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Immune responses in periodontal disease final.pptx
- 1. IMMUNE RESPONSES IN PERIODONTALDISEASE DR.N.AMBALAVANAN Prof & Head Dept. of Periodontics Meenakshi Ammal Dental College Chennai
- 2. Periodontitis is aninfectious disease caused by a small group of predominantly anaerobic, Gm - bacteria Bacteria are important but insufficient to cause disease A susceptible host is essential
- 3. PATHOGENESIS OF PERIODONTITIS Environmental& Acquired risk factors Genetic risk factors Microbial Challenge Host Immuno Inflam. response Connective Tissue Bone metabolism Clinical signs Of disease initiation & progression Antibody PMNs Antigens LPS Cytokines & Prostanoids Roy C.Page – Annals of Periodontology MMPs
- 4. IMMUNITY IS RESISTANCE Weneed immunity against Pathogenic Bacteria (Extra and Intracellular) Viruses (Intracellular) Fungi Protozoa Other parasites and also to protect us from Neoplastic cells
- 5. TYPES OF IMMUNITY –INNATE IMMUNITY – ADAPTIVE IMMUNITY
- 6.
- 7. ADAPTIVE IMMUNITY •Evolved inhigher forms of life •It is the most complex structural and functional immune system •Development & Evolution of MHC along with T cell differentiation are the hall marks of Adaptive immunity
- 8. •Hypersensitive reactions •Autoimmune disorders •Graftrejection •Excessive production of inflammatory cytokines Drawbacks of Adaptive Immunity
- 9. NEED FOR ADAPTIVEIMMUNITY IN HIGHLY EVOLVED LIFE FORMS •Longevity associated with neoplasms and more viral infections •Emergence into land and exposure to solar radiation •Homiothermy (warm blooded) •Viviparity
- 11. •Low molecular wt.proteins secreted by many cells (previously known as Lymphokines) •Assist in the regulation and development of Immune effector cells •Cell to Cell communication •Direct effector function •Autocrine, Paracrine or endocrine •Pleiotrophic CYTOKINES
- 12. IF PROTECTIVE Can weprevent? (by immunization) Can we arrest? (when disease has occurred IF NOT PROTECTIVE & TISSUE DESTRUCTIVE Is host modulation the only answer? IMMUNE RESPONSE IN PERIDONTAL DISEASES
- 13. SEQUENCE OF IMMUNERESPONSE IN PERIODONTAL DISEASES • Innate factors – complements, mast cells sends signals to endothelium thus initiating inflammation. • Acute inflammatory cells (neutrophils) protect local tissues by controlling the periodontal microbiota within the gingival crevice and JE • Chronic inflam.cells - macrophages and lymphocytes protect the entire host from within the subjacent connective tissues and do all that is necessary to prevent a local infection from becoming systemic and life threatening
- 15. Innate & AdaptiveImmune responses in Periodontal disease NEED TO KNOW • Pathogen associated Molecular Patterns • Toll like receptors • Antimicrobial peptides in the gingival epithelia • Bacterial antigens associated with periodontitis • APCs in gingiva • Role of T cells (TH1 or TH2 response) • Osteoimmunology (RANK & RANKL) • Autoimmune components in periodontal disease • Periodontal vaccine
- 16.
