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Immunology

Innate and adaptive immunity

Lecturer : Teridah Ginting


Learning objectives
To know how the innate immune system recognizes microbes
To list the component of innate immunity.
To know the role of innate immunity in stimulating adaptive
immune responses.
To understand the phase and types of humoral/adaptive
immune system.
To know the regulation of adaptive responses.
What is happening when pathogen enter our body?

1. pathogen recognition by cells of the innate immune system,


with cytokine release, complement activation and
phagocytosis of antigens.
2. the innate immune system triggers an acute inflammatory
response to contain the infection.
3. meanwhile, antigen presentation takes place with activation of
specific T helper cells.
4. CD4 helper T cells then co-ordinate a targeted antigen-specific
immune response involving two adaptive cell systems: humoral
immunity from B cells and antibodies, and cell-mediated
immunity from cytotoxic CD8 T cells
Immune
system

Innate Adaptive
Immediate Early induced Late
Pathogen
Physical PAMP, DAMP
barrier
(mucin, cilia) Recognition. TLR
Cell-mediated (T Humoral (B
APC (dendritic lymphocytes) Lymphocyte)
cells,
macrophage) Th2
T helper Plasma cells Clonal B
Recognition. TLR Th1 cells

Phagocytes Antibody
(macrophage, T cytotoxic Memory
Inflam
neutrophil),
basophil, mation
T
eosinophil, NK suppressor Complement
cascade

Complement Inflam
mation
Innate and adaptive immunity
Innate immunity
Innate immunity:
Happens early of infection
It consists of cellular and biochemical defense mechanisms
that are in place even before infection and are poised to
respond rapidly to infections.

The principal components of innate immunity are:


(1) physical and chemical barriers, such as epithelia and
antimicrobial chemicals produced at epithelial surfaces;
(2) phagocytic cells (neutrophils, macrophages), dendritic cells,
and natural killer (NK) cells and other innate lymphoid cells
(3) blood proteins, including members of the complement
system and other mediators of inflammation.
Functions of innate immunity
1. Innate immunity is the initial response to microbes that prevents,
controls, or eliminates infection of the host by many pathogens.
2. Innate immune mechanisms eliminate damaged cells and initiate
the process of tissue repair.
3. Innate immunity stimulates adaptive immune responses and can
influence the nature of the adaptive responses to make them
optimally effective against different types of microbes.

3 responses of innate immunity:


1. Inflammation recruitment of leukocytes, plasma protein
2. Antiviral defense secretion of substance to inhibit viral
replication
3. Stimulating adaptive immunity
How innate immune system recognizes microbes
How does innate immune response recognize?
Recognizes molecular structures that are produced by microbial
pathogens pathogen-associated molecular pattern (PAMP)
Recognizes endogenous molecules that are produced by or released
from damaged and dying cells damage-associated molecular
patterns (DAMPs)
Recognizes microbial products that are often essential for survival of
the microbes.
Types of cellular receptors, present in different locations in cells, and
soluble molecules in the blood and mucosal secretions to recognize
PAMPs and DAMPs pattern recognition receptor
The receptors are encoded by inherited (germline) genes, whereas
the genes encoding receptors of adaptive immunity are generated by
somatic recombination of gene segments in the precursors of mature
lymphocytes.
Innate immune system does not react against normal, healthy cells
and tissues
Unique features of mirobes
Bacteria, have cell walls, which are made up of peptidoglycans which are never
found in vertebrates.
Many bacterial cell surface polysaccharides, such as mannans, are not found
on the surfaces of host cells.
Gram negative bacteria (such as E.coli, Pseudomonas, Salmonella etc) all make
Lipopolysaccharide (LPS/endotoxin), which is made up Lipid A and
carbohydrates.
Some bacteria contain distinct structures known as teichoic acids and
lipoteichoic acids, not found in vertebrate cells. Teichoic acis are phosphate
linked polymers of ribitol or glycerol
The N-terminal amino acid of most bacterial proteins is formyl-methionine.
This is not found in vertebrates except in mitochondria
Bacterial lipoproteins (BLPs) contain a unique N-terminal lipo-amino acid, N-
acyl S-diacylglyceryl cysteine.
Bacterial DNA contains specific unmethylated CpG repeats that are not found
in vertebrate DNA
Double stranded RNA produced during viral infections may induce the
secretion of Type I interferons which have anti-viral properties.
Examples of PAMPs and DAMPs
Pattern recognition receptor (cellassociated)
Continue, Pattern recognition receptor (soluble)
TLR pathway

