Innate immune response

Innate Immune Response in Periodontum

Innate Immune Responsein Periodontal diseases

By: Reyam Ahmed Binbarek

OutlinesDefinition of Innate immune system.Components and their Mechanism.

DefinitionThe term innate immunity refers to the elements of the immune response that are determined by inherited factorshave limited specificity, fixed in what they do.do not change or improve during an immune response or as a result of previous exposure to a pathogen.

Function of Innate ImmunityKilling invading microbes

Activating the acquired (adaptive immunity)

Components of innate immunityIntact epithelial barriersLubrication of epithelium with fluids (saliva , GCF)Complement cascade.Cell signaling moleculesVasoactive peptidesAdhesion moleculesCells of innate immunityLinking Pathogenesis to Clinical Signs of Disease

chemical barrier (e.g.: antimicrobial peptides) physical barrier e.g. (Tight junction & rapid turnover)Functions of epithelia in innate immunity

-Release cell signaling molecules (e.g. :IL-1,IL-6,IL-8,TNF alpha ,PGE2)

Antimicrobial PeptidesAntimicrobial peptides are small, polycationic peptides that disrupt bacterial cell membranes and thereby directly kill bacteria with broad specificity.

Epithelial cells constitutively express antimicrobial peptides (e.g., hBDs, cathelicidins LL-37)Neutrophils are also a source of antimicrobial peptides (i.e., -defensins).

Expression sites of AMPs

AMP: has wider role in regulating innate and adaptive immune responses to infection.

Stimulate mast cell degranulation and cytokine production.Have a role in wound healing Has possible role in therapy for oral inflammatory diseases.

Components of innate immunityIntact epithelial barriersLubrication of epithelium with fluids (saliva , GCF)Complement cascade.Cell signaling moleculesVasoactive peptidesAdhesion moleculesCells of innate immunity

Gingival Crevicular Fluid GCFGCF originates from the postcapillary venules of the gingival plexus

It has a flushing action in the gingival crevicebring the blood components serum (e.g., neutrophils, antibodies, complement components) of the host defenses into the sulcus. The flow of GCF increases in inflammation

SalivaSaliva that is secreted from:

numerous minor salivary glands The action of saliva flow preventing the attachment of bacteria to the dentitionand the oral mucosal surfaces.

Function in innate immunity:


Complement Cascade20 serum glycoprotein's Circulating inactive in blood streamWhen activated have profound & powerful effects in stimulating inflammation (pro-inflammatory effects)

Complement CascadeFunctions:Recruitment of more phagocyte to area of infectionFacilitate binding of phagocyte to bacteria (Opsonisation)Cause bacterial killing (cell lysis)Hajishengallis, George, et al. 2015 "Complement involvement in periodontitis: molecular mechanisms and rational therapeutic approaches.Pathways:Alternative pathway : activated directly by bacterial endotoxin (LPS).Classical pathway: activated by formation of antigen-antibody complexes

Alternative Pathway

Late stage of alternative pathway

C5-9 =MAC membrane attack complexChemotaxis of phagocyteOpsonaziation

Components of innate immunityIntact epithelial barriersLubrication of epithelium with fluids (saliva , GCF)Complement cascade.Cell signaling moleculesVasoactive peptidesAdhesion moleculesCells of innate immunity

Cell Signaling MoleculesSome stimulate cells to release other molecules (cytokines)Some attract cells to areas of infection (chemokines)Other stimulate cells to perform other function (lymphokines)

Cell Signaling MoleculesEpithelial cells also secrete a range of cytokines in response to periodontal bacteria

Cell Signaling Molecules

Interleukin-1 Family Cytokines. IL-1 plays a key role in inflammation and immunity it is closely linked to the innate immune response, it induces the synthesis and secretion of other mediators that contribute to inflammatory changes and tissue damage.

