This document provides an overview of the molecular biology of the host-microbe interaction in periodontal disease. It discusses how the innate immune system recognizes microbes via pattern recognition receptors like TLRs. It also describes how innate immunity initiates and modulates the adaptive immune response. Key aspects of the pathogenesis of periodontal disease are explained, including the roles of pro-inflammatory cytokines, RANKL signaling, and MMPs in degrading periodontal tissues. Host genetic variations and intracellular signaling pathways are also discussed in modulating susceptibility to periodontal disease.

3. AMNA HASSAN
ROLL NO : 12
Chapter : 25
Molecular biology of the host microbe interaction in
periodontal disease

4. Topics outline
1 . I N N AT E I M M U N I T Y
ADAPTIVE IMMUNITY
PAT H O B I O LO G Y O F P E R I O D O N TA L
DISEASE
HOST CELL SIGNALING

5. INTRODUCTION
 Provides an overview of molecular biology of the host-parasite
relationship
 Deals with the microbiota associated LPS and other MAMPs
,innate responses,tLRs signaling and periodontal pathogenesis
 Includes pathobiology of periodontal disease
 Induction of disease by pro inflammatory cytokines

6. PATHOGENESIS OUTLINE
 Direct recognition of microbes by the host is mediated by the
recognition of MAMPs by PPR
 It requires expression of number of bioactive agents i.e. pro
inflammatory and anti inflammatory cytokines , growth factors and
enzymes
 Activated Biologic mediators are involved in the induction of
adaptive immunity

8. INNATE IMMUNITY
 Innate immunity is rapidly activated with in minutes
 Responsible for the defiance during initial hours and days of
infection
 Challenge is to discriminate among a large number of
periodontal pathogen from the host with a limited number of
cell surface receptor

9. H OW I N N AT E I M M U N E SYST E M
FUNCTIONS?
 The discovery of TLRs proved to b critical for recognition of
microbes.
 With in the periodontal tissues , the expression of various TLRs
appears to b increased in severe diseased states
 TLR are a type of PRR ( pattern recognition receptor) Egg
TLR1,TLR2,TLR3.TLR4. etch

10. CONTD..
 PPR can b secreted into plasma as humoral protein
 others are localized in the cytoplasm as intracellular sensors
 Soluble PRR include collectins,ficolins and acute phase
pentraxins (e.g. C reactive protein)
 The soluble mannose binding receptors can interact with
structures and activate complement system

11.  Other receptors are :
1. NOD proteins
Nod1 recognizes meso-DAP
peptidoglycan in most gram –
ve and +ve
Nod2
recognizes
MDP ,found
in both gram
–ve and +ve

12. CONTD
Retinoic inducible gene
 Cytoplasmic receptor family I(RLRs)
Recognizes viral
nucleic acid

13.  Receptors not only recognize various MAMPs to activate
INNATE RESPONSE but they also have a role in inflammation and
adaptive responses.
 Other cells also play important role and respond by expressing
biologically active molecules such as cytokines n MMPs which will
effect homeostasis of host tissue in periodontal environment

14. CELLS INVOLVED
Macrophages & PMNs as phagocytes
Dendritic cells as antigen presenting cells
Natural killer cells that recognizes n kill host
cells

15. Fibroblast and • Produce IL -6
osteoblasts ,prostaglandin E2,MMPs.
And RANKL
Work as a physical barrier, equipped
EPITHELIAL CELLS with PRR and respond to MAMPs by
secreting cytokines and chemokine's

16.  Commensals bacteria such as Streptococcus gordonii or
streptococcus sanguinis induce expression of antimicrobial
peptides without expression of IL 8
 Periodontopathogenic bacteria from the ORANGE BACTERIA
such as Fusobacterium nucleatum and Prevotella intermedia
induce strong expression of both anti microbial and IL -*8

17.  RED COMPLEX ORGANISM such as Ttreponema denticola,
Tannerella forsythia, Porphyromonas gingivalis suppress the
immune response by inhibiting anti microbial peptides and IL -8 or
both.

20. C E L L U L A R S I G N A L I N G I N I N N AT E I M M U N I T Y
RESPONSE
 MAMPs get recognize by PRR as a result signal is initiated -
>signal is transduced through cytoplasm and nucleus -> post
transitional modifications take place --- determine the cell
response to MMAPs
 Recognition of a ligand by TLR-- signals generated use
pathways similar to IL 1 receptors .

