Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Autoimmunity to protective molecules: is it the perpetuum mobile (vicious cycle) of autoimmune rheumatic diseases?

Abstract

Apoptotic defects and impaired clearance of cellular debris are considered key events in the development of autoimmunity, as they can contribute to autoantigen overload and might be involved in the initiation of an autoimmune response. The C1q protein and mannose-binding lectin are activators of the complement system. The pentraxins are a group of highly conserved proteins including the short pentraxins, C-reactive protein and serum amyloid P, and the long pentraxin family member, pentraxin 3, all of which are involved in innate immunity and in acute-phase responses. In addition to their role in innate immunity and inflammation, each of these proteins participates in the removal of damaged and apoptotic cells. In this article, we discuss the clinical significance of different levels of these proteins, their role in the induction of or protection against autoimmunity, and the presence of specific autoantibodies against them in various autoimmune diseases.

Key Points

  • C1q, mannose-binding lectin, C-reactive protein, serum amyloid P, and pentraxin 3 are involved in acute-phase responses, and they have an important role in the clearance of apoptotic cells

  • In conditions of deficiency or dysfunction of these so-called protective molecules, as in knockout models, autoimmunity might develop

  • Accelerated apoptosis and defective clearance of cellular debris might lead to continuous exposure of autoantigens, and to the generation of autoantibodies

  • Autoantibodies directed against protective molecules might neutralize their protective effects, impair their ability to clear apoptotic material, and thus contribute to the induction of autoimmunity

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Structure and interactions of C1q.
Figure 2: Functions of mannose-binding lectin.
Figure 3: The pentraxins CRP, SAP and PTX3.
Figure 4: The clearance of apoptotic cells.

Similar content being viewed by others

References

  1. Sherer Y et al. (2004) Autoantibody explosion in systemic lupus erythematosus: more than 100 different antibodies found in SLE patients. Semin Arthritis Rheum 34: 501–537

    CAS  PubMed  Google Scholar 

  2. Rosen A and Casciola-Rosen L (1999) Autoantigens as substrates for apoptotic proteases: implications for the pathogenesis of systemic autoimmune disease. Cell Death Differ 6: 6–12

    CAS  PubMed  Google Scholar 

  3. Cocca BA et al. (2002) Blebs and apoptotic bodies are B cell autoantigens. J Immunol 169: 159–166

    CAS  PubMed  Google Scholar 

  4. Mevorach D et al. (1998) Systemic exposure to irradiated apoptotic cells induces autoantibody production. J Exp Med 188: 387–392

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Kalden J (2004) Apoptosis in systemic autoimmunity. Autoimmunity Rev 3: S9–S10

    Google Scholar 

  6. Nauta AJ et al. (2003) Recognition and clearance of apoptotic cells: a role for complement and pentraxins. Trends Immunol 24: 148–153

    CAS  PubMed  Google Scholar 

  7. Sontheimer RD et al. (2005) C1q: its functions within the innate and adaptive immune responses and its role in lupus autoimmunity. J Invest Dermatol 125: 14–23

    CAS  PubMed  Google Scholar 

  8. Turner MW (2003) The role of mannose-binding lectin in health and disease. Mol Immunol 40: 423–429

    CAS  PubMed  Google Scholar 

  9. Gershov D et al. (2000) C-reactive protein binds to apoptotic cells, protects the cells from assembly of the terminal complement components, and sustain anti-inflammatory innate immune response: Implications for systemic autoimmunity. J Exp Med 192: 1353–1363

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Familian A et al. (2001) Chromatin-independent binding of serum amyloid P component to apoptotic cells. J Immunol 167: 647–654

    CAS  PubMed  Google Scholar 

  11. Garlanda C et al. (2005) Pentraxins at the crossroads between innate immunity, inflammation, matrix deposition, and female fertility. Ann Rev Immunol 23: 337–366

    CAS  Google Scholar 

  12. Kishore U and Reid KB (2000) C1q: structure, function, and receptors. Immunopharmacology 49: 159–170

    CAS  PubMed  Google Scholar 

  13. Botto M and Walport MJ (2002) C1q, autoimmunity and apoptosis. Immunobiology 205: 395–406

    CAS  PubMed  Google Scholar 

  14. McGrath FD et al. (2006) Evidence that complemnt protein C1q interacts with C-reactive protein through its globular head region. J Immunol 176: 2950–2957

    CAS  PubMed  Google Scholar 

  15. Botto M et al. (1998) Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies. Nat Genet 19: 56–59

    CAS  PubMed  Google Scholar 

  16. Mitchell DA et al. (1999) Cutting edge: C1q protects against the development of glomerulonephritis independently of C3 activation. J Immunol 162: 5676–5679

    CAS  PubMed  Google Scholar 

  17. Cortes-Hernandez J et al. (2004) Restoration of C1q levels by bone marrow transplantation attenuates autoimmune disease associated with C1q deficiency in mice. Eur J Immunol 34: 3713–3722