Toll-like receptors (TLRs) are an


evolutionarily conserved family of
pattern recognition receptors
expressed on many cell types that
recognize products of a wide variety of
microbes as well as molecules
expressed or released by stressed and
dying cells
NOD-like receptor
Cytosolic receptor for PAMP and DAMP.
Induced by cytoplasmic stimuli, e.g.
Bacterial products, crystals, K+ efflux,
reactive oxygen species, etc
Family of NOD proteins (Nucleotide
oligomerization domain-containing
protein)
Three NLR subfamilies, based on the
effector to initiate signaling: CARD
(caspase recruitment domain), Pyrin
domain, and BIR domain.
Respond to cytosolic PAMPs and DAMPs
by forming signaling complexes called
inflammasomes, which generate active
forms of the inflammatory cytokines IL-1
and IL-18.
Dysregulation of inflammasome
autoinflammatory syndrome Cryopyrin
associated autoimmune disorders)
RIG-like receptor
Cytosolic sensor of viral nucleic acid and inducing IFN type
I.
E.g: RIG1 (retinoic acid inducible gene 1) and MDA5
(melanoma differentiation associated gene 5)
Recognize different sets of viral RNAs based on the length
of the RNA ligands and can discriminate viral single-
stranded RNA from normal cellular single-stranded RNA
transcripts
Initiate signaling events that lead to phosphorylation and
activation of IRF3 and IRF7, as well as NF-B,
Other cell associated pathogen associated
receptor

Carbohydrate receptor (mannose receptor,


dectins, langerin (CD207))
Scavenger receptor
Formyl-peptide receptor
Component of innate immune system
First line of defense
1. Epithelial barriers
Epithelial cells form tight junctions, blocking passage of microbes between the cells.
The outer layer of keratin blocks microbial penetration into deeper layers of the epidermis.
Mucus, a viscous secretion containing glycoproteins called mucins, physically impairs
microbial invasion. Microbes coated with mucus may be prevented from adhering to
epithelium.
Ciliary action in the bronchial tree and peristalsis in the gut facilitate elimination of
microbes.
Containing intraepithelial T cell.
Antibacterial enzymes: lysozyme, secretory phospholipase A2.
Lysozyme is a glycosidase that breaks a specific chemical bond present in the peptidoglycan of the
bacterial cell wall.
Secreted in tears, saliva and by phagocytes.
Paneth cells, specialized epithelial cells in the base of the crypts in the small intestine.
Antimicrobial peptides: Epithelial cells secrete these into the fluids of the mucosal surface,
whereas phagocytes secrete them in tissues. Three important classes of antimicrobial
peptides in mammals are defensins, cathelicidins, and histatins.
Defensins: by cells of gut, skin keratinocytes, pulmonary surfactant.
Cathelicidins: by neutrophils, by macrophages, and by keratinocytes in the skin and epithelial cells in the lungs
and intestine in response to infection.
Histatins: by the parotid, sublingual, and submandibular glands in the oral cavity.
C-lectin: Paneth cells
Differentiated keratinocytes in the stratum
spinosum produce b-defensins and cathelicidins,
which are incorporated into secretory organelles
(lamellar bodies).

The airways are lined by ciliated epithelium. Beating


of the cilia moves a continuous stream of mucus
secreted by goblet cells, trapping and ejecting
potential pathogens.

In the intestine, specialized cells deep in the


epithelial crypts called Paneth cells produce several
kinds of antimicrobial proteins: a-defensins
(cryptdins) and the antimicrobial lectin RegIII.
2. Soluble (humoral) molecules in innate immunity

There are molecules in blood and extracellular


fluid that recognize microbes and promote
immune response.
Mechanisms:
1. Act as opsonin -- bind to microbes and enhance
the ability of neutrophil, macrophage and DC to
phagocyte them.
2. Attract more phagocyte cells to the site of
infection
3. Direct kill of microbes
Soluble (humoral) molecules in innate immunity