- 17. Innate immunity (non-specific) Physicalbarrier of sulcular and junctional epithelium with antimicrobial peptides, phagocytic and Nkcells Adaptive immunity (Specific) Comes into play once the epithelial barrier is breached. MHC system, Lymphocytes and Cytokines are central to adaptive immune response Innate & Adaptive immunity in Periodontium
- 18. INNATE IMMUNITY INPERIODONTAL DISEASES •Wall of neutrophils between the bacteria and the JE •Diminished function of neutrophils (intrinsic defect) responsible for the establishment and severity of periodontal diseases ? •Antigens released from bacteria modulate the inflammatory response eg. lipopolysacchrides, lipoteichoic acid , Peptidoglycans, lipid A proteins e
- 19. •Pattern recognition ofcore bacterial components by phagocytic cells •Pattern recognition receptors (PRRs) have the ability to discriminate between self and non-self •Recognition of common bacterial patterns ensures Polyspecificity INNATE DEFENSE by bacterial recognition
- 20. TOLL LIKE RECEPTORS •Transmembrane receptors named in reference to the class of genes in Drosophila known as Toll.Drosophila • Part of innate immune response of Drosophila to pathogens • Related proteins (toll-like receptors) are present in the mammals • Expressed in a number of tissues and a variety of cell types (Dendritic cells, epithelial cells, PMNs ) • Respond to bacterial LPS, lipoproteins, fimbriae etc
- 21. Response of Tolllike Receptors •TLR 2 responds to lipoteichoic acid and microbial lipoproteins •TLR 4 responds to LPS •TLR 5 responds to Flagellin •TLR 9 responds to bacterial DNA Bar code detection system •TLR5 + TLR4 = Flagellated Gm - bact. •TLR2 + TLR5 = Flagellated Gm+ bact.
- 22. MICROBIAL COMPONENT RECOGNITION& INTRACELLULAR SIGNALLING •Recognition through Toll-like receptors •Innate cell receptor binds to specific ligands •Response is immediate (hallmark of Inn.imm.) •Intracellular signaling through MAPK (mitogen activated protein kinase), PI3K (Phosphotidyl Inositol – 3 kinase) signaling transduction pathways •Expression of inflammatory cytokines with enhanced clearance of bacteria by promoting phagocytosis
- 23.
- 24. ALTERED INNATE IMMUNERESPONSE •Toll like receptor polymorphism and other genetic polymorphisms •Immunosuppressive therapy and neutrophil defects •P.gingivalis LPS disrupts the innate immune response by host cells within gingival tissues P.g LPS is a natural antagonist of E selectin expression. Thus disrupting the host response to other bacteria
- 25. INNATE IMMUNITY ANTIMICROBIAL PEPTIDES •JE& SE serves not only as a physical barrier but also has diverse range of antimicrobial peptides which can kill a range of bacteria •More than 800 of these molecules are identified •Eg.-neutrophil defensins, β defensins, Cathelicidins lysozyme, histatins, proline rich proteins, salivary agglutinin, cystatins, lactoferrins, salivary peroxidase, mucins, etc
- 26. • Membrane permiabilization, •Cell wall degradation, • Intracellular inhibition • Bacterial aggregation and oxidation •Toll like receptors induce defensin gene expression by epithelial cells •Defensins disrupt microbial cell wall resulting in leakage of contents Functions of Antimicrobial Peptides
- 27. MECHANISM OF POREFORMATION IN BACTERIAL CELL WALL BY DEFENSINS (Shai – Matsuzaki – Huang model) Defensins are attracted electrostatically to the negatively charged cell membrane. This is followed by displacement of membrane lipids in wedge like manner. Disruption of the microbial cell wall results in the leakage of the cytoplasmic contents.
- 28. Mechanism of poreformation in bacterial cell wall by defensins
- 29. •Activate the classicalcomplement pathway •Upregulate IL8 production •Chemotactic for both CD8 + and CD4 + T cells and immature dendritic cells. •Enhance the release of TNF α and IL1 from monocytes activated by bacteria DEFENSINS - LINK INNATE AND ADAPTIVE IMMUNE RESPONSES
- 30. •Oral, sulcular, junctionalepithelia are associated with Defensin expression •Neutrophil defensins are found in JE & connective tissue in association with PMNs •β defensins are found in oral epithelia of diseased sites. They are expressed in healthy gingiva also probably in response to commensal oral bacteria GINGIVAL DEFENSINS
- 31. •Expressed in oraland airway epithelia •Related to mammalian lipid binding proteins •These antibacterial proteins have selectivity for Gm – bacteria •Binds to LPS and exhibits anti- inflammatory activity Bactericidal/permeability-increasing protein like proteins
- 32. Bacterial Antigens Associatedwith Periodontitis • Over 20 bacterial species are implicated in the pathogenesis of Periodontitis. • Four bacterial species may be considered as major pathogens - P.gingivalis, B.forsythus, T.denticola, A.actinomycetemcomitans
- 33. Identification of Pathogen’sAntigens • Proteomic and Genomic Analysis:- by (2D)-PAGE(PolyAcrylamide Gel Electrophoresis) and by Western Blot and mass spectrometric techniques (PMF) • Epitope mapping analysis:- Identifying B cell & T cell antigenic determinants by using computer algorithm
- 34.