    CAS  PubMed  Google Scholar 

  18. Taylor PR et al. (2000) A hierarchical role for classical pathway complement proteins in the clearance of apoptotic cells in vivo. J Exp Med 7: 359–366

    Google Scholar 

  19. Mevorach D et al. (1998) Complement dependent clearance of apoptotic cells by human macrophages. J Exp Med 188: 2313–2320

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Pickering MC et al. (2000) Systemic lupus erythematosus, complement deficiency, and apoptosis. Adv Immunol 76: 227–234

    CAS  PubMed  Google Scholar 

  21. Walport MJ (2001) Complement—second of two parts. Complement at the interface between innate and adaptive immunity. N Eng J Med 344: 1140–1144

    CAS  Google Scholar 

  22. Trendelenburg M (2005) Antibodies against C1q in patients with systemic lupus erythematosus. Springer Semin Immunopathol 27: 276–285

    CAS  PubMed  Google Scholar 

  23. Sinico RA et al. (2005) Anti-C1q autoantibodies in lupus nephritis: prevalence and clinical significance. Ann NY Acad Sci 1050: 193–200

    CAS  PubMed  Google Scholar 

  24. Marto N et al. (2005) Anti-C1q antibodies in nephritis: correlation between titres and renal disease activity and positive predictive value in systemic lupus erythematosus. Ann Rheum Dis 64: 444–448

    CAS  PubMed  Google Scholar 

  25. Garred P et al. (2003) Mannose-binding lectin deficiency—revisited. Mol Immunol 40: 73–84

    CAS  PubMed  Google Scholar 

  26. Ogden CA et al. (2001) C1q and mannose binding lectin engagement of cell surface calreticulin and CD91 initiates macropinocytosis and uptake of apoptotic cells. J Exp Med 194: 781–795

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Satomura A et al. (2002) Significant elevations in serum mannose-binding lectin levels in patients with chronic renal failure. Nephron 92: 702–704

    CAS  PubMed  Google Scholar 

  28. Garred P et al. (2003) Association of mannose-binding lectin polymorphisms with sepsis and fatal outcome, in patients with systemic inflammatory response syndrome. J Infect Dis 188: 1394–1403

    CAS  PubMed  Google Scholar 

  29. Ip WK et al. (1998) Association of systemic lupus erythematosus with promoter polymorphisms of the mannose-binding lectin gene. Arthritis Rheum 41: 1663–1668

    CAS  PubMed  Google Scholar 

  30. Sullivan KE et al. (1996) Mannose-binding protein genetic polymorphisms in black patients with systemic lupus erythematosus. Arthritis Rheum 39: 2046–2051

    CAS  PubMed  Google Scholar 

  31. Garred P et al. (2001) Association of mannose-binding lectin gene variation with disease severity and infections in a population-based cohort of systemic lupus erythematosus patients. Genes Immun 2: 442–450

    CAS  PubMed  Google Scholar 

  32. Saevarsdottir S et al. (2001) Low mannose binding lectin predicts poor prognosis in patients with early rheumatoid arthritis. A prospective study. J Rheumatol 28: 728–734

    CAS  PubMed  Google Scholar 

  33. Jacobsen S et al. (2001) The influence of mannose binding lectin polymorphisms on disease outcome in early polyarthritis. J Rheumatol 8: 935–942

    Google Scholar 

  34. Graudal NA et al. (2000) The association of variant mannose-binding lectin genotypes with radiographic outcome in rheumatoid arthritis. Arthritis Rheum 43: 515–521

    CAS  PubMed  Google Scholar 

  35. Sullivan KE et al. (2003) Analysis of polymorphisms affecting immune complex handling in systemic lupus erythematosus. Rheumatology (Oxford) 42: 446–452

    CAS  Google Scholar 

  36. Mok MY et al. (2004) Antibodies to mannose binding lectin in patients with systemic lupus erythematosus. Lupus 13: 522–528

    CAS  PubMed  Google Scholar 

  37. Seelen MA et al. (2003) Autoantibodies against mannose-binding lectin in systemic lupus erythematosus. Clin Exp Immunol 134: 335–343

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Tsutsumi A et al. (2005) Mannose binding lectin: genetics and autoimmune disease. Autoimmun Rev 4: 364–372

    CAS  PubMed  Google Scholar 

  39. Pepys MB and Hirschfeld M (2003) C-reactive protein: a critical update. J Clin Invest 111: 1805–1812

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Du Clos TW and Mold C (2004) C-reactive protein. An activator of innate immunity and a modulator of adaptive immunity. Immunol Res 30: 261–277

    CAS  PubMed  Google Scholar 

  41. DuClos TW et al. (1994) Decreased autoantibody levels and enhanced survival of (NZB × NZW) F1 mice treated with C-reactive protein. Clin Immunol Immunopath 70: 22–27

    CAS  Google Scholar 

  42. Rodriguez W et al. (2005) Reversal of ongoing proteinuria in autoimmune mice by treatment with CRP. Arthritis Rheum 52: 642–650