1. Complement system
2. Collectins, pentraxins, and ficolins
3. Cytokines (TNF, IL1, IL6)
Complement nomenclature
The first proteins discovered belong to the classical pathway, and are
designated by the letter C followed by a number.
The native complement proteinssuch as the inactive zymogenshave a
simple number designation, for example C1 and C2.
The order of number is not sequence reaction but number of discovery. The
reaction sequence in the classical pathway, for example, is C1, C4, C2, C3, C5,
C6, C7, C8, and C9
Products of cleavage reactions are designated by adding a lowercase letter as
a suffix. For example, cleavage of C3 C3a (small) and C3b (bigger).
The larger fragment is always designated by the suffix b, except for C2 (C2a is
the larger fragment because it is the that enzymatically active fragment)
Another exception: naming of C1q, C1r, and C1s these are not cleavage
products of C1 but are distinct proteins that together comprise C1.
Alternative pathway naming are designated by different capital letters (e.g.
factor B and factor D). Activated complement components are sometimes
designated by a horizontal line, for example, C2a
Complements

A number of small proteins found in the blood,


in general synthesized by the liver, and normally
circulating as inactive precursors.
Function of complement
Complem Prod Functions
ent uct

Classical C1 (C1q: C1q Binds directly to pathogen surface or indirectly to Ab bound to pathogen,
C1r2:C1S thus allowing autoactivation of C1r
2
C1r Cleaves C1 to active protease
C1s Cleaves C4 and C2
C4 C4b Covalently binds to pathogen and opsonize it. Binds C2 for cleavage by C1s
C4a Peptide mediator of inflammation (weak)
C2 C2a Active enzyme of classical pathway C3/C5 convertase: cleaves C3 and C5
C2b Precursor of vasoactive C2 kinin
C3 C3b Many molecules of C3b bind to pathogen surface and act as opsonins.
Initiates amplification via alternative pathway. Binds C5 for cleavage by C2a
C3a Peptide mediator of inflammation (intermediate)
C3 C3b Binds to pathogen surface, binds B for cleavage by D, C3bBb is C3
Alternat
convertase and C3b2Bb is C5 convertase
ive
Factor B Ba Small fragment of B
Bb Bb is active enzyme of the C3 convertase C3bBb and C5 convertase C3b2Bb
Factor D D Plasma serine protease, cleaves B when it is bound to C3b to Ba and Bb
Properdin P Plasma protein that binds to bacterial surfaces and stabilizes the C3bBb
convertase
Pentraxins, Collectins, Ficollins
Pentraxins family: short pentraxins C-reactive protein (CRP), serum
amyloid P (SAP) and the long pentraxin PTX3 known as acute
phase reactants, because they content in plasma protein rise
during inflammation.

Collectins: mannose-binding lectin (MBL) and pulmonary


surfactant proteins SP-A and SP-D.

Ficollins: similar with collectins


3. Cellular components innate immunity

1) Phagocytes (macrophage, neutrophil, DC)


Cells whose primary function is to ingest and destroy microbes and get rid of
damaged tissues. Primarily macrophages and neutrophils, are the first line of
defense against microbes that breach epithelial barriers
Neutrophil (polymorph nuclear, azurophilic granules)
Mononuclear phagocyte (resident macrophage: Kupffer cell of liver, sinusoidal
macrophage of spleen, alveolar macrophage of lung). In human CD14++CD16
Activated macrophage produce chemoattractant (chemokines) to attract
neutrophils (also other monocytes and dendritic cells)
Phagocytosis occurs after the foreign body, a bacterial cell, has bound to
receptors:
1. Opsonin receptor: increase the phagocytosis of bacteria that have been coated with
immunoglobulin G (IgG) antibodies or with complement.
2. Scavenger receptor: bind to a large range of molecules on the surface of bacterial cells.
3. TLR: Binding to Toll-like receptors increases phagocytosis and causes the phagocyte to
release a group of hormones that cause inflammation.
Complement facilitate the uptake and destruction of pathogens
by phagocytic cells

Complement receptor bind pathogens


opsonized with complement
component.
There are 7 complement receptors.
3. Innate lymphoid cells (ILC): bone Bpne marrow
marrowderived cells with lymphocyte
morphology that serve diverse
antimicrobial functions
There are 3 subsets: ILC1, ILC2, ILC3

ILC1 Includes Natural Killer (NK) cells.