- 35. Dentritic cells • Dendriticcells represent a large family of APC • They are scattered in nearly all tissues of the body • Serve as a ‘bridge’ between innate and adaptive immune response • Maintain mucosal immune homeostasis to harmless commensal bacteria and to self antigens • Capture microbes and their antigens and present them in a mature form to the T cells
- 36. Human Dendritic Cells Blood MyeloidDC Plasmocytoid / Lymphoid DC Langerhans Cells (LCs) (in epidermis/epithelium) Interstitial DC (dermal DC) (in dermis/lamina propria) Lymph stream Veiled cells Secondary lymphoid organs Interdigitating DC Germinal Center Peripheral tissues
- 37. • CD1a +Langerhans cells are the principal cells involved in the response of oral mucosal epithelium to infection. • Large numbers are present within the healthy gingival epithelium. • Langerhans cells increase in number in gingivitis, experimental gingivitis & periodontitis. • Activated L cells ‘stall’ in the lamina propria and become CD83 + mature dendritic cells Langerhans Cells in oral mucosa
- 38. • Apart fromoropharyngeal and nasopharyngeal associated lymphoid tissues OLF is initiated in gingivitis by Langerhans cells or their progenitors homing to the gingival epithelium in response to PAMPs • OLF develops interproximally around the teeth in periodontitis • Formation of OLF is dependant on mature dendritic cells becoming stalled within the gingival lamina propria in the presence of a disregulatory cytokine milieu. Oral Lymphoid follicles
- 39.
- 40. • Immature dendriticcells possess an array of surface receptors that can recognize specific microbes by their molecular patterns • Important surface receptors are Toll like receptors and C- type lectin receptors • Best characterized molecular patterns are LPS, peptidoglycans, other constituents of cell wall and bacterial DNA • Interaction leads to receptor agonist signal transduction within dendritic cells which then recognizes the antigen as ‘friend or foe’ Antigen recognition by APCs
- 41. Cytokines in Dendriticcell maturation IL-1β and TNF α becomes elevated in chronic periodontitis and play direct role in a) Stimulating dendritic cell maturation b) Dendritic cell migration out of the epithelium towards the lymphatics c) Differentiation and Clonal expansion of T Cells
- 42. Role of dendriticCells in the immunopathology of chronic periodontitis (Cutler & jotwani)
- 43. Dentritic cell derivedosteoclasts (Cutler & Teng)
- 44. • T celllesion conversion to B cell lesion (Seymour et al 1979) • Altered CD4/CD8 ratio (Kinane et al 1989) • Polyclonal B cell activation (Tew et al. 1989) • Autologous mixed lymphocyte reactions (Kimura et al. 1991) • Antigen restricted immune responses (Ohyama et al.1998) • Th1/Th2 cytokine profiles (Taubman & Kawai 2001, Berglundh et al. 2002) Role of T&B cells in the pathogenesis of Periodontitis
- 45. ROLE OF TCELLS
- 46. Activation of antigenspecific T cells by APCs require 2 major signals. • Specific antigen recognition (Signal 1) and Costimulation (Signal 2). • Signal 1 is provided by the peptide-antigen-MHC molecule interaction on the dendritic cells with T cell receptors.(implies that the microbes have been captured and processed) • Signal 2 plays cooperative role in activating T cells for efficient antigen presentation (B7 molecules, ICAM, LFA-3, CD 40). Activation of T cells
- 47. • Implicated inthe pathogenesis of Ch.inflammatory Periodontal disease • Immunity to infection is controlled by distinct subset of T cells(Th1 and Th2 cells) classified on the basis of their cytokine profile • T cells may be induced to produce up to 22 different cytokines. • Another subset of Tcells with immunosuppressive function and distinct cytokine profile called regulatory T cells has recently been described Role of T cells in infection and Inflammation
