Transcript Riggs_Signal_Transduction-_PAMP_Presentation[1]

PATHOGEN ASSOCIATED MOLECULAR
PATTERNS AND ITS INVOLVEMENT IN THE
INNATE IMMUNE RESPONSE
By: Rebecca D. Riggs
INNATE IMMUNITY
The initial, immediate
response to an invading
organism by the host.
 2 Major Types of Innate
Response:




Inflammation
Antiviral Defense
Innate immune system is
triggered by many invading
molecules and we will
discuss Pathogen-Associated
Molecular Patterns (PAMPs)
in detail
INNATE IMMUNITY
There are many types of pattern recognition receptors
in different locations in tissues that respond to
invading organisms
 Recognition molecules are expressed by:

Phagocytes, mainly Macrophages and Neutrophils
 Dendritic cells
 Other cells


Receptors can be found on the plasma membrane or
endosomal membranes and in the cytoplasm of cells


Attacks bacteria outside cells as well as within cellular
compartments
Upon detection of the microbe or a damaged cell
Will Ingest and Destroy
 Initiate Inflammatory Response
 Activate Adaptive Immunity

PHAGOCYTES
First line of defense against invading pathogens
 2 Major Functions:

Ingest and Kill Bacteria
 Increase antimicrobial activity of the pathogen at the
site of initial infection


Polymorphonuclear Leukocytes AKA Neutrophils

Majority of White Blood Cells that circulate and initiate
inflammatory response
MACROPHAGES
Macrophages are Monocytes until Activated by an
Antigen
 Names vary depending on tissue location

Kuppfer Cells in the Liver
 Microglial Cells in Central Nervous System
 Osteoclasts in the Bone

Kill Bacteria by creating Reactive Oxygen &
Nitrogen Species that are toxic to microorganisms
 Secrete Cytokines that bind to Signaling Receptors
on other cells to enhance host response


Act on endothelial cells to recruit more monocytes to the
site of infection
CYTOKINES
Cytokines will initiate various Cellular
Responses depending on the type of Cytokine
and its target location.
CYTOKINES
DENDRITIC CELLS

Antigen presenting cells
Present Antigen to Naïve T Cell
 Naïve T Cell Differentiates into Effector T cells

Derived from bone marrow cells
 Present in skin and most tissues
 Most versatile PAMP recognition cell because of the
number of receptors both internal and external
 TLR signaling leads to Cytokine and costimulatory
molecule production

TYPES OF PAMPS
Lipopolysaccharide
layer of Gram (-)
Microorganisms
 Lipotechoic Acid and
Peptidoglycan of
Gram (+)
Microorganisms
 Flagellin
 DNA and RNA from
bacteria and viruses

MORE EXAMPLES OF PAMPS
PATHWAY ACTIVATION

PAMP binds to a TLR to
activate cell signaling
TYPES OF TOLL LIKE RECEPTORS (TLR)
9 functional TLR’s
 Found on cell surface and
intracellular membranes
 TLR-1, 2, 4, 5, 6 are located
on the plasma membrane
and recognize PAMPs
 TLR-3, 7, 8, 9 are located
inside the cell, on endosomes
and recognize nucleic acid
ligands from both bacteria
and viruses

SPECIFICITY OF TLRS CAN BE
INFLUENCED BY NON-TLR
MOLECULES

TLR4 response to LPS
LPS binds to soluble LPS-binding protein in blood or
extracellular fluid
 Protein MD2 bind to Lipid A of LPS
 Complex promotes binding to receptor

OVERVIEW
OF THE PAMP
SIGNALLING CASCADE
PATHWAYS INITIATED BY TLR’S
MAP KINASE CASCADE
JNK SIGNALING PATHWAY
APOPTOSIS
The TNF-R can activate caspase 8 to
initiate the extrinsic pathway of apoptosis
P38 PATHWAY
Mammalian p38s are activated by extracellular stimuli:
UV, Heat, Inflammatory Cytokines (TNF-a & IL-1)
other Growth Factors
 Many Receptor Mechanisms



Toll-Like Receptors activated by LPS to induce apoptosis
Dependent upon stimuli and on the cell type.

Insulin Stimulates p38 in 3T3-L1 adipocytes but
downregulates p38 activity in chick neuron cells.
Activated by Map Kinase Kinase, specifically MKK3
and MKK6
 Controls apoptosis and the release of cytokines by
macrophages and neutrophils as well as other cellular
responses

P38
P38

Apoptosis
Known to occur consecutively with activation of p38
pathway
 Dependent upon cell type. Can promote cell death in
some cells while others it enhances survival, growth,
and differentiation.


Inflammation
Activates production of inflammatory cytokines
 Production of enzymes involved in connective tissue
restructuring (COX2)
 Expression of intracellular enzymes (iNOS) which
regulates oxidation



P38 AND JNK
Often Co-activated due to overexpression of
MAP3Ks
 Pathways are turned off by MAP Kinase
Phosphatases

RESOURCES

Zarubin, T. HAN, J. Activation and signaling of the
p38 MAP kinase pathway. Department of
Immunology, The Scripps Research Institute, 10550
N. Torrey Pines Road, La Jolla, CA, 92037, USA
http://www.nature.com/cr/journal/v15/n1/full/7290257
a.html