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![HISTORY
• In 1891-BUNCHER found a heat liable factor in blood that was capable of
killing the bacteria and named-”alexin”[means ward off].
• In 1895-BORDENT discovered that the this heat liable activity in serum is
responsible for the lysis of the bacteria .
• In 1899-EHRLICH named the heat liable substance as – complement.](https://image.slidesharecdn.com/complementsystemanditsroleinperiodontalinflammation-240426120017-696134b8/75/COMPLEMENT-SYSTEM-AND-ITS-ROLE-IN-PERIODONTAL-INFLAMMATION-pptx-5-2048.jpg)
![• FUNCTIONS:-
• These include the recruitment and activation of inflammatory
cells .
via the C3a and C5a anaphylatoxins that activate specific G-
protein-coupled receptors, C3aR and C5aR [CD88], respectively),
microbial opsonization and phagocytosis (e.g., through the C3b or
C4b opsonin).
• Direct lysis of susceptible targeted microbes (by means of the
C5b-9 membrane attack complex)](https://image.slidesharecdn.com/complementsystemanditsroleinperiodontalinflammation-240426120017-696134b8/75/COMPLEMENT-SYSTEM-AND-ITS-ROLE-IN-PERIODONTAL-INFLAMMATION-pptx-25-2048.jpg)
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Similar to COMPLEMENT SYSTEM AND ITS ROLE IN PERIODONTAL INFLAMMATION.pptx
COMPLEMENT SYSTEM AND ITS ROLE IN PERIODONTAL INFLAMMATION.pptx
- 1. COMPLEMENT SYSTEM AND ITSROLE IN PERIODONTAL INFLAMMATION PRESENTED BY-DR ANKITA PRIYA
- 2. CONTENT INTRODUCTION HISTORY FUNCTION OF COMPLEMENT SYSTEM COMPONENTS PATHWAYS OF COMPLEMENT SYSTEM TLR COMPLEMENT AND ACUTE INFLAMMATION COMPLEMENT AND PERIODONTITIS PATHOGENS CONCLUSION REFERENCES
- 3. INTRODUCTION • It isnamed “complement system” because it was first identified as heat liable component of serum that “complemented or augment “ antibodies in the killing of bacteria. • The complement system is the major effector of cellular and humoral branch of immune system. • Plays major role in both innate and adaptive immunity.
- 4. • Complement systemrepresents a group of more than 40 proteins which augment or complement the immune response . • Most of these proteins are found in serum or on cell surface. • Synthesized in ( major) liver as inactive precursors and are activated by proteolysis during their interaction in a sequential manner. • Also produced by blood monocytes , tissue macrophages(C1,C2,C3,C4,C5,factor B,C1- INA,factor D and H).
- 5. HISTORY • In 1891-BUNCHERfound a heat liable factor in blood that was capable of killing the bacteria and named-”alexin”[means ward off]. • In 1895-BORDENT discovered that the this heat liable activity in serum is responsible for the lysis of the bacteria . • In 1899-EHRLICH named the heat liable substance as – complement.
- 6. Complement system Complement component Properdin systemRegulatory protein • C1 to C9 • C1- C1q,C1r,C1s
- 7. • Lysis ofcells, bacteria, and viruses • Opsonization, which promotes phagocytosis of particulate antigens. • Binding to specific complement receptors on cells of the immune system , triggering specific cell functions, inflammation, and secretion of immunoregulatory molecules. • Immune clearance, which removes immune complexes from the circulation and deposits them in the spleen and liver. The Function of complement
- 9. THE COMPLEMENT COMPONENTS •These components constitute 5% (by weight) of the serum globulin fraction. • Most circulate in the serum in functionally inactive forms as proenzymes, or zymogens, which are inactive until proteolytic cleavage, which removes an inhibitory fragment and exposes the active site. • The complement-reaction sequence starts with an enzyme cascade. • Complement components are designated by numerals (C1–C9), by letter symbols (e.g., factor D).
- 10. • Peptide fragmentsformed by activation of a component are denoted by small letters. In most cases, the smaller fragment resulting from cleavage of a component is designated “a” and the larger fragment designated “b” • (e.g., C3a, C3b; note that C2 is an exception: C2a is the larger cleavage fragment). • The larger fragments bind to the target near the site of activation. • The smaller fragments diffuse from the site and can initiate localized inflammatory responses by binding to specific receptors.
- 12. • There arethree major pathways of complement activation: • 1.Classical pathway • 2.Alternative pathway • 3.Lectin pathway PATHWAYS OF COMPLEMENT ACTIVATION
- 13. 4 main stagesin activation of any complement pathways :- 1. Initiation of pathway different in all pathway 2. Formation of C3 convertase 3. Formation of C5 convertase same in all pathway 4. Formation of membrane attack complex (MAC)
- 14.
- 18.
- 22. C5 Ligand forC5-convertases, progenitor for C5a and C5b. C5b Initiates MAC formation. C6 Membrane insertion of MAC. C7 Membrane insertion of MAC. C8 Induces pore formation. C9 Forms lytic pore. MAC constituents.
- 23. • The complementsystem is a central component of inflammation that enables endothelial and leukocytes to recognize and binds foreign substance for which they lack receptors. • Complement promotes inflammation by generating the following:- 1. A vasoactive substance termed kinin like , C2a which induces pain and increases vascular permeability and dilation. 2. Molecules ,termed anaphylatoxins ,C3a and C5a ,which produce anaphylaxis by inducing mast cell secretion. 3. A chemotaxin,C5a,which attracts leukocytes and stimulates phagocytes secretions . 4. An opsonin, iC3b, covalently bound to molecular aggregates , particles or cells which enables phagocytes to ingest them. CARRANZZA 10TH EDITION
- 24. • The complementcascade can be triggered by distinct mechanisms (classical, lectin, or alternative). • All 3 of which converge at the third complement component (C3) and lead to the generation of effectors that mediate diverse functions.
- 25. • FUNCTIONS:- • Theseinclude the recruitment and activation of inflammatory cells . via the C3a and C5a anaphylatoxins that activate specific G- protein-coupled receptors, C3aR and C5aR [CD88], respectively), microbial opsonization and phagocytosis (e.g., through the C3b or C4b opsonin). • Direct lysis of susceptible targeted microbes (by means of the C5b-9 membrane attack complex)
- 26. • TLRs arepattern-recognition receptors (PRRs) that recognize pathogen associated molecular patterns (PAMPs) from microorganisms or danger-associated molecular patterns (DAMPs) from damaged tissue. • The TLR family now consists of ten members in humans (TLR1- TLR10). • Toll-like receptors (TLRs) are a class of proteins that play key role in the innate immune system. TALL LIKE RECEPTOR
- 27. • TLRs arecategorized as a type of type I integral transmembrane proteins, usually consisting of three domains—an N- terminal domain (NTD) located outside the membrane, a middle single helix transmembrane domain traversing the membrane, and a C-terminal domain (CTD) . STRUCTURE OF TLR Sameer AS, Nissar S. Toll-Like Receptors (TLRs): Structure, Functions, Signaling, and Role of Their Polymorphisms in Colorectal Cancer Susceptibility. Biomed Res Int. 2021 Sep 12;2021:1157023
- 28. • Toll-like receptorsare essential molecular receptors through which the immune system "senses" the risk to protect the host from pathogenic microorganisms or endogenous threats. • Numerous roles of TLRs have been identified, the recognition of self and non-self antigens detection of invading pathogens bridging the innate and adaptive immunity regulation of cytokine production regulate proliferation and survival of the host cell FUNCTIONS Nie L, Cai SY, Shao JZ, Chen J. Toll-Like Receptors, Associated Biological Roles, and Signaling Networks in Non-Mammals. Front Immunol. 2018 Jul 2;9:1523
- 29. CROSS -TALK INTERACTIONSOF COMPLEMENT • An important cross talk interaction of complement involves its interplay with TLRs ,leading to the amplification of innate immune and inflammatory responses . • Upon infections or tissue damage , complements and TLRs are swiftly activated and engaged in cross talk signaling in different myeloid cell types , namely monocytes /macrophages ,neutrophiles and dc. • Although these can be potentially amplify innate immune responses against infection ,and may contribute to destructive inflammatory responses.
- 30. Reis ES, MastellosDC, Hajishengallis G, Lambris JD. New insights into the immune functions of complement. Nat Rev
- 31. • The signalingpathways activated downstream of complement receptors (c3aR,or C5aR1) TLRs (2 or 4) converge at MAPKS (Extracellular signal- regulated kinase -1 and -2 and c-jun N- terminal kinase) • (turn) enhance activations of activator protein 1 and nuclear factor-b, key transcriptions factor which involve in inflammatory cytokines. COACTIVATIONS OF COMPLEMENT AND TLRS MIGHT HAVE DETRIMENTAL EFFECTS IN THE SETTING OF PERIODONTIUM. Carranza 14th edition
- 32. • IL-6 andother proinflammatory cytokines promote prompt synthesis of acute- phase proteins, including the pentraxins: • CRP, serum amyloid P protein and pentraxin-3, the levels of which are all increased in periodontitis . • Pentraxins are capable of recognizing bacteria and apoptotic cells . • Upon binding, pentraxins enhance binding of C1q and thus activation of the CP . Moreover, CRP has been shown to bind to ficolin 2, which stabilizes the binding of CRP to bacteria and activates the LP . Complement and the acute phase of inflammation
- 33. • Surfactant proteinsD (Sp-D) and (Sp-A) play a key role in inhibiting spontaneous inflammatory events, and simultaneously protect the host from pathogenic bacteria . • Surfactant proteins are capable of binding to bacteria via carbohydrate- binding domains, which facilitates binding of C1q or the binding of bacteria to Toll-like receptor (TLR) 4 , which leads to enhanced phagocytosis of the targeted bacteria as well as modulation of the accompanying cytokine production . • Elevated levels of Sp-D have been shown in patients with periodontitis Damgaard C, Holmstrup P, Van Dyke TE, Nielsen CH. The complement system and its role in the pathogenesis of periodontitis: current concepts. J Periodont Res 2014; doi:10.1111/jre.12209.
- 35. • The GCFin the gingival crevice contains a functional complement system. • Complement are, in general, either absent or present at low concentrations in the GCF of healthy individuals, but abundantly present in both the GCF and serum of patients with periodontitis. • When there is dysregulation or overactivated, complement switches from homeostatic to a pathological effector , or evidenced by its involvement in several inflammatory disorders . Complement and periodontitis CARRANZA 14TH EDITION
- 36. • Thus, C1q,factor B, factor Bb, C3, C3a, C3b, C3c, C3d, C4, C5, C5a, C5b and C9 have all been detected in diseased periodontal tissue, on the surface of subgingival bacteria and in the GCF from patients with established periodontitis. Damgaard C, Holmstrup P, Van Dyke TE, Nielsen CH. The complement system and its role in the pathogenesis of periodontitis: current concepts. J Periodont Res 2014; doi:10.1111/jre.12209.
- 37. • Increased localactivation of complement in the periodontal tissues : increases the intensity of the local inflammatory response, resulting in increased vascular permeability, vasodilatation and recruitment of inflammatory cells, resulting in excessive release of reactive oxygen species, Damgaard C, Holmstrup P, Van Dyke TE, Nielsen CH. The complement system and its role in the pathogenesis of periodontitis: current concepts. J Periodont Res 2014; doi:10.1111/jre.12209. Altogether, this may clinically manifest as: (i) edematous gingiva; (ii) loss of attachment; and (iii) ultimately bone resorption.
- 39. Grande MA, BelstrømD, Damgaard C, Holmstrup P, Thangaraj SS, Nielsen CH, Palarasah Y. Complement split product C3c in saliva as biomarker for periodontitis and response to periodontal treatment. J Periodontal Res. 2021 Jan;56(1):27-33. doi: 10.1111/jre.12788. Epub 2020 Jul 18. PMID: 32681659; PMCID: PMC7891408.
- 40. Complement and periodontalpathogens According to the polymicrobial synergy and dysbiosis (PSD) model, • the host immune response is initially subverted by keystone pathogens with the help of accessory pathogens and is subsequently over-activated by pathobionts -which • leads to destructive inflammation in susceptible hosts . • Therefore, periodontitis is not a bacterial infection in the classical sense (i.e., not caused by a single or a select few pathogens) but, rather, represents a polymicrobial community-induced perturbation of host homeostasis that leads to destructive inflammation in susceptible individuals .
- 43. Recent studies inmice and non-human primates indicate that complement is involved in both the dysbiotic transformation of the periodontal microbiota and the inflammatory response that leads to destruction of periodontal bone . In this model of periodontal disease pathogenesis, C5aR (CD88) is a target of immune subversion by P. gingivalis leading to the dysbiotic transformation of the microbiota, which in turn causes destructive inflammation that is largely dependent on C3 activation . This involvement of C3 may entail synergism with TLRs, as suggested by previous findings on the interactions of complement and the TLR signaling system in the periodontium and other tissue. Hajishengallis G, Maekawa T, Abe T, Hajishengallis E, Lambris JD. Complement Involvement in Periodontitis: Molecular Mechanisms and Rational Therapeutic Approaches. Adv Exp Med Biol. 2015;865:57-74. doi: 10.1007/978-3-319-18603-0_4.
- 45.
- 46.
- 47. Evasion and exploitationof complement by pathogenic oral bacteria In general, bacteria can evade complement through three strategies: (i) proteolytic inactivation of complement components; (ii) recruitment of inhibitory regulators of complement; (iii) hijacking of inhibitory regulators of complement
- 48. • P. gingivalisis an asaccharolytic, anaerobic bacteria • require peptides and hemin, and thus depends on the continuous flow of inflammatory serum exudates to obtain essential nutrients for its survival. To achieve this • They inhibits the complement cascade by enzymatic breakdown of C3, mediated by a group of cysteine proteases called gingipains. • They also degrade C5b which inhibits MAC formation .
- 49. • Prevotella intermediapossesses the ability to break down C3 via extracellular cystein proteases interpain A (InpA) • Interestingly, the breakdown of C3 by gingipains from P. gingivalis and InpA from P. intermedia synergizes attenuation and provides protection to other bacteria, which are normally sensitive to complement-mediated lysis. • gingipains and InpA at low concentrations activates rather than inactivates complement .
- 50. • Gingipains andInpA conc gradually decline with increasing distance to the biofilm, allowing complement activation peripherally • This propagates the inflammatory state by fueling bacteria within the biofilm with nutrients from inflammatory plasma exudates, and causes damage to the periodontal tissue.
- 51. • Aggregatibacter actinomycetemcomitansproduces an outer membrane protein, (Omp100) • which binds factor H and thereby accelerates inactivation of C3b and inhibits C3b- and MAC-deposition on the surface of the bacterium. • A recent study showed that T. forsythia is resistant to killing by human complement. • The CP and the LP were inhibited due to the efficient degradation of MBL, ficolin 2, ficolin 3 and C4 by karilysin .
- 52. • The proactiverelease of C5a enhances P. gingivalis induced IL-6 production ,and the inflammatory reaction that follows contributes to nutrient procurement and deepening of the pockets, providing more room for bacterial growth . • Cleavage of C5 to C5a by gingipains, InpA and karilysin, • induce migration of neutrophils , but the high C5a concentrations in the periodontal tissues “paralyze” neutrophils and protect bacteria from being phagocytized by macrophages. Exploitation
- 53. Disale PR, ZopeS, Suragimath G, Varma AS, Pisal A. Toll-like receptors: molecular microbe sensors in periodontium. World J Dent. 2019 Dec 1;10:396-401.
- 54. • In periodontalpocket (TLR2,TLR4,TLR5 and TLR6) expression is increased enabling epithelial cell recognition of extracellular microbial str. • That induces production of IL-8 and MMP by epithelial cells. These IL-8 promotes angiogenesis and induce chemotaxis and activation of neutrophiles to accumate in the inflamed periodontium. • Then reactive species and granules enzyme released activated neutrophiles and it kill bacterias and challenges periodontal biofilm barrier itself. • Once barrier broken,fibroblast,endothelial cell and immune cells in c.t become exposed to invading mocrobes that leads to bind to TLRs.
- 55. • This leadto increased release of proinflammatory cytokines that favors the development of a pathogenic biofilm in subject with suspectibility to periodontitis. Damgaard C, Holmstrup P, Van Dyke TE, Nielsen CH. The complement system and its role in the pathogenesis of periodontitis: current concepts. J Periodont Res 2014; doi:10.1111/jre.12209.
- 56.
- 57. REFERENCES • CARRANZA 10THEDITION • CARRANZA 14TH EDITION • CARRANZA 11TH EDITION • CP BAVEJA –TEXTBOOK OF MICROBIOLOGY • Damgaard C, Holmstrup P, Van Dyke TE, Nielsen CH. The complement system and its role in the pathogenesis of periodontitis: current concepts. J Periodont Res 2014; doi:10.1111/jre.12209. • Reis ES, Mastellos DC, Hajishengallis G, Lambris JD. New insights into the immune functions of complement. Nat Rev Immunol. 2019 Aug;19(8):503-516. doi: 10.1038/s41577-019-0168-x. PMID: 31048789; PMCID: PMC6667284. • Grande MA, Belstrøm D, Damgaard C, Holmstrup P, Thangaraj SS, Nielsen CH, Palarasah Y. Complement split product C3c in saliva as biomarker for periodontitis and response to periodontal treatment. J Periodontal Res. 2021 Jan;56(1):27-33. doi: 10.1111/jre.12788. Epub 2020 Jul 18. PMID: 32681659; PMCID: PMC7891408. • Disale PR, Zope S, Suragimath G, Varma AS, Pisal A. Toll-like receptors: molecular microbe sensors in periodontium. World J Dent. 2019 Dec 1;10:396-401. • Sameer AS, Nissar S. Toll-Like Receptors (TLRs): Structure, Functions, Signaling, and Role of Their Polymorphisms in Colorectal Cancer Susceptibility. Biomed Res Int. 2021 Sep 12;2021:1157023 • https://doi.org/10.1016/j.smim.2016.03.006
- 59. Regulator of complementsystem
- 60. Inducers of phagocytosis, oxidative burst, productionof proinflammatory cytokines and histamine release. C3a Anaphylatoxin, ligand for C3aR. C3aR Binds C3a. C5a Anaphylatoxin, ligand for C5aR and C5L2. C5aR Binds C5a, expressed on plasma membranes. C5L2 Binds C5a, predominantly intracellular expressed. CR1 Binds C3b and iC3b, cofactor for factor I, accelerates decay of convertases. CR3 Binds iC3b. CR4 Binds iC3b. iC3b Opsonin, primary ligand for CR3 and CR4. CRIg Binds C3b and iC3b. Damgaard C, Holmstrup P, Van Dyke TE, Nielsen CH. The complement system and its role in the pathogenesis of periodontitis: current concepts. J Periodont Res 2014; doi:10.1111/jre.12209.