- 48. Regulatory T cells Threesubsets of Regulatory T cell • Tr1- secrete high levels of IL-10 and low to moderate levels of TGF β– prevents development of Th1 mediated autoimmune diseases and suppresses responses to pathogens • Th3 CD4 + cells which secrete TGF β • CD4 + CD25 + Tcells causes immunosuppression by inhibition of IL2 production
- 49. • Th1 andTh2 cells determine whether cell mediated or humoral immunity dominates • IFNγ produced by Th1 cells inhibit Th2 cells while IL4 & IL10 produced by Th2 cells inhibit Th1 cells • Once either subset becomes dominant it suppresses other subset making it difficult to change the immune response pattern T cell determine the type of immunity
- 50. T cell subsetsinduced in infection Perio 2000 Vol-35
- 51. CYTOKINE PROFILE INPERIODONTAL DISEASE Essence of Pathogenesis Disease Health High Low High Low IL- 1β, TNF-α, IFN-γ PGE2 MMPs IL- 10, TGF-β IL- 1ra, TIMPs
- 52. RANKL – linksimmune cells to pathogenic bone loss • RANKL is a tumor necrosis factor related cytokine • RANKL is expressed by T & B cells, Osteoblasts, stromal cells, chondrocytes and mesenchymal cells • Factors from T cells such as IL7, IL18, TNFα and more importantly RANKL (Receptor activator of nuclear factor- kB ligand) have been shown to affect bone remodeling • RANKL, its cell surface receptor RANK and a soluble decoy receptor osteoprotegerin are the key molecules that regulate osteoclast differentiation and function
- 53. Tcells and Osteoclasticbone resorption Activated Tcell
- 54. Potential Intervention strategiesto prevent periodontal bone resorption
- 55. Gingivitis Strong innate immune response Th1 Cellmediated immunity & Protective antibody production Stable Lesion Periodontitis Poor innate immune response Periodontopathic bacteria Polyclonal B cell activation Th2 Non-protective antibody production Progressive Lesion (Hypothesis–1) Th2 Response leads to progressive Periodontitis
- 56. Hypothesis – 2 TH1response leads to attachment loss
- 57. Bacterial products induceapoptosis of T cells • Periodontal bacteria can induce apoptosis of T cells • Bacterial products act as negative regulators of T cell activation Important pathogenic mechanisms promoting infection, inflammation and disease.
- 58. ROLE OF BCELLS
- 59. Th cells andB cell antigen presentation function Rodriguez & Pinto
- 60. B Lymphocytes • BLymphocytes and Plasma Cells dominate in Periodontitis lesions • Subsets of B cells such as B-1a and B-2 are present • B-2 cells represent the traditional B cells • B-1a cells produce autoantibodies of IgM type followed by isotyping switching to IgG type • B cells and Plasma cells contribute to tissue destruction in Periodontitis through MMP 8 and MMP 13
- 61. Distribution of cellproportions in Periodontitis lesions Plasma cells B cells T helper T cytotoxic PMN Mae Others JCP 2005 – vol-32
- 62. • B cellsand plasma cells produce and secrete Immunoglobulins (IgG2) that prevent bacterial adherence, inactivate bacterial toxins and act as opsonins for phagocytosis by PMNs. • However production of non protective antibodies (poor avidity and poor antigenicity) could result in progressive lesion B cells and antibodies in periodontal disease
- 63. IgG2 serotype productionby DC and NK cells
- 64. Induction of IgG2platelet activating factor and PGE2
- 65. Polyclonal B cellactivation • Polyclonal B cell activation is induced by periodontopathic organism • Usually leads to production of low avidity and non specific antibodies • Continual activation of B cells results in production of high levels of IL1 resulting in tissue destruction.
- 66. Antibodies against PeriodontalPathogens are protective (A recent study) • Serum levels of IgG antibodies against A.a or P.g were higher in periodontitis-stable patients than those with active periodontitis • Elevated levels of IgG antibodies against A.a and P.g have a detectable protective effect against periodontal infections. (Rams, Listgarten and Slots – JPR 2006)
- 67. Autoimmune components inPeriodontitis • Anticollagen antibodies • Auto-antibodies to desmosomal proteins • Self heat shock protein 60(hsp60) might be a target for autoimmune response due to molecular mimicry between human hsp60 and its bacterial homologue GroEL.
- 68. Hsp60 induced immuneresponse in periodontitis
- 69. Regulatory Components ofAdaptive host response in Periodontitis JCP 2005 – vol-32
- 70. IMMUNIZATION AGAINST PERIODONTITIS Isit possible? IMMUNIZATION
- 71. • Common bacterialantigens of periodontal pathogens should be identified and their potential as vaccine candidates should be evaluated. • This could lead to the development of a multispecies vaccine for periodontitis. Antigenic protein Identification for Vaccine development
- 72. • Target antigens(multiple?)need to be identified and purified • Preclinical testing in animal models (mice, rats etc). Primary safety testing is often specifically studied in guinea-pigs • Vaccine should be approved as an investigational new drug by FDA before human trials Vaccine for Periodontitis
- 73. Periodontal Vaccine- human trials •Phase I (less than 20 healthy subjects), Phase II (50 to 200 subjects) and Phase III (up to several thousand subjects) should be performed to test the power of vaccine • Takes 50 years for Biologics Application approval(BLA) • Periodontal vaccine that go beyond testing in animal models have not been performed yet
- 74. P.gingivalis antigens asvaccine candidates • Whole cell formalin-killed P.gingivalis • Gingipains – Arg-X and Lys-X cysteine proteinases and adhesins • Outer membrane proteins (prevents Coaggregation)
- 75. • Periodontitis iscaused by complex polymicrobial infection • Biofilms protected from host immune responses • Bacteria disconnect from biofilms by swarming dispersal, clumping dispersal and surface disposal • P.gingivalis invades epithelial cells protecting it from humoral immune factors Difficulties encountered in developing a periodontal vaccine
- 76. Treatment induced humoralimmunity • Non-surgical treatment (SRP) causes bacteremia leading to elevated levels of antibodies • Termed as ‘uncontrolled’ immunization against periodontal pathogens • Studies have given different results in terms of antibody avidity
- 77. Other strategies • Probiotics?– live microorganisms administered in adequate amounts with beneficial health effects on the host • Vaccine against P.gingivalis specific Heat Shock protein (HSP60, GroEL) to prevent autoimmune responses
- 78. Host Modulation • Modulationof Arachidonic Acid metabolites (NSAIDS) • Modulation of MMPs – SDD (Doxycline - 20 mg twice daily) • Modulation of bone remodeling (Bisphosphanates) • Inhibit Inflammatory cytokines (IL1 & TNFα) through recombinant human IL11 (rhIL-11) • Inhibition of Nitric Oxides by MEG (Mercaptoalkylguanidines)
- 79. To conclude • Geneticpolymorphism combined with environmental factors and specific pathogens seem to play an important role in the progression of periodontal diseases • Immune responses are protective(in some) and destructive (in others) • Periodontal vaccine is a distant dream (we have still not developed a vaccine for caries) • Host modulation is the most prevalent strategy at present (Is it that effective?) (How long?)
- 80.