AMNA HASSANROLL NO : 12

Chapter : 25

Molecular biology of the host microbe interaction in

periodontal disease

1. INNATE IMMUNITYADAPTIVE IMMUNITY

PATHOBIOLOGY OF PERIODONTAL DISEASE

HOST CELL S IGNALING

Topics outline

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

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

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

HOW INNATE IMMUNE SYSTEM 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

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

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

CONTD

Cytoplasmic receptor family Retinoic inducible gene I(RLRs)

Recognizes viral nucleic acid

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

CELLS INVOLVED

Macrophages & PMNs as phagocytes

Dendritic cells as antigen presenting cells

Natural killer cells that recognizes n kill host cells

• Produce IL -6 ,prostaglandin E2,MMPs. And RANKL

Fibroblast and osteoblasts

EPITHELIAL CELLSWork as a physical barrier, equipped with PRR and respond to MAMPs by secreting cytokines and chemokine's

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

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.

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 R E S P O N S E

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 .

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

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

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.

HOST MICROBE INTERACTIONS

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.

PAT H O B I O LO GY O F P E R I O D O N TA L D I S E A S E

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

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

Once activated by cytokines, bioactive molecules , and

MAMPs ,infiltrating cells produce other inflammatory cells that

modulate the activity of other cells

Ccytkines include Cytokines include are : IL-1@,IL-1b,IL -6 ant TNF@

Pro inflammatory : LIF ,IFN-,CNTF ,TGFb ,G

M-CSF,IL-11,IL-12,IL-17,IL-18,IL-8

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

A characteristic type of cytokine profile is associated with each type of

periodontal disease ( gingivitis or periodontitis)

Th-1 type cytokine have been associated with gingivitis

Th-2 were found in high levels in 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

RO L E O F R A N K L I N P E R I O D O N TA L D I S EA S E

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

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

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

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.

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

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

THERAPEUTIC STRATEGIES

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