Skip to main content
SpringerLink
Log in

Complement C3 as a Target of Host Modulation in Periodontitis

  • Chapter
  • First Online:
Emerging Therapies in Periodontics

Abstract

Although originally identified as a blood-based antimicrobial system, complement is now regarded as a central regulator of immune and inflammatory responses and tissue homeostasis. When dysregulated or overactivated, however, complement can turn from a homeostatic to a pathological effector that drives a number of inflammatory disorders. In this context, destructive periodontal inflammation in humans is correlated with elevated complement activity. Moreover, mechanistic studies in mice have causally linked the central complement component C3 and downstream signaling pathways in the induction of periodontal dysbiosis and inflammation that leads to alveolar bone loss. Consistent with this, pharmacological inhibition of C3 activation by a locally administered drug (Cp40/AMY-101) was shown to suppress both induced and naturally occurring periodontitis in non-human primates. Thus, C3-targeted intervention represents a promising host-modulation approach to treat human periodontitis.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 139.99
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. Lamont RJ, Koo H, Hajishengallis G. The oral microbiota: dynamic communities and host interactions. Nat Rev Microbiol. 2018;16:745–59. https://doi.org/10.1038/s41579-018-0089-x.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Hajishengallis G. Periodontitis: from microbial immune subversion to systemic inflammation. Nat Rev Immunol. 2015;15(1):30–44. https://doi.org/10.1038/nri3785.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Lalla E, Papapanou PN. Diabetes mellitus and periodontitis: a tale of two common interrelated diseases. Nat Rev Endocrinol. 2011;7(12):738–48. https://doi.org/10.1038/nrendo.2011.106. nrendo.2011.106 [pii].

    Article  PubMed  Google Scholar 

  4. Potempa J, Mydel P, Koziel J. The case for periodontitis in the pathogenesis of rheumatoid arthritis. Nat Rev Rheumatol. 2017;13(10):606–20. https://doi.org/10.1038/nrrheum.2017.132.

    Article  PubMed  Google Scholar 

  5. D’Aiuto F, Gkranias N, Bhowruth D, Khan T, Orlandi M, Suvan J, et al. Systemic effects of periodontitis treatment in patients with type 2 diabetes: a 12 month, single-centre, investigator-masked, randomised trial. Lancet Diabetes Endocrinol. 2018;6(12):954–65. https://doi.org/10.1016/S2213-8587(18)30038-X.

    Article  PubMed  Google Scholar 

  6. Tonetti MS, D'Aiuto F, Nibali L, Donald A, Storry C, Parkar M, et al. Treatment of periodontitis and endothelial function. N Engl J Med. 2007;356(9):911–20. https://doi.org/10.1056/NEJMoa063186. 356/9/911 [pii].

    Article  PubMed  Google Scholar 

  7. Eke PI, Dye BA, Wei L, Slade GD, Thornton-Evans GO, Borgnakke WS, et al. Update on prevalence of periodontitis in adults in the United States: NHANES 2009 to 2012. J Periodontol. 2015;86(5):611–22. https://doi.org/10.1902/jop.2015.140520.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Kassebaum NJ, Bernabe E, Dahiya M, Bhandari B, Murray CJ, Marcenes W. Global burden of severe periodontitis in 1990-2010: a systematic review and meta-regression. J Dent Res. 2014;93(11):1045–53. https://doi.org/10.1177/0022034514552491.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Beikler T, Flemmig TF. Oral biofilm-associated diseases: trends and implications for quality of life, systemic health and expenditures. Periodontol 2000. 2011;55(1):87–103. https://doi.org/10.1111/j.1600-0757.2010.00360.x.

    Article  PubMed  Google Scholar 

  10. Brown LJ, Johns BA, Wall TP. The economics of periodontal diseases. Periodontol 2000. 2002;29:223–34. prd290111 [pii].

    PubMed  Google Scholar 

  11. Diaz PI, Hoare A, Hong BY. Subgingival microbiome shifts and community dynamics in periodontal diseases. J Calif Dent Assoc. 2016;44(7):421–35.

    PubMed  Google Scholar 

  12. Lamont RJ, Hajishengallis G. Polymicrobial synergy and dysbiosis in inflammatory disease. Trends Mol Med. 2015;21(3):172–83. https://doi.org/10.1016/j.molmed.2014.11.004.

    Article  PubMed  Google Scholar 

  13. Bartold MP, Van Dyke TE. Host modulation: controlling the inflammation to control the infection. Periodontol 2000. 2017;75(1):317–29. https://doi.org/10.1111/prd.12169.

    Article  PubMed  Google Scholar 

  14. Hajishengallis G. Immunomicrobial pathogenesis of periodontitis: keystones, pathobionts, and host response. Trends Immunol. 2014a;35(1):3–11. https://doi.org/10.1016/j.it.2013.09.001.