    CAS  PubMed  Google Scholar 

  43. Szalai AJ et al. (2003) Delayed lupus onset in (NZB × NZW) F1 mice expressing a human C-reactive protein transgene. Arthritis Rheum 48: 1602–1611

    CAS  PubMed  Google Scholar 

  44. Shai R et al. (1999) Genome-wide screen for systemic lupus erythematosus susceptibility genes in multiplex families. Hum Mol Genet 8: 639–644

    CAS  PubMed  Google Scholar 

  45. Hirshfeld GM and Pepys MB (2003) C-reactive protein and cardiovascular disease: new insights from an old molecule. Q J Med 96: 793–807

    Google Scholar 

  46. Arici M and Walls J (2001) End-stage renal disease, atherosclerosis, and cardiovascular mortality: Is C-reactive protein the missing link? Kidney Int 59: 407–414

    CAS  PubMed  Google Scholar 

  47. Pepys MB et al. (1982) C-reactive protein in SLE. Clin Rheum Dis 8: 91–103

    CAS  PubMed  Google Scholar 

  48. Sjowall C et al. (2002) Autoantibodies to C-reactive protein is a common finding in SLE, but not in primary Sjogren syndrome, rheumatoid arthritis or inflammatory bowel disease. J Autoimmunity 19: 155–160

    Google Scholar 

  49. Bell SA et al. (1998) Autoantibodies to C-reactive protein (CRP) and other acute-phase proteins in systemic lupus erythematosus. Clin Exp Immunol 113: 327–332

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Sjowall C et al. (2004) Serum levels of autoantibodies against monomeric C-reactive protein are correlated with disease activity in systemic lupus erythematosus. Arthritis Res Ther 6: R87–R94

    CAS  PubMed  Google Scholar 

  51. Lin BF et al. (1990) IL-1 and IL-6 mediate increased production and synthesis by hepatocytes of acute-phase serum amyloid P-component (SAP). Inflammation 14: 297–313

    CAS  PubMed  Google Scholar 

  52. Noursadeghi M et al. (2000) Role of serum amyloid P component in bacterial infection: protection of the host or protection of the pathogen. Proc Natl Acad Sci USA 97: 14584–14589

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Bickerstaff MCM et al. (1999) Serum amyloid P component controls chromatin degradation and prevents antinuclear autoimmunity. Nat Med 5: 694–697

    CAS  PubMed  Google Scholar 

  54. Zandman-Goddard G et al. (2005) Anti-serum amyloid P (SAP) antibodies in SLE patients correlate with disease activity. Ann Rheum Dis 64: 1698–1702

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Mantovani A et al. (2003) Pentraxin 3, a non-redundant soluble pattern recognition receptor involved in innate immunity. Vaccine 21 (Suppl 2): S43–S47

    PubMed  Google Scholar 

  56. Nauta AJ et al. (2003) Biochemical and functional characterization of the interaction between pentraxin 3 and C1q. Eur J Immunol 33: 465–473

    CAS  PubMed  Google Scholar 

  57. Muller B et al. (2001) Circulating levels of the long pentraxin PTX3 correlate with severity of infection in critically ill patients. Crit Care Med 29: 1404–1407

    CAS  PubMed  Google Scholar 

  58. Latini R et al. (2004) Lipid Assessment Trial Italian Network (LATIN) Investigators. Prognostic significance of the long pentraxin PTX3 in acute myocardial infarction. Circulation 110: 2349–2354

    CAS  PubMed  Google Scholar 

  59. Napoleone E et al. (2004) The long pentraxin PTX3 up-regulates tissue factor in activated monocytes: another link between inflammation and clotting activation. J Leukoc Biol 76: 203–209

    CAS  PubMed  Google Scholar 

  60. Luchetti MM et al. (2000) Expression and production of the long pentraxin PTX3 in rheumatoid arthritis (RA). Clin Exp Immunol 119: 196–202

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Luchetti MM et al. (2004) Scleroderma fibroblasts constitutively express the long pentraxin PTX3. Clin Exp Rheumatol 22 (Suppl 3): S66–S72

    CAS  PubMed  Google Scholar 

  62. Fazzini F et al. (2001) PTX3 in small-vessel vasculitides: an independent indicator of disease activity produced at sites of inflammation. Arthritis Rheum 44: 2841–2850

    CAS  PubMed  Google Scholar 

  63. Trouw LA et al. (2004) Anti-C1q autoantibodies deposit in the glomeruli are only pathogenic in combination with glomerular C1q-containing immune complexes. J Clin Invest 116: 678–688

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yehuda Shoenfeld.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kravitz, M., Shoenfeld, Y. Autoimmunity to protective molecules: is it the perpetuum mobile (vicious cycle) of autoimmune rheumatic diseases?. Nat Rev Rheumatol 2, 481–490 (2006). https://doi.org/10.1038/ncprheum0290

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncprheum0290

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing