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8/3/2019 Innate Immunity A Nobel Prize winning Topic 2011
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Dr.T.V.Rao. MD
INNATE IMMUNITY
NOBEL PRIZE WINNING TOPIC - 2011
DR.T.V.RAO MD 1
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2011 NOBEL PRIZE IN PHYSIOLOGY OR
MEDICINE
The 2011 Nobel Prize in Physiology or Medicine was
awarded to Bruce Beutler at the Scripps Research
Institute in California, Jules Hoffmann at the French
National Center for Scientific Research and RalphSteinman at The Rockefeller University in New York
City. Beutler and Hoffman helped to elucidate innate
immunity, the non-specific array of initial responses by
the bodys immune system that can recognize invadingmicroorganisms as being foreign and try to destroy
them.
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The Nobel Prize in
Physiology or Medicine
2011 was divided, one half
jointly to Bruce A. Beutler
and Jules A. Hoffmann "fortheir discoveries
concerning the activation of
innate immunity"and the
other half to Ralph M.Steinman "for his discovery
of the dendritic cell and its
role in adaptive immunity".
THE NOBEL PRIZE IN PHYSIOLOGY OR
MEDICINE 2011
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Infection of the humanbody by pathogenicmicroorganisms such as
bacteria, viruses,parasites or fungi triggersthe immune response. Itoccurs in a two-stepprocess: innate immunity
halts the infection, andadaptive immunitysubsequently clears it.
THE IMMUNE SYSTEM
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We are constantly being
exposed to infectious
agents and yet, in most
cases, we are able to resist
these infections. It is ourimmune system that
enables us to resist
infections. The immune
system is composed of twomajor subdivisions, the innate
or non-specific immune
system and the adaptive or
specific immune system
OVERVIEW OF THE IMMUNE SYSTEM
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no need for prolonged induction
no clonal expansion of Ag
specificity
act quickly
immediate direct response 0-4 hrs
rapid induced 4-96 hrs
failure ==> adaptive immune
response
dependence on germ line encoded
receptors
high discrimination of host and
pathogen
INNATE IMMUNITY :DEFINITION
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What happens when the physical andchemical barriers are breached?
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Characteristics:- rapid- does not generate immunologic memory- dependent upon germ line encoded receptors recognizing
structures common to many pathogens
Innate Immunity-First Line of Defense
InnateImmunity
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Leukocyte Players ofInnate Immune Responses
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The elements of the innate (non-
specific) immune system include
anatomical barriers, secretory
molecules and cellular
components. Among the
mechanical anatomical barriers
are the skin and internal
epithelial layers, the movement
of the intestines and the
oscillation of broncho-pulmonary
cilia.Associated with theseprotective surfaces are chemical
and biological agents.
INNATE (NON-SPECIFIC) IMMUNITY
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The Innate Immune Systemcomposed of ?
- includes physical, chemical, and cellular barriers
- physical barriers include skin and mucusmembranes
- chemical barriers include stomach acidity,secreted anti-microbial peptides
- cellular barriers include macrophages, neutrophils
- innate immune response activation occurs withinminutes of pathogen recognition
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HOW INNATE IMMUNITY PROTECTS
1. Provides a barrier to prevent the spread of infection Mechanical (tight junctions, movement)
Chemical (fatty acids, enzymes, pH, antimicrobial peptides)
Microbiological (normal flora)
Mucosal surfaces
Nasopharyngeal, Oral, Respiratory, Intestinal tract
Urogenital tract
Skin (epithelial cells)
Wounds, burns, insect bites
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INNATE IMMUNITY 3. Initiates an inflammatory response
Reaction to injury or infection
Trauma to tissues or cells
Presence of foreign matter (self vs. non-self)
Infectious agents (viruses, bacteria, fungi)
Delivers effector molecules & immune cells to the site ofinfection
Components
Leukocytes & secreted factors
Blood vessels
Plasma proteins
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Once the PRRs are activated by the PAMPs,
phagocytosis is initiated
Phagocytosis is active process:
- Internalization of pathogen into phagosome- Acidification of phagosome
- Fusion of phagosome with lysosomes thatcontain anti-microbial compounds
(phagolysosome)- This may be sufficient to kill the pathogen
- If not, reactive oxygen and nitrogenspecies may need to be generated
Macrophage Microbial Killing
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INNATE IMMUNITY Provides signals to activate and regulate the type of
adaptive immune response generated
Stimulation of co-stimulatory molecules
B7 family (CD80/86, PD-L, ICOSL) TNFR family (OX40L)
Induction of a cytokine/chemokine response Cytokines: IL-12, IL-23, IL-4
Chemokine's: CXCR1, CXCR2, CCL20 a variety and depends on stimulus
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FIRST LINE OF DEFENSE -- EPITHELIA
Mechanical
tight junctions, air/fluid flow, ciliary rejection
Chemical
lysozyme, pH, defensins, surfactant opsonins, TOX(ROX)
Microbiological
normal protective flora competition, antimicrobial colicin
Inductive
receptors that recognize pathogens and signal other
innate and adaptive immune response
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Neutrophils
Eosinophil's
Basophils/Mast Cells Monocytes
Macrophages
Natural Killer Cells Platelets
CELLS OF INNATE IMMUNITY
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LEUKOCYTE TERMINOLOGY
TWO SYSTEMS
Nuclear Morphology
Mononuclear Cells
Monocytes/Macrophages
Lymphocytes
Polymorph nuclearCells
Polymorphonuclear Leukocytes, PMNLs, PMNs
Granule Morphology
Granulocytes
Neutrophils (neutral), Eosinophil's (orange), Basophils (blue)
Agranulocytes
Lymphocytes, Macrophages,DR.T.V.RAO MD 21
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COMPARATIVE MORPHOLOGY OF
GRANULOCYTES
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L k Pl f
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Leukocyte Players ofInnate Immune Responses
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Innate Immune Receptors
Innate immune receptors are not clonally distributed
Binding of receptors results in rapid response
Innate immune receptors mediate three functions:
- phagocytic receptors to stimulate pathogen uptake
- chemotactic receptors that guide phagocytes to site ofinfection
- stimulate production of effector molecules and cytokines
that induce innate responses and also influence
downstream adaptive immune responses
P th R iti
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Most microorganisms express repeating patterns of
molecular structures termed Pathogen AssociatedMolecular Patterns (PAMPs)
Innate immune system has evolved mechanisms capable ofrecognizing these repeating patterns termed Pattern
Recognition Receptors (PRRs)
Examples of Pattern Recognition Receptors:- Mannose-Binding Lectin (MBL)
- Macrophage Mannose Receptor- Scavenger Receptors- Toll-like Receptors (TLRs)- Nod-like Receptors (NLRs)- RNA helicases (RIG-I, MDA-5)
Pathogen Recognition
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PHAGOCYTOSIS Phagocytosis
Definition: uptake of large particles (>0.5 mm)
Actin-dependent, clathrin-independent
High rate & efficiency of internalization Professional phagocytic cells
Macrophages
Neutrophils These cells have phagocytic receptors
External receptors
FcR, CR3, Mannose receptor
Internal receptors
TLRs
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Blood - Called monocytes (1-6%
WBC)
Tissues - Called macrophages
mature form of monocytes
normally found in tissues suchas gastrointestinal tract, lung,
liver and spleen
Functions:
Phagocytose and kills after
bactericidal mechanisms areactivated (T cells)
Produce cytokines/chemokines
(initiates inflammation)
Is an antigen presenting cell
(co-stim. Molecules)
MACROPHAGES
(MQ)
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Present in blood (55-60%
of WBC)
Not normally present in
tissues
Short lifespan - 12 hours
Functions:
First at the site of
infection/injury
Ingest and kill microbes
after bactericidal
mechanisms are activated
(binding to pathogen)
NEUTROPHILS
(PMN)
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Granulocytic Leukocyte
Most Abundant White Blood Cell
2-6 x 103 cells/L
4075 % ofleukocytes
Very Short Lifetime
t1/2 = 6 hours
55 % of Bone Marrow Weight
Devoted to Neutrophil Production
HUMAN NEUTROPHIL
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Human Neutrophil Size In blood:
Volume = 300 m3 sphere (300 fl vs. 90 fl for RBC)
Diameter = 8.3 m
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EOSINOPHIL
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EOSINOPHIL
EM MORPHOLOGY
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Receptors
recognition ofpathogens
chemical signals
Transduction pathways
G proteins, Kinases
Effector activation
gene induction
motility, secretion
adherence,phagocytosis
SIGNAL TRANSDUCTION
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G PROTEIN CYCLE
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Toll Like Receptors (TLRs)
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Toll-Like Receptors (TLRs)
Cellular Localization:- Lysosomal localization (i.e. subcellular) of TLR-3 and TLR7-9
- TLR-3 and 7-9 recognize viral/bacterial nucleic acids
- lysosomal expression isolates pathogen nucleic acid recognition away
from potential cross-reaction with host mammalian nucleic acid motifs
TNFa
IFNab
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G PROTEIN-COUPLED RECEPTORS
Largest receptor family appx ~1000 types
Bind proteins, peptides, absorb light
Highly homologous in structure
Gab protein exchange factors
G protein splitters ==> Ga-GTP & Gb
Primary transducers are Ga-GTP & Gb
Activate membrane phospholipases and cyclases
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GTPa b
GTP
a b GDP
GDP
a b a
GDP
b
GTP GDP
P
L
C
INTERNALIZED
GDP
a
P110
PIP2 PIP3
Receptor - G protein
CouplingR
R
RR
R
L
L
L
L
LL
L
L
L
L
L
L
L
a
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GPCR OF INNATE IMMUNITY
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Peptide receptors
fMLF receptor-- chemotaxis toward bacteria