    Article  PubMed  Google Scholar 

  15. Hajishengallis G. The inflammophilic character of the periodontitis-associated microbiota. Mol Oral Microbiol. 2014b;29(6):248–57. https://doi.org/10.1111/omi.12065.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Ricklin D, Hajishengallis G, Yang K, Lambris JD. Complement: a key system for immune surveillance and homeostasis. Nat Immunol. 2010;11(9):785–97. https://doi.org/10.1038/ni.1923.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Varela JC, Tomlinson S. Complement: an overview for the clinician. Hematol Oncol Clin North Am. 2015;29(3):409–27. https://doi.org/10.1016/j.hoc.2015.02.001.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Morgan BP, Walters D, Serna M, Bubeck D. Terminal complexes of the complement system: new structural insights and their relevance to function. Immunol Rev. 2016;274(1):141–51. https://doi.org/10.1111/imr.12461.

    Article  PubMed  Google Scholar 

  19. Ekdahl KN, Teramura Y, Hamad OA, Asif S, Duehrkop C, Fromell K, et al. Dangerous liaisons: complement, coagulation, and kallikrein/kinin cross-talk act as a linchpin in the events leading to thromboinflammation. Immunol Rev. 2016;274(1):245–69. https://doi.org/10.1111/imr.12471.

    Article  PubMed  Google Scholar 

  20. Hajishengallis G, Lambris JD. More than complementing tolls: complement-toll-like receptor synergy and crosstalk in innate immunity and inflammation. Immunol Rev. 2016;274(1):233–44. https://doi.org/10.1111/imr.12467.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Hajishengallis G, Reis ES, Mastellos DC, Ricklin D, Lambris JD. Novel mechanisms and functions of complement. Nat Immunol. 2017;18(12):1288–98. https://doi.org/10.1038/ni.3858.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Dempsey PW, Allison ME, Akkaraju S, Goodnow CC, Fearon DT. C3d of complement as a molecular adjuvant: bridging innate and acquired immunity. Science. 1996;271(5247):348–50.

    PubMed  Google Scholar 

  23. Freeley S, Kemper C, Le Friec G. The “ins and outs” of complement-driven immune responses. Immunol Rev. 2016;274(1):16–32. https://doi.org/10.1111/imr.12472.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Strainic MG, Liu J, Huang D, An F, Lalli PN, Muqim N, et al. Locally produced complement fragments C5a and C3a provide both costimulatory and survival signals to naive CD4+ T cells. Immunity. 2008;28(3):425–35. https://doi.org/10.1016/j.immuni.2008.02.001. S1074-7613(08)00071-X [pii].

    Article  PubMed  PubMed Central  Google Scholar 

  25. Strainic MG, Shevach EM, An F, Lin F, Medof ME. Absence of signaling into CD4(+) cells via C3aR and C5aR enables autoinductive TGF-beta1 signaling and induction of Foxp3(+) regulatory T cells. Nat Immunol. 2013;14:162–71. https://doi.org/10.1038/ni.2499.

    Article  PubMed  Google Scholar 

  26. Kwan WH, van der Touw W, Paz-Artal E, Li MO, Heeger PS. Signaling through C5a receptor and C3a receptor diminishes function of murine natural regulatory T cells. J Exp Med. 2013;210(2):257–68. https://doi.org/10.1084/jem.20121525.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Lambris JD, Dobson NJ, Ross GD. Release of endogenous C3b inactivator from lymphocytes in response to triggering membrane receptors for beta 1H globulin. J Exp Med. 1980;152(6):1625–44.

    PubMed  Google Scholar 

  28. Sundsmo JS. The leukocyte complement system. Fed Proc. 1982;41(14):3094–8.

    PubMed  Google Scholar 

  29. Arbore G, Kemper C, Kolev M. Intracellular complement—the complosome—in immune cell regulation. Mol Immunol. 2017;89:2–9. https://doi.org/10.1016/j.molimm.2017.05.012.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Arbore G, West EE, Spolski R, Robertson AA, Klos A, Rheinheimer C, et al. T helper 1 immunity requires complement-driven NLRP3 inflammasome activity in CD4(+) T cells. Science. 2016;352(6292):aad1210. https://doi.org/10.1126/science.aad1210.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Liszewski MK, Elvington M, Kulkarni HS, Atkinson JP. Complement’s hidden arsenal: new insights and novel functions inside the cell. Mol Immunol. 2017;84:2–9. https://doi.org/10.1016/j.molimm.2017.01.004.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Liszewski MK, Kolev M, Le Friec G, Leung M, Bertram PG, Fara AF, et al. Intracellular complement activation sustains T cell homeostasis and mediates effector differentiation. Immunity. 2013;39(6):1143–57.

    PubMed  PubMed Central  Google Scholar 

  33. Asgari E, Le Friec G, Yamamoto H, Perucha E, Sacks SS, Kohl J, et al. C3a modulates IL-1β secretion in human monocytes by regulating ATP efflux and subsequent NLRP3 inflammasome activation. Blood. 2013;122(20):3473–81. https://doi.org/10.1182/blood-2013-05-502229.

    Article  PubMed  Google Scholar 

  34. Triantafilou K, Hughes TR, Triantafilou M, Morgan BP. The complement membrane attack complex triggers intracellular Ca2+ fluxes leading to NLRP3 inflammasome activation. J Cell Sci. 2013;126(Pt 13):2903–13. https://doi.org/10.1242/jcs.124388.

