Complement system and periodontitis
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Complement system and periodontitis
- 1. COMPLEMENT SYSTEM AND PERIODONTITIS Dr R Viswa Chandra MDS;DNB;PhD
- 4. “Defence Wall” is largely because of the complement system
- 5. Immune Subversion of the Complement system in Periodontitis
- 6. Complement cross-talk pathways and their exploitation by P gingivalis
- 7. P gingivalis vs Complement system
- 8. What is the effect of AA comitans on Complement system? What is the effect of complement cascade on alveolar bone in periodontitis? What are the drugs to combat complement cascade in periodontitis?
Editor's Notes
- Integrins are proteins that function mechanically, by attaching the cell cytoskeleton to the extracellular matrix (ECM), and biochemically, by sensing whether adhesion has occurred.
- The complement system, also known as complement cascade, is a part of the immune system that enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inflammation, and attack the pathogen's cell membrane. It is part of the innate immune system. Each pathway contains two convertases responsible for the cleavage of C3 and C5 molecules, proteins central to the complement cascade. C3 and C5 convertases produce the potent C3a and C5a anaphylatoxins, respectively. They account for about 10% of the globulin fraction of blood serum. The complement system consists of a number of small proteins that are synthesized by the liver, and circulate in the blood as inactive precursors. Activation of the classical complement pathway occurs when antigen-antibody complexes bind to C1q, a subcomponent of the C1 complement protein. Alternative pathway activation can be initiated by polysaccharides and yeast of bacterial origin while the lectin pathway is activated by bacterial or viral carbohydrate-based pathogen-associated molecular patterns (PAMPs). The body initially does this by recognizing molecules unique to groups of related microorganisms and are not associated with human cells. These unique microbial molecules are called pathogen-associated molecular patterns or PAMPs. They are recognized by toll-like receptors (TLRs). The lectin pathway is activated after the recognition and binding of PAMPs by lectin proteins including MBL, ficolin H, and ficolin. Alternative pathway activation also occurs via a process known as ‘tick-over’, during which C3 undergoes spontaneous hydrolysis (Bexborn et al., 2008). Mannan-binding lectin serine protease 1 is involved in the lectin pathway of the complement system and is responsible for cleaving C4 and C2 into fragments to form a C3-convertase.[6] It complexes with the pathogen recognition molecules of lectin pathway, the mannose-binding lectin and the ficolins. Ficolins (Fi+Col+Lin) are a group of oligomeric lectins with subunits consisting of both collagen (Col)-like long thin stretches and fibrinogen (Fi)-like globular domain. Factor B circulates in the blood as a single chain polypeptide. Upon activation of the alternative pathway, it is cleaved by complement factor D yielding the noncatalytic chain Ba and the catalytic subunit Bb. The active subunit Bb is a serine protease that associates with C3b to form the alternative pathway C3 convertase.
- Adaptive immunity is an immunity that occurs after exposure to an antigen either from a pathogen or a vaccination. This part of the immune system is activated when the innate immune response is insufficient to control an infection.
- Complement and TLR involvement in dysbiosis and inflammatory bone loss in periodontitis. The classic, lectin, and alternative pathways converge at and activate the central complement component, C3, resulting in the generation of various effectors, such as, the C3b opsonin, the inflammatory anaphylatoxins C3a and C5a, and the C5b-9 membrane attack complex (MAC). The C3a and C5a activation fragments activate respectively C3aR and C5aR1, which cross-talk with Toll-like receptors (TLRs) and synergistically activate inflammatory leukocytes. TLRs also upregulate the expression of C3aR and C5aR1. Inflammation induced by complement-TLR crosstalk interactions not only causes gingival tissue destruction and bone loss in periodontitis but also contributes to the remodeling of a symbiotic microbiota into a dysbiotic one, thereby further potentiating destructive inflammation. TLRs act on APCs.
- CR3 is a β2 integrin (CD11b/CD18) that plays diverse roles in immunity and inflammation, including iC3b-mediated phagocytosis, promotion of leukocyte migration to sites of extravascular inflammation, and induction of cytokine response. 1. CR3 was shown to co-associate with pattern-recognition receptors, such as CD14 and TLRS (TLR2 and TLR4) P. gingivalis is particularly strong in activating CR3. This in turn downregulates IL-12 p35 and p40 mRNA expression. IL-12 is involved in the differentiation of naive T cells into Th1 cells.[3] It is known as a T cell-stimulating factor, which can stimulate the growth and function of T cells. It stimulates the production of interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) from T cells and natural killer (NK) cells, and reduces IL-4 mediated suppression of IFN-γ.[4] T cells that produce IL-12 have a coreceptor, CD30, which is associated with IL-12 activity. IL-12 plays an important role in the activities of natural killer cells and T lymphocytes. Inhibition of bioactive IL-12 through this mechanism in vivo results in impaired immune clearance of P. gingivalis. 2. Moreover, P. gingivalis uses its gingipains to attack C5 and release biologically C5a [87, 150]. Upon C5aR binding, C5a stimulates Gαi-dependent intracellular Ca2+ signaling which synergistically enhances the otherwise weak cAMP responses induced by TLR2/TLR1 activation alone. The ensuing activation of the cAMP-dependent protein kinase A (PKA) pathway inactivates glycogen synthase kinase-3β (GSK3β) and impairs the inducible nitrogen synthase (iNOS)-dependent killing of the pathogen in macrophages in vitro and in vivo [87] . Induction of the high-output iNOS usually occurs in an oxidative environment, and thus high levels of NO have the opportunity to react with superoxide leading to peroxynitrite formation and cell toxicity. These properties may define the roles of iNOS in host immunity, enabling its participation in anti-microbial and anti-tumor activities as part of the oxidative burst of macrophages.[
- C4 binding protein (C4BP)Binds to C4b; decay accelerating and cofactor activity. Factor H Binds to C3b; has decay accelerating activity of the AP C3 and C5 convertases and cofactor activity CD46 Blocks the C9 association with C5b-8 to prevent C5b-9 formation on host cells