22. ADAPTIVE IMMUNITY
 Innate immunity plays a role in initiating and modulating
adaptive immune responses
 Innate immune mechanisms are not turned off once the
adaptive responses is activated
 Cells from adaptive immune response also express PRRs and
respond to MAMPs

23.  The adaptive immune response is characterized by the activities of
pathogen-specific B and T lymphocytes
 the cell type primarily responsible for translating innate signals into
adaptive immunity is the dendritic cell (DC).
 adaptive immunity initiates with DCs recognizing MAMPs in the sites
of infection then subs migrating into the regional draining lymph
nodes
 It then present the processed antigen peptides in the context of
major histocompatibility complex (MHC) molecules to naive T
lymphocytes

25.  in periodontal diseases, both MAMPs and inflammatory
cytokines are usually present to fully activate the DCs, which
suggests that there is no impairment to a competent activation of
adaptive immunity.

27. H O ST M I C RO B E I N T E R AC T I O N S
 DCs activated by MAMPs and inflammatory cytokines (also induced by MAMPs in
innate immune/resident cells) will initiate an adaptive immune response by driving
naive T lymphocytes into a CD8+ (for cytotoxic response) or CD4+ with Th1 or
Th2 phenotypes.
 more pieces have been added to the puzzle, including the regulatory T
lymphocytes (Tregs), which appear to have their inhibitory functions suppressed by
activated DCs.
 Activated T cells and their “specific” cytokine profiles will modulate the
inflammatory response and also the activation of B lymphocytes.

32. PAT H O B I O L O G Y O F P E R I O D O N TA L
DISEASE
 Host response to periodontal expression of various pro
inflammatory and anti inflammatory cytokines, growth factors and
enzymes that are the result of activation of multiple signaling
pathways
 PPR signaling is the most important interface between the host
and the microbes

34. C Y T O K I N E S A N D M E D I AT O R S O F
I N F L A M M AT I O N
 Local inflammatory reaction is characterized by an initial
increase in blood flow , enhanced vascular permeability , and
influx of cell from blood to crevice
 For acute and rapid defense the mediators involved are
1. Histamine
2. Bradykinin
3. PGE2 and nitrous oxide

36.  Once activated by cytokines, bioactive molecules , and MAMPs
,infiltrating cells produce other inflammatory cells that modulate
the activity of other cells
Pro inflammatory : LIF
Cytokines include are : IL- ,IFN-,CNTF ,TGFb ,GM-
 Ccytkines include
1@,IL-1b,IL -6 ant TNF@ CSF,IL-11,IL-12,IL-17,IL-
18,IL-8

37. Anti inflammatory are : IL-4,IL-10,IL-13,IL-
16,INF-@,IL-1Ra etc

38.  A characteristic type of cytokine profile is associated with each type of
periodontal disease ( gingivitis or periodontitis)
 Once immune and inflammatory processes are initiated and
complex cytokines network is established ,inflammatory
molecules play a direct role in degradation of both mineralized
and non mineralized tissues of periodontium

39. R O L E O F R A N K L I N P E R I O D O N TA L
DISEASE
 Rankl plays a pivotal role in bone response since it is involved in
osteoclast differentiation , activation and survival
 As periodontal disease progresses - collagen fibres &
connective tissue attachment to tht tooth is destroyed ---
junctional epithelial cells proliferate apically along the root surface
---- CLINICALLY seen as ATTACHMENT LOSS

41.  E.g. : MMPs released from different cell lesions --- capable of
degrading all components of ECM
 MMPs increases with inflammation and disease activity
 Detection in saliva is a host response bio marker of periodontal
disease

42. CONTD…
 RANKL is secreted by fibroblasts ,osteoblast, chondrocytes
,mesenchymal cells and T and B lymphocytes.
• OPG is the endogenous inhibitor of RANKL
• It functions as its decoy receptor
• Secreted by osteoblastic cells ,bone marrow stromal
cells and fibroblast

43.  The ratio between RANKL and OPG is the current
paradigm for modulation of coupled bone turnover and
specifically in periodontal disease
 Patients with advanced periodontitis presents with high
level of RANKL.

44. Based on susceptibility analysis ,individual
difference in the host response to MAMPs and to
host derived cytokines that are the result of
genetic variations may also play important role in
modulating the pathogenesis of periodontal
disease

45. CELL SIGNALING EVENTS
1. Production of cytokines and inflammatory mediators is usually
a tightly controlled that is initiated by external stimuli>
2. Signals are rapidly transduced through the cytoplasm into the
nucleus ----gene expression === DNA transcription
3. Final assembly of biologically active protein there a great
number of regulatory mechanism

46. T H E R A P E U T I C ST R AT EG I ES
 Strategies have develop to target the host response to LPS
mediated tissue destruction
 Doxycycline
 Scaling root planning
 Surgical therapy
 MMP inhibitors
 TNF & IL -1 antagonist