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
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
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
Similar content being viewed by others
References
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
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
Cocca BA et al. (2002) Blebs and apoptotic bodies are B cell autoantigens. J Immunol 169: 159–166
Mevorach D et al. (1998) Systemic exposure to irradiated apoptotic cells induces autoantibody production. J Exp Med 188: 387–392
Kalden J (2004) Apoptosis in systemic autoimmunity. Autoimmunity Rev 3: S9–S10
Nauta AJ et al. (2003) Recognition and clearance of apoptotic cells: a role for complement and pentraxins. Trends Immunol 24: 148–153
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
Turner MW (2003) The role of mannose-binding lectin in health and disease. Mol Immunol 40: 423–429
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
Familian A et al. (2001) Chromatin-independent binding of serum amyloid P component to apoptotic cells. J Immunol 167: 647–654
Garlanda C et al. (2005) Pentraxins at the crossroads between innate immunity, inflammation, matrix deposition, and female fertility. Ann Rev Immunol 23: 337–366
Kishore U and Reid KB (2000) C1q: structure, function, and receptors. Immunopharmacology 49: 159–170
Botto M and Walport MJ (2002) C1q, autoimmunity and apoptosis. Immunobiology 205: 395–406
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
Botto M et al. (1998) Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies. Nat Genet 19: 56–59
Mitchell DA et al. (1999) Cutting edge: C1q protects against the development of glomerulonephritis independently of C3 activation. J Immunol 162: 5676–5679
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
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
Mevorach D et al. (1998) Complement dependent clearance of apoptotic cells by human macrophages. J Exp Med 188: 2313–2320
Pickering MC et al. (2000) Systemic lupus erythematosus, complement deficiency, and apoptosis. Adv Immunol 76: 227–234
Walport MJ (2001) Complement—second of two parts. Complement at the interface between innate and adaptive immunity. N Eng J Med 344: 1140–1144
Trendelenburg M (2005) Antibodies against C1q in patients with systemic lupus erythematosus. Springer Semin Immunopathol 27: 276–285
Sinico RA et al. (2005) Anti-C1q autoantibodies in lupus nephritis: prevalence and clinical significance. Ann NY Acad Sci 1050: 193–200
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
Garred P et al. (2003) Mannose-binding lectin deficiency—revisited. Mol Immunol 40: 73–84
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
Satomura A et al. (2002) Significant elevations in serum mannose-binding lectin levels in patients with chronic renal failure. Nephron 92: 702–704
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
Ip WK et al. (1998) Association of systemic lupus erythematosus with promoter polymorphisms of the mannose-binding lectin gene. Arthritis Rheum 41: 1663–1668
Sullivan KE et al. (1996) Mannose-binding protein genetic polymorphisms in black patients with systemic lupus erythematosus. Arthritis Rheum 39: 2046–2051
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
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
Jacobsen S et al. (2001) The influence of mannose binding lectin polymorphisms on disease outcome in early polyarthritis. J Rheumatol 8: 935–942
Graudal NA et al. (2000) The association of variant mannose-binding lectin genotypes with radiographic outcome in rheumatoid arthritis. Arthritis Rheum 43: 515–521
Sullivan KE et al. (2003) Analysis of polymorphisms affecting immune complex handling in systemic lupus erythematosus. Rheumatology (Oxford) 42: 446–452
Mok MY et al. (2004) Antibodies to mannose binding lectin in patients with systemic lupus erythematosus. Lupus 13: 522–528
Seelen MA et al. (2003) Autoantibodies against mannose-binding lectin in systemic lupus erythematosus. Clin Exp Immunol 134: 335–343
Tsutsumi A et al. (2005) Mannose binding lectin: genetics and autoimmune disease. Autoimmun Rev 4: 364–372
Pepys MB and Hirschfeld M (2003) C-reactive protein: a critical update. J Clin Invest 111: 1805–1812
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
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
Rodriguez W et al. (2005) Reversal of ongoing proteinuria in autoimmune mice by treatment with CRP. Arthritis Rheum 52: 642–650
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
Shai R et al. (1999) Genome-wide screen for systemic lupus erythematosus susceptibility genes in multiplex families. Hum Mol Genet 8: 639–644
Hirshfeld GM and Pepys MB (2003) C-reactive protein and cardiovascular disease: new insights from an old molecule. Q J Med 96: 793–807
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
Pepys MB et al. (1982) C-reactive protein in SLE. Clin Rheum Dis 8: 91–103
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
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
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
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
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
Bickerstaff MCM et al. (1999) Serum amyloid P component controls chromatin degradation and prevents antinuclear autoimmunity. Nat Med 5: 694–697
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
Mantovani A et al. (2003) Pentraxin 3, a non-redundant soluble pattern recognition receptor involved in innate immunity. Vaccine 21 (Suppl 2): S43–S47
Nauta AJ et al. (2003) Biochemical and functional characterization of the interaction between pentraxin 3 and C1q. Eur J Immunol 33: 465–473
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
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
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
Luchetti MM et al. (2000) Expression and production of the long pentraxin PTX3 in rheumatoid arthritis (RA). Clin Exp Immunol 119: 196–202
Luchetti MM et al. (2004) Scleroderma fibroblasts constitutively express the long pentraxin PTX3. Clin Exp Rheumatol 22 (Suppl 3): S66–S72
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
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
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Rights 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
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/ncprheum0290
This article is cited by
-
The role of defective clearance of apoptotic cells in systemic autoimmunity
Nature Reviews Rheumatology (2010)
-
Protective molecules and their cognate antibodies: new players in autoimmunity
Autoimmunity Highlights (2010)
-
Pentraxins, Anti-pentraxin Antibodies, and Atherosclerosis
Clinical Reviews in Allergy & Immunology (2009)
-
Plasma Pentraxin3 is a Novel Marker for Nonalcoholic Steatohepatitis (NASH)
BMC Gastroenterology (2008)
-
Tobacco smoking and autoimmune rheumatic diseases
Nature Clinical Practice Rheumatology (2007)