Produces IFNgamma
ILC2 TH2-like. Secretes IL-5, IL-9 and IL-
13, and express the GATA2 transcription
factor.
ILC3 TH17-like produce IL-22 and/or IL-
17 and express the transcription factor
RORt
NK Cells
5% to 15% of the mononuclear cells in the blood and spleen.
Rare in other lymphoid organs but are more abundant in certain
organs such as the liver and gravid uterus. NK cells in the blood
appear as large lymphocytes with numerous cytoplasmic
granules.
Do not express diverse, clonally distributed antigen receptors
typical of B and T cells. They use germline DNA-encoded
receptors to distinguish pathogen-infected cells from healthy
cells.
CD56++/CD3- and
Most human blood NK cells express CD16
Functions of NK cells
Effector functions
Releases perforin that
facilitates entry of
granzymes into target
cell apoptosis
Activated by IL-12 and
secretes IFN-gamma
that increase capacity
of macrophage in killing
microbes
4. Basophil, eosinophil and mast cell
Mast cells express receptor for IgE. Release
histamine when bind to antigen
Basophils expresses IgE receptor
Eosinophils produces enzyme that causes
damage to parasite wall
5. Antigen presenting cells (this will start adaptive
immune response)
Antigen-presenting cells (APCs) are cells that capture microbial
and other antigens, carry them to nearby lymph nodes, display
them to lymphocytes, and provide signals that stimulate the
proliferation and differentiation of the lymphocytes.
Dendritic cells, macrophage, B lymphocyte
DC is major APC
Dendritic cells
Have essential recognition and effector roles in innate
immunity. DCs express more different types of TLRs and
cytoplasmic pattern recognition receptors
Plasmacytoid dendritic cells express abundant amounts of the
endosomal TLRs (TLRs 3, 7, 8, 9), which recognize nucleic acids
of viruses that have been internalized into the cell.
Dendritic cells are uniquely capable of triggering and directing
adaptive T cellmediated immune responses, and this is
dependent on their innate immune responses to microbes. This
capability reflects the ability of dendritic cells to take up
microbial protein antigens, to transport them to lymph nodes
where naive T cells home, and to display the protein antigens in
a form that the T cells can recognize.
Dendritic cells
Follicular dendritic cells. reside in lymphoid follicles
Responses of innate immunity

3 responses of innate immunity:


Inflammation recruitment of leukocytes and plasma
protein (reddish, fever, swelling, pain, loss of
function)
Antiviral defense secretion of substance to inhibit
viral replication
Stimulating adaptive immunity
Complement and inflammation

Small complement fragments


C3a and C5a (especially C5a) act
on specific receptors on
endothelial cells and mast cells
to produce local inflammatory
responses.
When produced in large
amounts or injected
systemically, they induce a
generalized circulatory collapse,
producing a shock-like
syndrome similar to that seen
in a systemic allergic reaction
involving antibodies of the IgE
class Such a reaction is termed
anaphylactic shock
Vascular in inflammation
Leukocyte recruitment (chemotaxis) and phagocytosis
Neutrophils, followed by monocytes, from blood into tissues are recruited under
the influence of cytokines secreted at the site of infection, e.g. TNF, IL-1, IL-6
TNF and IL-1 also stimulate various cells to secrete chemokines, such as CXCL1 and
CCL2, that bind to receptors on neutrophils and monocytes, respectively, and
stimulate directional movement of leukocytes.

Microbe can
be directly
bound to
phagocyte
receptor or
opsonized
Antiviral response

Viral infections is to induce the expression of type I interferons


(and type III), whose most important action is to inhibit viral
replication.
Type I IFNs: IFN /
Type III IFNs: IFN1/2/3
Effects:
Inhibit viral protein synthesis
Degradation of viral DNA
Degradation of viral gene expression and protein assembly
Stimulation of adaptive immunity

The innate immune response provides signals that function in


concert with antigen to stimulate the proliferation and
differentiation of antigen-specific T and B lymphocytes.

Adaptive immune response starts when antigen


presenting cells, e.g. dendritic cells are activated
Adaptive immunity

Adaptive immunity (specific or acquired immunity)


Form of immunity develops as a response to infection and
adapts to the infection.
Specific : able to distinguish different substances
Memory : ability to respond more vigorously to repeated
exposures to the same microbe
Component: Lymphocyte and their secreted products
1. Humoral Adaptive immunity
2. Cell-mediated immunity
Reference

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