Complement receptors C5a, C3a -- chemotaxis toward sites of
complement activation
Lipid receptors
Leukotriene (LTB4), Eiosanoid (LPXA4), PAF, PG
Chemokine receptors
CXC (IL-8), CC (MCP), CXXXC(Fractalkine)
nomenclature from amino terminal cysteines
IL-8, MCP induce extravasation of neuts, M Fractalkine - monocyte /endothelial adhesion
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KILLING MECHANISMS Phagosome - membrane bounded vesicle that becomes acidified
Lysozome - granules that contain products that damage or kill pathogens
Enzymes
Lysozyme - dissolves cell walls of some bacteria
Acid hydrolases - digests bacteria
Proteins
Lactoferrin - binds Fe++ needed for bacterial growth
Vitamin B12-binding protein
Peptides
Defensins and cationic proteins - direct antimicrobials
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Activated macrophages secrete proteins that drive
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Activated macrophages secrete proteins that driveinnate response
Cytokines
- induce response by binding to specific receptors
- can function in autocrine or paracrine manner
- cytokines (and their receptors) are clustered according to structural similarities
- critical cytokines secreted by macrophages following activation include TNFa,
IL-1, IL-6, IL-12 to stimulate inflammation and phagocytosis/killing
Chemokines
- diverse family of chemotactic cytokines, induce directed chemotaxis of cells
- all related in amino acid structure
- certain chemokines induce cell activation in addition to cell recruitment- promiscuous in receptor usage, each can bind more than one receptor
- likewise, receptors are promiscuous
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KILLING MECHANISMS - CONT. Respiratory Burst
Activated following phagocytosis
Stimulated by PRR
Requires increased oxygen consumption
Produces substances that are directly toxic to the bacteria
Oxygen-derived products
O2-, H2O2 & Myeloperoxidase
Nitrogen-derived products
NO (nitrogen oxide)
Produced by inducible NO synthase (iNOS) enzyme
Enzyme is induced by cytokines (LT, TNFb)
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NADPH OXIDASEMitochondrial-independentrespiratory burst
P47phox & p67phoxnormally resides in the
cytoplasma.
P47phox becomeshyperhposphorylatedfollowing phagocytosis andbinds to p67phox.
These components moveto the membrane and bindthe NADPH complexresulting in an active
complex.DR.T.V.RAO MD 41
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ENZYME REACTIONS OF
RESPIRATORY BURST
Respiratory BurstNADPH NADP+ Superoxide
+ dismutase
2 O2 2 O-
H2O2
Myeloperoxidase
Enzyme which is stored in primary granules of PMN & MQ and uses the products of the
respiratory burst.
H2O2 + C1-
Chloramines
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Clinical symptoms of inflammation:
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Clinical symptoms of inflammation:pain, redness, heat, swelling
1. Increased vascular diameter, increased blood flow (heat, redness)
2. Activation of vascular endothelium to express adhesion molecules, increasesleukocyte binding
3. PMNs are first cell type recruited to site, followed later by monocytes
4. Increased vascular permeability results in local swelling and pain
Microvascular coagulation helps prevent pathogen spread into bloodstream (physical barrier)
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CHEMOKINE'S
Infection induces the
release of various
chemokine's
Theses substances bindspecific and sometimes
shared receptors to
recruit various types of
immune cells to the site
of infection
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DENDRITIC CELLS
DCs link innate and adaptive immunity DCs are immature as they circulate waiting to encounter
pathogens
At this point, they are highly phagocytic, but not goodstimulators of adaptive T cell responses
Once they are activated by pathogens and activation of
their PRRs, they secrete cytokines to initiateinflammation and then they migrate to lymph nodes andmature
As mature DCs they are excellent APCs for T cellstimulation
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THE CURRENT KNOWLEDGE HELPS FOR
NEWER VACCINE TRENDS
The detailed understanding of the immune
system provided by the new Nobel laureates has
given other researchers the ability to improve
vaccines and to attempt to stimulate immunereactions to cancer. Their insights also inform
efforts to damp down the immune system when
it becomes too zealous, which can lead toexcessive inflammation and autoimmunity.
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FOR FURTHER INFORMATION . . . Immunology Project Resources
Understanding Autoimmune Disease
http://www.niaid.nih.gov/publications/autoimmune/work.htm
Antibody descriptions [IgG, IgM, IgA]
http://sprojects.mmi.mcgill.ca/immunology/Ig_text.htm
Immunology Hyperlinked History & Molecular Movies
http://www.bio.davidson.edu/courses/Immunology/Bio307.html
Nature Magazine & Immunology
http://www.nature.com/nature/view/030102.html
NCBI Genome
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=1589796
NCBI Genome Base
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=1589796
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Programme created by Dr.T.V.Rao MD
for Medical and Paramedical students in
the Developing World