IL-1 stimulates the synthesis of:PGE2, platelet-activating factor, nitrous oxide, therebychemokine CXCL8ICAM-1 on endothelial cells

Vascular changes Increasing blood flowfacilitating the infiltration of neutrophils

mainly produced by Monocytes, Macrophages, Neutrophils, fibroblasts, keratinocytes, epithelial cells, B cells, and osteocytesIL-1 synergizes with other pro-inflammatory cytokines and PGE2 to induce bone resorption.

Tumor Necrosis Factor-. Secreted by Macrophages as well as by other cell types, in response to bacterial LPS. Macrophages Endothelial cellsActivationBy LPSTNF-aE-Selectinfacilitate leukocyte recruitment

Stimulate secretionActivatedStimulate secretion

TNF- although it possesses similar activity to IL-1 but has a less potent effect on osteoclasts, and it is present at lower levels in inflamed gingival tissues than IL-1. GCF levels of TNF- increase as gingival inflammation develops, and higher levels are found in individuals with periodontitis

Clinical importanceThe importance of TNF- and IL-1 in periodontal pathogenesis is unquestioned, and it has particularly been highlighted by studies showing that the application of antagonists to IL-1 and TNF- resulted in an 80 % reduction in recruitment of inflammatory cells in proximity to the alveolar bone and a 60% reduction in bone loss. Assuma, R., et al.(1998)

The chemokine

Immune responses, Repair &inflammation,Regulate osteoclast activity by influencing myeloid cell differentiation into osteoclastsThey also play important role in :

Clinically importanceThe chemokine CXCL8 (IL-8), has been demonstrated to be localized in the gingival tissues in areas of plaque accumulation and in the presence of neutrophil infiltration, and it has also been found in GCF. Similar chemotactic gradients are also present in the gingiva of periodontally healthy individuals, which suggests a role for this process in the maintenance of periodontal health and which supports the findings of infiltrating neutrophils being present even in clinically healthy tissues. By Tonetti MS et al (1998),

Clinically importance cont.CCL2 and CCL5 (RANTES ) play a role in macrophage migration.CCL3 (MIP- 1 ) and CXCL10 play a role in T-cell migration in inflamed periodontal tissues.Silva, T. A., et al. (2007)Haytural, O., et al.2015 "Impact of periodontitis on chemokines in smokers.

Prostaglandin E2. The prostaglandins, including PGE2, are derived from the COX pathway of arachidonic acid metabolism. There are two main iso-forms of the COX enzyme: COX -1 and COX -2. COX -1: is constitutively expressed and has anti-thrombogenic and cyto-protective functions. COX -2: is induced after stimulation with various cytokines, and LPS.

Prostaglandin E2.

PGE-2:Increase vascular permeabilityIncrease vasodilatationIncrease PMNL chemotaxisStimulate bone resorption


Vasoactive peptidesVasoactive peptides like histamine play crucial role in development of inflammation.Histamine released from mast cells upon stimulation by complement C3A and C5A or PGE2 & cause vasodilatation .Increase vascular permeability to allow entrance of defense product to the tissues

Vasodilatation: bring more blood cells and plasma proteins (complement , antibody)Slow down blood flow allowing PMNLs to touch vessel walls

Vasoactive peptides


Adhesion MoleculesAdhesion molecules used to stick to each other or to components of the intercellular matrixExamples : intercellular adhesion molecules I and II (ICAM-1 and II)endothelial adhesion molecule I (ELAM-1) E-selectinLeukocyte function antigen 1 (LFA-1)

Expression of these molecules may turn of or on by cytokine (IL-1 & IL-10)

Sequences of AdhesionRolling: slowing down of PMNL due vasodilatation Make and break contacts between PMNL and vascular endothelial cellsMargination: as slowing down receptor binding become stronger and PMNL become immobilized by: adhesion of integrin molecules e.g. LFA-1 with complentary endothelial receptor e.g. ICAM-IDiapedesis: allow PMNL to pass through leaky vessels wall and enter tissues.Chemotaxis: by IL-8 and bacterial


PhagocytesProfessional phagocytic cells Neutrophils and MacrophagesThese cells have phagocytic receptorsExternal receptor: FcR, CR3, Mannose receptor,TLRsInternal receptors: TLRs

PAMPPathogen-associated molecular patterns,

NeutrophilPresent in blood (55-60% of WBC)Have short life (24hours) Once PMNL arrives at the site of infection it kills bacteria by intercellular (oxidative & non-oxidative) and extracellular methods

Mechanism of Action

Non-Oxidative

Oxidative killing

Enzymes: lysozymes dissolve cell wall of some bacteriaAcid hydrolyses: digest bacteriaProteins: lactoferrinPeptides: Defensins direct killingOxygen-derived products: O 2 - , H 2 O 2 & Myeloperoxidase Nitrogen-derived products NO (nitrogen oxide) Produced by inducible NO synthase (iNOS) enzyme Enzyme is induced by cytokines (LT, TNF )

Lucarini, Guendalina, et al. (2016) "Uncoupling of Vascular Endothelial Growth Factor (VEGF) and Inducible Nitric Oxide Synthase (iNOS) in Gingival Tissue of Type 2 Diabetic Patients.

Clinically importanceThe importance of neutrophils to the maintenance of periodontal health is demonstrated clinically by the observations of severe periodontitis in patients with neutrophil defects

such asNeutropenia, leukocyte adhesion deficiency (LAD-1),Chediak-Higashi syndrome,Papillon-Lefvre syndrome, chronic granulomatous disease (CGD),

( are often related to severe and early-onset forms of periodontitis) Del Fabbro, M., et al. (2000)

MacrophagesBlood: monocyte (1-5% WBCs)Tissues: MacrophagesMature form of monocyteNormally found in tissuesFunction similar as PMNLs but also act as APCs

Produce cytokines/chemokinebridging gap between innate & acquired immunityAPCsPhagocytosis

N.b :Excessive and inappropriate or dysregulated immune responses lead to chronic inflammation and the concomitant tissue destruction associated with periodontal disease.

Bystander damage


Linking Pathogenesis to Clinical Signs of Disease Epithelium

Physical barrierChemical barrierRelease cytokinesFurther invasion of bacteria

DefensinsLL-37

Determine the outcome of host-microbial interaction

ChemokinesAttract Neutrophilsrelease

Linking Pathogenesis to Clinical Signs of Disease ContIf the bacterial challenge persistCellular & fluid infiltration continueNeutrophilsMMPsLysozymeCytokinesROS

Deeping of the pocketdetachment of cells at the coronal aspect of the junctional epithilum epithelium proliferates lead to necrosis of epithelial that distant from C.Tpocket epithelium becomes thin & ulcerated & bleeds more readily, results in more B.O.P

Breakdown of collagenTissue damageFibroblast loss ability to repair

Linking Pathogenesis to Clinical Signs of Disease ContAdvancing inflammatory approaches the alveolar boneOsteoclastic bone resorption protective mechanism to prevent bacterial invasion leads to tooth mobility and even tooth loss.

The concentration of inflammatory mediators The inflammatory mediators must penetrate to a critical distance of the alveolar boneTwo critical factors that determine whether bone loss occurs

ReferencesDel Fabbro, M., et al. "[Congenital neutrophil defects and periodontal diseases]." Minerva stomatologica 49.6 (2000): 293-311.Assuma, R., et al. "IL-1 and TNF antagonists inhibit the inflammatory response and bone loss in experimental periodontitis." The Journal of Immunology 160.1 (1998): 403-409.Tonetti MS, Imboden MA, Lang NP: Neutrophil migration into the gingival sulcus is associated with transepithelial gradients of interleukin-8 and ICAM-1. Perio ontol 69:1139 1147, 1998. Silva, T. A., et al. "Chemokines in oral inflammatory diseases: apical periodontitis and periodontal disease." Journal of dental research 86.4 (2007): 306-319.Hajishengallis, George, et al. "Complement involvement in periodontitis: molecular mechanisms and rational therapeutic approaches." Immune Responses to Biosurfaces. Springer International Publishing, 2015. 57-74.

Health & Medicine

Innate immune response