    Article  PubMed  Google Scholar 

  35. Benoit ME, Clarke EV, Morgado P, Fraser DA, Tenner AJ. Complement protein C1q directs macrophage polarization and limits inflammasome activity during the uptake of apoptotic cells. J Immunol. 2012;188(11):5682–93. https://doi.org/10.4049/jimmunol.1103760.

    Article  PubMed  Google Scholar 

  36. Sorbara MT, Foerster EG, Tsalikis J, Abdel-Nour M, Mangiapane J, Sirluck-Schroeder I, et al. Complement C3 drives autophagy-dependent restriction of cyto-invasive bacteria. Cell Host Microbe. 2018;23(5):644–52.e5. https://doi.org/10.1016/j.chom.2018.04.008.

    Article  PubMed  Google Scholar 

  37. Tam JC, Bidgood SR, McEwan WA, James LC. Intracellular sensing of complement C3 activates cell autonomous immunity. Science. 2014;345(6201):1256070. https://doi.org/10.1126/science.1256070.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Bottermann M, Foss S, Caddy SL, Clift D, van Tienen LM, Vaysburd M, et al. Complement C4 prevents viral infection through capsid inactivation. Cell Host Microbe. 2019;25(4):617–29. e7. https://doi.org/10.1016/j.chom.2019.02.016.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Hovingh ES, van den Broek B, Jongerius I. Hijacking complement regulatory proteins for bacterial immune evasion. Front Microbiol. 2016;7:2004. https://doi.org/10.3389/fmicb.2016.02004.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Ricklin D, Mastellos DC, Reis ES, Lambris JD. The renaissance of complement therapeutics. Nat Rev Nephrol. 2018;14(1):26–47. https://doi.org/10.1038/nrneph.2017.156.

    Article  PubMed  Google Scholar 

  41. Beikler T, Peters U, Prior K, Eisenacher M, Flemmig TF. Gene expression in periodontal tissues following treatment. BMC Med Genet. 2008;1:30. https://doi.org/10.1186/1755-8794-1-30. 1755-8794-1-30 [pii].

    Article  Google Scholar 

  42. Courts FJ, Boackle RJ, Fudenberg HH, Silverman MS. Detection of functional complement components in gingival crevicular fluid from humans with periodontal diseases. J Dent Res. 1977;56(3):327–31.

    PubMed  Google Scholar 

  43. Niekrash CE, Patters MR. Assessment of complement cleavage in gingival fluid in humans with and without periodontal disease. J Periodontal Res. 1986;21(3):233–42.

    PubMed  Google Scholar 

  44. Nikolopoulou-Papaconstantinou AA, Johannessen AC, Kristoffersen T. Deposits of immunoglobulins, complement, and immune complexes in inflamed human gingiva. Acta Odontol Scand. 1987;45(3):187–93.

    PubMed  Google Scholar 

  45. Patters MR, Niekrash CE, Lang NP. Assessment of complement cleavage in gingival fluid during experimental gingivitis in man. J Clin Periodontol. 1989;16(1):33–7.

    PubMed  Google Scholar 

  46. Rautemaa R, Meri S. Protection of gingival epithelium against complement-mediated damage by strong expression of the membrane attack complex inhibitor protectin (CD59). J Dent Res. 1996;75(1):568–74.

    PubMed  Google Scholar 

  47. Schenkein HA, Genco RJ. Gingival fluid and serum in periodontal diseases. II. Evidence for cleavage of complement components C3, C3 proactivator (factor B) and C4 in gingival fluid. J Periodontol. 1977;48(12):778–84.

    PubMed  Google Scholar 

  48. Popadiak K, Potempa J, Riesbeck K, Blom AM. Biphasic effect of gingipains from Porphyromonas gingivalis on the human complement system. J Immunol. 2007;178(11):7242–50.

    PubMed  Google Scholar 

  49. Schenkein HA, Genco RJ. Complement cleavage products in inflammatory exudates from patients with periodontal diseases. J Immunol. 1978;120(5):1796.

    Google Scholar 

  50. Niekrash CE, Patters MR. Simultaneous assessment of complement components C3, C4, and B and their cleavage products in human gingival fluid. II. Longitudinal changes during periodontal therapy. J Periodontal Res. 1985;20(3):268–75.

    PubMed  Google Scholar 

  51. Zhan Y, Zhang R, Lv H, Song X, Xu X, Chai L, et al. Prioritization of candidate genes for periodontitis using multiple computational tools. J Periodontol. 2014;85(8):1059–69. https://doi.org/10.1902/jop.2014.130523.

    Article  PubMed  Google Scholar 

  52. Hillebrandt S, Wasmuth HE, Weiskirchen R, Hellerbrand C, Keppeler H, Werth A, et al. Complement factor 5 is a quantitative trait gene that modifies liver fibrogenesis in mice and humans. Nat Genet. 2005;37(8):835–43. https://doi.org/10.1038/ng1599. ng1599 [pii].

    Article  PubMed  Google Scholar 

  53. Chai L, Song Y-Q, Zee K-Y, Leung WK. Single nucleotide polymorphisms of complement component 5 and periodontitis. J Periodontal Res. 2010;45:301–8.

