Dalmasso P, et al.: Radioimmunoassay of the attack complex of complement in serum from patients with systemic lupus erythematosus. N Engl J Med 1985, 312:1594- 1599.

    Article  PubMed  CAS  Google Scholar 

  10. Abrass CK, Nies KM, Louie JS, et al.: Correlation and predictive accuracy of circulating immune complexes with disease activity in patients with systemic lupus erythematosus. Arthritis Rheum 1980, 23:273- 282.

    Article  PubMed  CAS  Google Scholar 

  11. Morrow WJW, Isenberg DA, Todd-Porkropek A, et al.: Useful laboratory measurements in the management of systemic lupus erythematosus. Quart J Med 1982, 202:125- 138.

    Google Scholar 

  12. Esdaile JM, Abrahamowicz M, Joseph L, et al.: Laboratory tests as predictors of disease exacerbations in systemic lupus erythematosus: why some tests fail. Arthritis Rheum 1996, 39:370- 378.

    Article  PubMed  CAS  Google Scholar 

  13. Esdaile JM, Joseph L, Abrahamowicz M, et al.: Routine immunologic tests in systemic lupus erythematosus: is there a need for more studies? J Rheumatol 1996, 23:1891- 1896.

    PubMed  CAS  Google Scholar 

  14. Ratnoff WD: Inherited deficiencies of complement in rheumatic diseases. Rheum Dis Clin North Am 1996, 22:75- 94.

    Article  PubMed  CAS  Google Scholar 

  15. Barilla-LaBarca ML, Atkinson JP: Rheumatic syndromes associated with complement deficiency. Curr Opin Rheumatol 2003, 15:55- 60.

    Article  PubMed  CAS  Google Scholar 

  16. Inagi R, Miyata T, Madea K, et al.: Fut-175 as a potent inhibitor of C5/C3 convertase activity for production of C5a and C3a. Immunol Lett 1991, 27:49.

    Article  PubMed  CAS  Google Scholar 

  17. Pfeifer PH, Kawahara MS, Hugli TE: Possible mechanism for in vitro complement activation in blood and plasma samples: Futhan/EDTA controls in vitro complement activation. Clin Chem 1999, 45:1190- 1199.

    PubMed  CAS  Google Scholar 

  18. Lloyd W, Schur PH: Immune complexes, complement, and anti-DNA in exacerbations of systemic lupus erythematosus (SLE). Medicine 1981, 60:208- 217.

    Article  PubMed  CAS  Google Scholar 

  19. Ricker DM, Hebert LA, Rohde R, et al.: Serum C3 levels are diagnostically more sensitive and specific for systemic lupus erythematosus activity than are serum C4 levels. Am J Kidney Dis 1991, 19:678- 685.

    Google Scholar 

  20. Cameron JS, Lessof MH, Ogg CS, et al.: Disease activity in the nephritis of systemic lupus erythmatosus in relation to serum complement concentrations, DNA-binidng capacity, and precipitating anti-DNA antibody. Clin Exp Immunol 1976, 25:418- 427.

    PubMed  CAS  Google Scholar 

  21. Swaak AJ, Groenwold J, Bronsveld W: Pedictive value of complement profiles and anti-dsDNA in systemic lupus erythematosus. Ann Rheum Dis 1986, 45:359- 366.

    Article  PubMed  CAS  Google Scholar 

  22. Ting C-K, Hsieh K-H: A long term immunological study of childhood onset systemic lupus erythematosus. Ann Rheum Dis 1992, 51:45- 51.

    PubMed  CAS  Google Scholar 

  23. Sturfelt G, Jonasson L, Sjoholm AG: Sequential studies of complement activation in systemic lupus erythematosus. Scand J Rheumatol 1985, 14:184- 196.

    PubMed  CAS  Google Scholar 

  24. Wild G, Watkins J, Ward AM, et al.: C4a anaphylatoxin levels as an indicator of disease activity in systemic lupus erythematosus. Clin Exp Immunol 1990, 80:167- 170.

    Article  PubMed  CAS  Google Scholar 

  25. Belmont HM, Hopkins P, Edelson HS, et al.: Complement activation during systemic lupus erythematosus. C3a and C5a anaphylatoxins circulate during exacerbations of disease. Arthritis Rheum 1986, 29:1085- 1089.

    Article  PubMed  CAS  Google Scholar 

  26. Hopkins P, Belmont HM, Buyon JP, et al.: Increased levels of plasma anaphylatoxins in systemic lupus erythematosus predict flares of the disease and may elicit vascular injury in lupus cerebritis. Arthritis Rheum 1988, 31:632- 641.