    PubMed  Google Scholar 

  54. Hajishengallis G, Lamont RJ, Graves DT. The enduring importance of animal models in understanding periodontal disease. Virulence. 2015a;6(3):229–35. https://doi.org/10.4161/21505594.2014.990806.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Hajishengallis G, Liang S, Payne MA, Hashim A, Jotwani R, Eskan MA, et al. Low-abundance biofilm species orchestrates inflammatory periodontal disease through the commensal microbiota and complement. Cell Host Microbe. 2011;10(5):497–506. https://doi.org/10.1016/j.chom.2011.10.006.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Liang S, Krauss JL, Domon H, McIntosh ML, Hosur KB, Qu H, et al. The C5a receptor impairs IL-12-dependent clearance of Porphyromonas gingivalis and is required for induction of periodontal bone loss. J Immunol. 2011;186(2):869–77. https://doi.org/10.4049/jimmunol.1003252.

    Article  PubMed  Google Scholar 

  57. Maekawa T, Abe T, Hajishengallis E, Hosur KB, DeAngelis RA, Ricklin D, et al. Genetic and intervention studies implicating complement C3 as a major target for the treatment of periodontitis. J Immunol. 2014b;192(12):6020–7. https://doi.org/10.4049/jimmunol.1400569.

    Article  PubMed  Google Scholar 

  58. Maekawa T, Krauss JL, Abe T, Jotwani R, Triantafilou M, Triantafilou K, et al. Porphyromonas gingivalis manipulates complement and TLR signaling to uncouple bacterial clearance from inflammation and promote dysbiosis. Cell Host Microbe. 2014a;15(6):768–78. https://doi.org/10.1016/j.chom.2014.05.012.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Abe T, Hosur KB, Hajishengallis E, Reis ES, Ricklin D, Lambris JD, et al. Local complement-targeted intervention in periodontitis: proof-of-concept using a C5a receptor (CD88) antagonist. J Immunol. 2012;189(11):5442–8. https://doi.org/10.4049/jimmunol.1202339.

    Article  PubMed  Google Scholar 

  60. Hajishengallis G, Lambris JD. Crosstalk pathways between toll-like receptors and the complement system. Trends Immunol. 2010;31(4):154–63. https://doi.org/10.1016/j.it.2010.01.002.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Zhang X, Kimura Y, Fang C, Zhou L, Sfyroera G, Lambris JD, et al. Regulation of toll-like receptor-mediated inflammatory response by complement in vivo. Blood. 2007;110(1):228–36.

    PubMed  PubMed Central  Google Scholar 

  62. Reis ES, Mastellos DC, Hajishengallis G, Lambris JD. New insights into the immune functions of complement. Nat Rev Immunol. 2019;19(8):503–16.

    PubMed  PubMed Central  Google Scholar 

  63. Schaefer L. Extracellular matrix molecules: endogenous danger signals as new drug targets in kidney diseases. Curr Opin Pharmacol. 2010;10(2):185–90. https://doi.org/10.1016/j.coph.2009.11.007.

    Article  PubMed  Google Scholar 

  64. Malm S, Jusko M, Eick S, Potempa J, Riesbeck K, Blom AM. Acquisition of complement inhibitor serine protease factor I and its cofactors C4b-binding protein and factor H by Prevotella intermedia. PLoS One. 2012;7(4):e34852. https://doi.org/10.1371/journal.pone.0034852.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Potempa M, Potempa J, Okroj M, Popadiak K, Eick S, Nguyen KA, et al. Binding of complement inhibitor C4b-binding protein contributes to serum resistance of Porphyromonas gingivalis. J Immunol. 2008;181(8):5537–44.

    PubMed  Google Scholar 

  66. Asakawa R, Komatsuzawa H, Kawai T, Yamada S, Goncalves RB, Izumi S, et al. Outer membrane protein 100, a versatile virulence factor of Actinobacillus actinomycetemcomitans. Mol Microbiol. 2003;50(4):1125–39.

    PubMed  Google Scholar 

  67. McDowell JV, Huang B, Fenno JC, Marconi RT. Analysis of a unique interaction between the complement regulatory protein factor H and the periodontal pathogen Treponema denticola. Infect Immun. 2009;77(4):1417–25.

    PubMed  PubMed Central  Google Scholar 

  68. Jusko M, Potempa J, Karim AY, Ksiazek M, Riesbeck K, Garred P, et al. A metalloproteinase karilysin present in the majority of Tannerella forsythia isolates inhibits all pathways of the complement system. J Immunol. 2012;188(5):2338–49. https://doi.org/10.4049/jimmunol.1101240.

    Article  PubMed  Google Scholar 

  69. Paramonov N, Rangarajan M, Hashim A, Gallagher A, Aduse-Opoku J, Slaney JM, et al. Structural analysis of a novel anionic polysaccharide from Porphyromonas gingivalis strain W50 related to Arg-gingipain glycans. Mol Microbiol. 2005;58(3):847–63. https://doi.org/10.1111/j.1365-2958.2005.04871.x. MMI4871 [pii].

    Article  PubMed  Google Scholar 

  70. Slaney JM, Gallagher A, Aduse-Opoku J, Pell K, Curtis MA. Mechanisms of resistance of Porphyromonas gingivalis to killing by serum complement. Infect Immun. 2006;74(9):5352–61.

    PubMed  PubMed Central  Google Scholar 

  71. Blom AM, Hallstrom T, Riesbeck K. Complement evasion strategies of pathogens-acquisition of inhibitors and beyond. Mol Immunol. 2009;46(14):2808–17. https://doi.org/10.1016/j.molimm.2009.04.025. S0161-5890(09)00194-1 [pii].

    Article  PubMed  Google Scholar 

  72. Krauss JL, Potempa J, Lambris JD, Hajishengallis G. Complementary Tolls in the periodontium: how periodontal bacteria modify complement and Toll-like receptor responses to prevail in the host. Periodontol 2000. 2010;52(1):141–62. https://doi.org/10.1111/j.1600-0757.2009.00324.x.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Potempa J, Pike RN. Corruption of innate immunity by bacterial proteases. J Innate Immun. 2009;1:70–87.

    PubMed  Google Scholar 

  74. Potempa M, Potempa J, Kantyka T, Nguyen KA, Wawrzonek K, Manandhar SP, et al. Interpain A, a cysteine proteinase from Prevotella intermedia, inhibits complement by degrading complement factor C3. PLoS Pathog. 2009;5(2):e1000316.

    PubMed  PubMed Central  Google Scholar 

  75. Slaney JM, Curtis MA. Mechanisms of evasion of complement by Porphyromonas gingivalis. Front Biosci. 2008;13:188–96.

    PubMed  Google Scholar 

  76. Miller DP, McDowell JV, Bell JK, Goetting-Minesky MP, Fenno JC, Marconi RT. Analysis of the complement sensitivity of oral treponemes and the potential influence of FH binding, FH cleavage and dentilisin activity on the pathogenesis of periodontal disease. Mol Oral Microbiol. 2014;29(5):194–207. https://doi.org/10.1111/omi.12054.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Yamazaki T, Miyamoto M, Yamada S, Okuda K, Ishihara K. Surface protease of Treponema denticola hydrolyzes C3 and influences function of polymorphonuclear leukocytes. Microbes Infect. 2006;8(7):1758–63.

    PubMed  Google Scholar 

  78. Schenkein HA, Berry CR. Activation of complement by Treponema denticola. J Dent Res. 1991;70(2):107–10.

    PubMed  Google Scholar 

  79. Berton G, Laudanna C, Sorio C, Rossi F. Generation of signals activating neutrophil functions by leukocyte integrins: LFA-1 and gp150/95, but not CR3, are able to stimulate the respiratory burst of human neutrophils. J Cell Biol. 1992;116(4):1007–17. https://doi.org/10.1083/jcb.116.4.1007.

    Article  PubMed  Google Scholar 

  80. Kim S, Elkon KB, Ma X. Transcriptional suppression of interleukin-12 gene expression following phagocytosis of apoptotic cells. Immunity. 2004;21(5):643–53.

    PubMed  Google Scholar 

  81. Mevorach D, Mascarenhas JO, Gershov D, Elkon KB. Complement-dependent clearance of apoptotic cells by human macrophages. J Exp Med. 1998;188(12):2313–20.

    PubMed  PubMed Central  Google Scholar 

  82. Wright SD, Silverstein SC. Receptors for C3b and C3bi promote phagocytosis but not the release of toxic oxygen from human phagocytes. J Exp Med. 1983;158(6):2016–23. https://doi.org/10.1084/jem.158.6.2016.

    Article  PubMed  Google Scholar 

  83. Dai S, Rajaram MV, Curry HM, Leander R, Schlesinger LS. Fine tuning inflammation at the front door: macrophage complement receptor 3-mediates phagocytosis and immune suppression for Francisella tularensis. PLoS Pathog. 2013;9(1):e1003114. https://doi.org/10.1371/journal.ppat.1003114.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Ernst JD. Macrophage receptors for Mycobacterium tuberculosis. Infect Immun. 1998;66(4):1277–81.

    PubMed  PubMed Central  Google Scholar 

  85. Hajishengallis G, Lambris JD. Microbial manipulation of receptor crosstalk in innate immunity. Nat Rev Immunol. 2011;11(3):187–200. https://doi.org/10.1038/nri2918.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Hajishengallis G, McIntosh ML, Nishiyama S-I, Yoshimura F. Mechanism and implications of CXCR4-mediated integrin activation by Porphyromonas gingivalis. Mol Oral Microbiol. 2012;28:239–49. https://doi.org/10.1111/omi.12021.

    Article  Google Scholar 

  87. Hellwig SM, van Oirschot HF, Hazenbos WL, van Spriel AB, Mooi FR, van De Winkel JG. Targeting to Fcg receptors, but not CR3 (CD11b/CD18), increases clearance of Bordetella pertussis. J Infect Dis. 2001;183(6):871–9.

    PubMed  Google Scholar 

  88. Lambris JD, Ricklin D, Geisbrecht BV. Complement evasion by human pathogens. Nat Rev Microbiol. 2008;6(2):132–42.

    PubMed  PubMed Central  Google Scholar 

  89. Makkawi H, Hoch S, Burns E, Hosur K, Hajishengallis G, Kirschning CJ, et al. Porphyromonas gingivalis stimulates TLR2-PI3K signaling to escape immune clearance and induce bone resorption independently of MyD88. Front Cell Infect Microbiol. 2017;7:359. https://doi.org/10.3389/fcimb.2017.00359. (Article no. 359).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Brecx MC, Nalbandian J, Ooya K, Kornman KS, Robertson PB. Morphological studies on periodontal disease in the cynomolgus monkey. II. Light microscopic observations on ligature-induced periodontitis. J Periodontal Res. 1985;20(2):165–75.

    PubMed  Google Scholar 

  91. Ebersole JL, Kirakodu S, Novak MJ, Stromberg AJ, Shen S, Orraca L, et al. Cytokine gene expression profiles during initiation, progression and resolution of periodontitis. J Clin Periodontol. 2014;41(9):853–61. https://doi.org/10.1111/jcpe.12286.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Kornman KS, Holt SC, Robertson PB. The microbiology of ligature-induced periodontitis in the cynomolgus monkey. J Periodontal Res. 1981;16(4):363–71.

    PubMed  Google Scholar 

  93. Mastellos DC, Yancopoulou D, Kokkinos P, Huber-Lang M, Hajishengallis G, Biglarnia AR, et al. Compstatin: a C3-targeted complement inhibitor reaching its prime for bedside intervention. Eur J Clin Investig. 2015;45(4):423–40. https://doi.org/10.1111/eci.12419.

    Article  Google Scholar 

  94. Qu H, Ricklin D, Bai H, Chen H, Reis ES, Maciejewski M, et al. New analogs of the clinical complement inhibitor compstatin with subnanomolar affinity and enhanced pharmacokinetic properties. Immunobiology. 2013;218(4):496–505. https://doi.org/10.1016/j.imbio.2012.06.003.

    Article  PubMed  Google Scholar 

  95. Ricklin D, Lambris JD. Complement in immune and inflammatory disorders: pathophysiological mechanisms. J Immunol. 2013;190(8):3831–8. https://doi.org/10.4049/jimmunol.1203487.

    Article  PubMed  Google Scholar 

  96. Sahu A, Kay BK, Lambris JD. Inhibition of human complement by a C3-binding peptide isolated from a phage-displayed random peptide library. J Immunol. 1996;157(2):884–91.

    PubMed  Google Scholar 

  97. Belibasakis GN, Bostanci N. The RANKL-OPG system in clinical periodontology. J Clin Periodontol. 2012;39(3):239–48. https://doi.org/10.1111/j.1600-051X.2011.01810.x.

    Article  PubMed  Google Scholar 

  98. Maekawa T, Briones RA, Resuello RR, Tuplano JV, Hajishengallis E, Kajikawa T, et al. Inhibition of pre-existing natural periodontitis in non-human primates by a locally administered peptide inhibitor of complement C3. J Clin Periodontol. 2016;43:238–49. https://doi.org/10.1111/jcpe.12507.

    Article  PubMed  PubMed Central  Google Scholar 

  99. Bostanci N, Bao K, Li X, Maekawa T, Grossmann J, Panse C, et al. Gingival exudatome dynamics implicate inhibition of the alternative complement pathway in the protective action of the C3 inhibitor Cp40 in non-human primate periodontitis. J Proteome Res. 2018;17(9):3153–75. https://doi.org/10.1021/acs.jproteome.8b00263.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Attstrom R, Laurel AB, Lahsson U, Sjoholm A. Complement factors in gingival crevice material from healthy and inflamed gingiva in humans. J Periodontal Res. 1975;10(1):19–27.

    PubMed  Google Scholar 

  101. Chapple IL, Matthews JB. The role of reactive oxygen and antioxidant species in periodontal tissue destruction. Periodontol 2000. 2007;43:160–232.

    PubMed  Google Scholar 

  102. Eskan MA, Jotwani R, Abe T, Chmelar J, Lim JH, Liang S, et al. The leukocyte integrin antagonist Del-1 inhibits IL-17-mediated inflammatory bone loss. Nat Immunol. 2012;13(5):465–73. https://doi.org/10.1038/ni.2260.

    Article  PubMed  PubMed Central  Google Scholar 

  103. Hajishengallis G, Moutsopoulos NM, Hajishengallis E, Chavakis T. Immune and regulatory functions of neutrophils in inflammatory bone loss. Semin Immunol. 2016;28(2):146–58. https://doi.org/10.1016/j.smim.2016.02.002.

    Article  PubMed  PubMed Central  Google Scholar 

  104. Hernandez M, Gamonal J, Tervahartiala T, Mantyla P, Rivera O, Dezerega A, et al. Associations between matrix metalloproteinase-8 and -14 and myeloperoxidase in gingival crevicular fluid from subjects with progressive chronic periodontitis: a longitudinal study. J Periodontol. 2010;81(11):1644–52. https://doi.org/10.1902/jop.2010.100196.