    Article  PubMed  CAS  Google Scholar 

  27. Porcel JM, Ordi J, Castro-Salomo A, et al.: The value of complement activation products in the assessment of systmeic lupus erythematosus flares. Clin Immunol Immunopathol 1995, 74:283- 288.

    Article  PubMed  CAS  Google Scholar 

  28. Senaldi G, Makinde VA, Vergani D, Isenberg DA: Correlation of the activation of the fourth component of complement (C4) with disease activity in systemic lupus erythematosus. Ann Rheum Dis 1988, 47:913- 917.

    PubMed  CAS  Google Scholar 

  29. Buyon JP, Tamerius J, Belmont HM, Abramson SB: Assessment of disease activity and impending flare in patients with systemic lupus erythematosus: comparison of the use of compelment split products and conventional measurements of complement. Arthritis Rheum 1992, 35:1028- 1037.

    Article  PubMed  CAS  Google Scholar 

  30. Manzi S, Rairie JE, Carpenter AB, et al.: Sensitivity and specificity of plasma and urine complement split products as indicators of lupus disease activity. Arthritis Rheum 1996, 39:1178- 1188.

    Article  PubMed  CAS  Google Scholar 

  31. Tieley CA, Romans DG, Crookston MC: Localization of Chido and Todgers determinants to the C4d fragment of human C4. Nature 1978, 276:713- 715.

    Article  Google Scholar 

  32. Atkinson JP, Chan AC, Karp DR, et al.: Origin of the fourth component of complement related Chido and Rodgers blood group antigens. Complement 1988, 5:65- 76.

    PubMed  CAS  Google Scholar 

  33. King DE, Navratil JS, Liu C-C, et al.: A new assay for SLE diagnosis and assessment of disease activity. Arthritis Rheum 2002, 46:S294.

    Google Scholar 

  34. Manzi S, Navratil JS, Ruffing MJ, et al.: Measurement of erythrocyte C4d and complement receptor 1 in systemic lupus erythematosus. Arthritis Rheum 2004, In press. First report describing a novel assay that measures levels of erythrocyte- bound complement activation products and erythrocyteexpressed complement receptor 1. Also demonstrating that this assay has greater sensitivity and specificity for diagnosis of SLE than currently available tests.

  35. Johnson JJ, Manzi S, Navratil JS, et al.: Platelets are decorated by complement ligands in patients with systemic lupus erythematosus (SLE): an etiologic clue and biomarker for cardiovascular disease. Athritis Rheum 2003, 48:S656.

    Google Scholar 

  36. Navratil JS, Manzi S, Kao A, et al.: Platelets are decorated by complement ligands in patients with systemic lupus erythematosus (SLE): an etiologic clue and biomarker of cardiovascular disease [abstract]. Mol Immunol 2004, 41:69.

    Google Scholar 

  37. Ross GD, Yount WJ, Walport MJ, et al.: Disease-associated loss of erythrocyte complement receptors (CR1, C3b receptors) in patients with systemic lupus erythematosus and other diseases involving autoantibodies and/or complement activation. J Immunol 1985, 135:2005- 2014.

    PubMed  CAS  Google Scholar 

  38. Wilson JG, Wong WW, Murphy EEI, et al.: Deficiency of the C3b/C4b receptor (CR1) of erythrocytes in systemic lupus erythematosus: analysis of the stability of the defect and of a restriction fragment length polymorphism of the CR1 gene. J Immunol 1987, 138:2706- 2710.

    CAS  Google Scholar 

  39. Liu C-C, Manzi S, Ahearn JM: Reticulocytes bearing C4- derived ligands may serve as "instant messengers" of disease activity in systemic lupus erythematosus [abstract]. Mol Immunol 2004, 41:147.

    Article  CAS  Google Scholar 

  40. Manzi S, Meilahn EN, Rairie JE, et al.: Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Farmingham study. Am J Epidemiol 1997, 145:408–415.

    PubMed  CAS  Google Scholar 

  41. Urowitz M, Gladman D, Bruce I: Atherosclerosis and systemic lupus erythematosus. Curr Rheumatol Rep 2000, 2:19- 23.

    PubMed  CAS  Google Scholar 

  42. Roman MJ, Shanker BA, Davis A, et al.: Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus. N Engl J Med 2003, 349:2399- 2406.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Liu, CC., Manzi, S., Danchenko, N. et al. New advances in measurement of complement activation: Lessons of systemic lupus erythematosus. Curr Rheumatol Rep 6, 375–381 (2004). https://doi.org/10.1007/s11926-004-0012-5

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11926-004-0012-5

Keywords

Navigation