    Article  PubMed  Google Scholar 

  105. Kajikawa T, Briones RA, Resuello RRG, Tuplano JV, Reis ES, Hajishengallis E, et al. Safety and efficacy of the complement inhibitor AMY-101 in a natural model of periodontitis in non-human primates. Mol Ther Methods Clin Dev. 2017;6:207–15. https://doi.org/10.1016/j.omtm.2017.08.001.

    Article  PubMed  PubMed Central  Google Scholar 

  106. Risitano AM, Ricklin D, Huang Y, Reis ES, Chen H, Ricci P, et al. Peptide inhibitors of C3 activation as a novel strategy of complement inhibition for the treatment of paroxysmal nocturnal hemoglobinuria. Blood. 2014;123(13):2094–101. https://doi.org/10.1182/blood-2013-11-536573.

    Article  PubMed  PubMed Central  Google Scholar 

  107. Mastellos DC, Ricklin D, Hajishengallis E, Hajishengallis G, Lambris JD. Complement therapeutics in inflammatory diseases: promising drug candidates for C3-targeted intervention. Mol Oral Microbiol. 2016;31(1):3–17. https://doi.org/10.1111/omi.12129.

    Article  PubMed  Google Scholar 

  108. Reis ES, Berger N, Wang X, Koutsogiannaki S, Doot RK, Gumas JT, et al. Safety profile after prolonged C3 inhibition. Clin Immunol. 2018;197:96–106. https://doi.org/10.1016/j.clim.2018.09.004.

    Article  PubMed  PubMed Central  Google Scholar 

  109. Rafail S, Kourtzelis I, Foukas PG, Markiewski MM, DeAngelis RA, Guariento M, et al. Complement deficiency promotes cutaneous wound healing in mice. J Immunol. 2015;194(3):1285–91. https://doi.org/10.4049/jimmunol.1402354.

    Article  PubMed  Google Scholar 

  110. Dutzan N, Kajikawa T, Abusleme L, Greenwell-Wild T, Zuazo CE, Ikeuchi T, et al. A dysbiotic microbiome triggers Th17 cells to mediate oral mucosal immunopathology in mice and humans. Sci Transl Med. 2018;10(463):eaat0797. https://doi.org/10.1126/scitranslmed.aat0797.

    Article  PubMed  PubMed Central  Google Scholar 

  111. Hajishengallis G, Lambris JD. Complement and dysbiosis in periodontal disease. Immunobiology. 2012;217(11):1111–6. https://doi.org/10.1016/j.imbio.2012.07.007.

    Article  PubMed  PubMed Central  Google Scholar 

  112. Hajishengallis G, Maekawa T, Abe T, Hajishengallis E, Lambris JD. Complement involvement in periodontitis: molecular mechanisms and rational therapeutic approaches. Adv Exp Med Biol. 2015b;865:57–74. https://doi.org/10.1007/978-3-319-18603-0_4.

    Article  PubMed  PubMed Central  Google Scholar 

  113. Ignatius A, Schoengraf P, Kreja L, Liedert A, Recknagel S, Kandert S, et al. Complement C3a and C5a modulate osteoclast formation and inflammatory response of osteoblasts in synergism with IL-1beta. J Cell Biochem. 2011;112(9):2594–605. https://doi.org/10.1002/jcb.23186.

    Article  PubMed  PubMed Central  Google Scholar 

  114. Kourtzelis I, Li X, Mitroulis I, Grosser D, Kajikawa T, Wang B, et al. DEL-1 promotes macrophage efferocytosis and clearance of inflammation. Nat Immunol. 2019;20(1):40–9. https://doi.org/10.1038/s41590-018-0249-1.

    Article  PubMed  Google Scholar 

  115. Zhang Y, Keenan A, Lindorfer MA, Pitcher GR, Taylor RP, Lambris JD, et al. Activation of alternative complement pathway without complement factor D. Mol Immunol. 2017;89:173. https://doi.org/10.1016/j.molimm.2017.06.153.

    Article  Google Scholar 

  116. DiScipio RG. The activation of the alternative pathway C3 convertase by human plasma kallikrein. Immunology. 1982;45(3):587–95.

    PubMed  PubMed Central  Google Scholar 

  117. Tonetti MS, Chapple IL, Working Group 3 of Seventh European Workshop on P. Biological approaches to the development of novel periodontal therapies—consensus of the Seventh European Workshop on Periodontology. J Clin Periodontol. 2011;38(Suppl 11):114–8. https://doi.org/10.1111/j.1600-051X.2010.01675.x.

    Article  PubMed  Google Scholar 

  118. Genco RJ, Genco FD. Common risk factors in the management of periodontal and associated systemic diseases: the dental setting and interprofessional collaboration. J Evid Based Dent Pract. 2014;14(Suppl):4–16. https://doi.org/10.1016/j.jebdp.2014.03.003.

    Article  PubMed  Google Scholar 

  119. Heitz-Mayfield LJ. Disease progression: identification of high-risk groups and individuals for periodontitis. J Clin Periodontol. 2005;32(Suppl 6):196–209. https://doi.org/10.1111/j.1600-051X.2005.00803.x. CPE803 [pii].

    Article  PubMed  Google Scholar 

  120. Joshi V, Matthews C, Aspiras M, de Jager M, Ward M, Kumar P. Smoking decreases structural and functional resilience in the subgingival ecosystem. J Clin Periodontol. 2014;41(11):1037–47. https://doi.org/10.1111/jcpe.12300.

    Article  PubMed  Google Scholar 

  121. Joss A, Adler R, Lang NP. Bleeding on probing. A parameter for monitoring periodontal conditions in clinical practice. J Clin Periodontol. 1994;21(6):402–8.

    PubMed  Google Scholar 

  122. Kinane DF, Attstrom R, European Workshop in Periodontology group B. Advances in the pathogenesis of periodontitis. Group B consensus report of the fifth European Workshop in Periodontology. J Clin Periodontol. 2005;32(Suppl 6):130–1. https://doi.org/10.1111/j.1600-051X.2005.00823.x.

    Article  PubMed  Google Scholar 

  123. Lang NP, Adler R, Joss A, Nyman S. Absence of bleeding on probing. An indicator of periodontal stability. J Clin Periodontol. 1990;17(10):714–21.

    PubMed  Google Scholar 

  124. Loe H, Anerud A, Boysen H, Morrison E. Natural history of periodontal disease in man. Rapid, moderate and no loss of attachment in Sri Lankan laborers 14 to 46 years of age. J Clin Periodontol. 1986;13(5):431–45.

    PubMed  Google Scholar 

  125. Ramseier CA, Anerud A, Dulac M, Lulic M, Cullinan MP, Seymour GJ, et al. Natural history of periodontitis: disease progression and tooth loss over 40 years. J Clin Periodontol. 2017;44(12):1182–91. https://doi.org/10.1111/jcpe.12782.

    Article  PubMed  Google Scholar 

  126. Schatzle M, Loe H, Lang NP, Heitz-Mayfield LJ, Burgin W, Anerud A, et al. Clinical course of chronic periodontitis. III. Patterns, variations and risks of attachment loss. J Clin Periodontol. 2003;30(10):909–18.

    PubMed  Google Scholar 

Download references

Acknowledgments

The authors are supported by grants from the U.S. National Institutes of Health (AI068730 and AI030040 to J.D.L.; DE015254, DE024153, and DE024716 to G.H.) and the European Commission (FP7-DIREKT 602699 to J.D.L.).

Conflict of Interest Statement: J.D.L. is the founder of Amyndas Pharmaceuticals, which is developing complement inhibitors (including third-generation compstatin analogs such as AMY-101). J.D.L. and G.H are inventors of patents or patent applications that describe the use of complement inhibitors for therapeutic purposes, some of which are developed by Amyndas Pharmaceuticals. J.D.L. is also the inventor of the compstatin technology licensed to Apellis Pharmaceuticals (i.e., 4(1MeW)7W/POT-4/APL-1 and PEGylated derivatives such as APL-2/pegcetacoplan). The other authors declare no competing interest.

Author information

Authors and Affiliations

  1. Department of Basic and Translational Sciences, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA

    George Hajishengallis, Tetsuhiro Kajikawa & Xiaofei Li

  2. Division of Pediatric Dentistry, Department of Preventive and Restorative Sciences, University of Pennsylvania Penn Dental Medicine, Philadelphia, PA, USA

    Evlambia Hajishengallis

  3. Research Center for Advanced Oral Science, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan

    Tomoki Maekawa

  4. Division of Oral Diseases, Department of Dental Medicine, Karolinska Institutet, Stockholm, Sweden

    George N. Belibasakis & Nagihan Bostanci

  5. Division of Biodiagnostic Sciences and Technologies, INRASTES, National Center for Scientific Research ‘Demokritos’, Athens, Greece

    Dimitrios C. Mastellos

  6. Amyndas Pharmaceuticals, Glyfada, Greece

    Despina Yancopoulou

  7. Center for Clinical and Translational Research, Forsyth Institute, Cambridge, MA, USA

    Hatice Hasturk

  8. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    John D. Lambris

Authors
  1. George Hajishengallis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tetsuhiro Kajikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Evlambia Hajishengallis
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tomoki Maekawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiaofei Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. George N. Belibasakis
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nagihan Bostanci
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Dimitrios C. Mastellos
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Despina Yancopoulou
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hatice Hasturk
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. John D. Lambris
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to George Hajishengallis .

Editor information

Editors and Affiliations

  1. School of Dental Medicine, Department of Periodontics, University of Pennsylvania, Philadelphia, PA, USA

    Sinem Esra Sahingur

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Hajishengallis, G. et al. (2020). Complement C3 as a Target of Host Modulation in Periodontitis. In: Sahingur, S. (eds) Emerging Therapies in Periodontics. Springer, Cham. https://doi.org/10.1007/978-3-030-42990-4_2

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-42990-4_2

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-42989-8

  • Online ISBN: 978-3-030-42990-4

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation