Innate immunity

Innate
immunity
26th March 2021
Nattasasi Suchamalawong, MD.
Pediatric Allergy and Immunology Unit
King Chulalongkorn Memorial Hospital

Outline
● Overview of innate immunity
● Recognition of microbes and damaged self
● Cell-associated pattern recognition receptors and sensors of innate immunity
● Cellular component
● Soluble recognition and effector molecule
● The inflammatory response
● The antiviral response
● Stimulation of adaptive immunity
● Homeostasis in the innate immune response

Abbas_Cellular and Molecular Immunology, 9th ed
Bankova L.etal.middleton’s 9th edition,2020.1-19
Innate immunity
- The first line of host defense against infections
- Exist before exposure to microbes
- React to products of microbes and injured cell
- The cellular components of the innate immune system
include epithelial barriers and leukocytes
-Phagocytic cell : neutrophils, macrophages
-Antigen presenting cell: Dendritic cell
-Degranulating cell : mast cells, Eosinophils ,Basophils
-NK cells

Turvey SE, Broide D, J Allergy Clinical imm, 2010
Components of Innate immunity
1.Anatomical barrier
- Physical barriers
- Chemical barriers
2.Cellular
- Phagocytic cells
- Dendritic cell
- NK cells, ILC
3.Soluble proteins
- Complement
- Cytokines, Chemokines
- Antimicrobial peptides (AMPs)

Functions & Reaction of innate immune responses
1.Initial reactions to microbes that serve to prevent, control, or eliminate
infection of the host by many pathogens.
Deficiencies, inhibition, or elimination of innate immunity increase
susceptibility to infections, even when the adaptive immune system is
intact and functional.
Many pathogenic microbes have evolved strategies to resist innate immunity
that are crucial for the virulence of microbes.
Innate immune responses to such microbes may keep the infection in check
until adaptive immune responses are activated.

The functions of innate immune responses
2. Innate immunity eliminates damaged cells and initiates the process of
tissue repair.
Innate responses may occur as a result of infection or it may be sterile cell
and tissue damage in the absence of infection.
3. Stimulate adaptive immune responses and make them optimally effective
against different types of microbes.

The Reaction of innate immune responses
2 major types of protective reactions of the innate immune system are
inflammation and antiviral defense.
- Inflammation
- Circulating leukocytes and plasma proteins are brought into sites of
infection in tissues.
- Major reaction to damaged or dead cell
- Antiviral defense
- Mechanisms prevent virus replication
- Eliminating reservoirs of viral infection without an inflammatory reaction.

Comparative features of innate and adaptive immunity
Attribute Innate immunity Adaptive immunity
Response time Immediate responses and do not
require prior exposure to microbe.
Several days as clones of antigen-
specific lymphocytes
Diversity No appreciable change in quality or
magnitude of repeated exposure
(exception NK cell)
Repeated exposure to a microbe
enhances rapidity, magnitude, and
effectiveness
Number & Type
of receptor
Recognizes only about 1000 products
of microbes and damaged cells.
Recognize millions of different
microbial antigens, and can also
recognize non microbial
environmental Ag
Memory response No memory cell or Trained immunity Memory cell

None or limited memory Memory cell

Trained immunity
Netea G. Mihai et al. Nature review. Immunology., June 2020.375-388
• Innate immune memory : innate immune system can enhance responsiveness
to subsequent triggers. Greater protection against reinfection.
• Secondary response : quicker and stronger response against pathogens but
less specific and shorter duration than adaptive immune memory.
• Epigenetic reprogramming, alterations in gene expression and cellular
function without changes to the original DNA sequence.
• E.g. β-glucan, LPS or the bacillus Calmette–Guérin (BCG) vaccine.

Trained immunity
Suratannon N et al. Asian Pac J Allergy Immunol 2020;38:170-177
long-term epigenetic reprogramming of innate immune cells (myeloid
cells and NK cells) and occurs upon exposure to homeostasis perturbance by
pathogens.
Effect : increase immune response upon secondary stimulation
( same or even unrelated pathogens)
increase production of IFN-γ, IL-1β, IL-6, and TNF-α cytokines
(key cytokines in immune response to many pathogens) .
Trained immunity : very important protective mechanism against (re)infection,
and likely is of great importance especially in early life.

Trained immunity
Suratannon N et al. Asian Pac J Allergy Immunol 2020;38:170-177

Trained immunity and tolerance: two opposite functional programmes
of innate immunity.
Zhong chao et al. Front. Immunol., 21 February 2020
Netea G. Mihai et al. Nature review. Immunology., June 2020.Volume 20375-388
Found mainly monocyte/macrophage or NK cell

Summary of training programs induced in
monocytes/macrophages.
Zhong chao et al. Front. Immunol., 21 February 2020

Central and Peripheral trained immunity.
mononuclear phagocyte lineage
(monocytes and macrophages)
memory NK cells undergo a secondary
expansion and can more rapidly
degranulate and release cytokines, resulting
in a more protective immune response
changes in the chromatin accessibility
Netea G. Mihai et al. Nature review. Immunology., June 2020.375-388

Epigenetic reprogramming underlies the induction of trained immunity.
Netea G. Mihai et al. Nature review. Immunology., June 2020.Volume 20.375-388
deposition of chromatin changes DNA methylation proinflammatory factors
quicker & enhanced recruitment
of transcription factors and gene
expression

Recognition of Microbes and Damaged self
• “Pathogen associated molecular patterns (PAMPs)”
: Molecular structure produce by microbial pathogens that required for survival.
: not mammalian cells
: Shared by entire classes of pathogens
• “Damage associated molecular patterns (DMAPs) ”
: recognizes endogenous molecules that are produced by or released from damaged
and dying cells at both infection and sterile injury
• Cellular receptors : Pattern recognition receptors (PRRs)

Examples recognize of PAMPs & DAMPs patterns
Unmethylate CpG DNA

Bankova L.et al. middleton’s 9th edition,2019.1-19
Recognition of Microbes and Damaged self
• Cell-associated recognition molecules
• Phagocytes, DCs, epithelial cells, and others
• Recognize both pathogen and damaged cells
“Pattern Recognition Receptors (PRRs)”
• Soluble recognition (effector) molecules
• Facilitate clearance by enhancing uptake

• Principle functions of PRRs
1.) Opsonization
2.) Activation of complement
3.) Phagocytosis
4.) Activation of proinflammatory signaling pathways
5.) Induction of apoptosis
Pattern Recognition Receptors (PRRs)

Secreted PRRs
AMPs : Defensins & Cathelicidin
Opsonization , chemoattractant
Phagocytosis, Complement activation
Mannose receptors (CD206)
•C - Type Lectin Receptors
• Recognized carbohydrates (Mannose)
- Bacterial, Fungus, Parasite
• Expressed on Macrophage
• Phagocytosis, NF-kB activation

Pattern Recognition Molecules of the Innate Immune System
Cytosolic DNA Sensors stimulator of IFN genes pathway
RIG-like receptors
C-type lectin–like receptors
Toll-like receptors
NOD-like receptors

Cellular locations of pattern
recognition receptors of the
innate immune system.
1
2
3
4
5
1
Anti-viral response
1.) Toll-like receptors (TLRs)
2.) NOD-like receptors (NLRs)
3.) Retinoid acid–inducible gene
(RIG)-like receptors (RLRs)
4.) Cytosolic DNA sensor (CDS)
5.) C-Type Lectin Receptors (CLRs)

Cell-associated PRRs and sensors of innate immunity
• Most cell types express PRRs and therefore are capable of participating
in innate immune responses.
• Phagocytes, especially macrophages, and DCs express the widest
variety and greatest number of these receptors.
• Role of phagocyte: detecting microbes and damaged cells and
ingesting for destruction
• Role of DCs: reacting to microbes in ways that elicit inflammation and
subsequence adaptive immunity .

-Type I integral membrane glycoprotein
-Extracellular region : Leucine rich repeat motifs (receptors, bind
directly to PAMPs) , cysteine rich flanking motif.
- Transmembrane domain
- Toll/IL-1 receptor (TIR) : homology domain found in their
cytoplasmic tails, essential for signaling.
Toll-like receptors (TLRs)
Cysteine rich
flanking motif
9 different functional TLRs in human
• TLRs 1, 2, 4, 5 and 6 are expressed on plasma membranes.
• TLRs 3, 7, 8, and 9 are mainly expressed inside cells on endoplasmic
reticulum and endosomal membranes.
Cell-associated PRRs and sensors of innate immunity

• TLRs 1, 2, 4, 5 and 6
- expressed on plasma membrane
- recognize various PAMPs in the
extracellular environment
• TLRs 3, 7, 8, and 9
expressed inside cells on endoplasmic
reticulum and endosomal membranes
• UNC-93B is required for the endosomal
localization and proper function of TLRs
3, 7, 8, and 9

• LPS-binding protein in the blood or
extracellular fluid
• CD14 is expressed by most cells
(except endothelial cells) as a
soluble protein or as a
glycophosphatidylinositol-linked
membrane protein.
• MD2 (myeloid differentiation
protein 2) binds to LPS, forming
a complex that then interacts with
TLR4

• TLR 3 signal through TRIF- pathway
and activates type I IFN >> antiviral
state.
• TLR4, induce both inflammatory and
antiviral responses. (signal through both
MyD88 ,TRIF- pathway )
Signaling pathways and functions of TLRs.
1. MyD88 –dependent pathway
(Myeloid differentiation primary
response gene 88)
cell surface TLRs engage the
adaptor
• NF-kB (inflammation)
activation.
2. TLR signaling uses the adaptor
: TRIF-dependent pathway
(TIR-domain-containing adaptor
inducing IFN-β)
• Type I IFNs (anti-viral)
All TLR except TLR3 signal through
MyD88 and capable of activating
NF-KB >> inflammatory response
• TLR 7 and TLR 9 in the endosome use
MyD88 and activate both NF-κB and IRFs>>
induce both inflammatory and antiviral

• UNC-93B
: multiple-transmembrane-spanning protein in ER
- required for endosomal localization & proper function of TLRs 3,7,8,9
- unknown mechanism
- genetic def. in UNC-93B >>
viral infections esp. Herpes simplex encephalitis

Defective recognition by TLR
Netea MG, new England journal med ,2011 N Engl J Med 2011; 364:60-70

Cytosolic Receptors for PAMPs and DAMPs
• 3 major classes of these cytosolic receptors
• NOD–like receptors (NLRs)
• RIG (retinoic acid-inducible gene)-like receptors
• Cytosolic DNA sensors (CDs)
• Similar to TLRs, are linked to signal transduction pathways that promote
type I IFN production.

NOD-Like Receptors: NOD1 and NOD2
• NOD : Nucleotide oligomerization domain
• A family of more than 20 different cytosolic proteins
• recognize PAMPs and DAMPs in cytosol.
• Typical NLRs include :
• C-terminal leucine-rich repeat domain (LRR): presence of ligand
• Central NOD (NACHT) domain required for NLR proteins to bind to one
another and form oligomers
• N-terminal effector binding domain (NBD) : CARD, PYD, BIR

N-terminal
effector domain
C-terminal
leucine-rich-repeat

• NOD1 and NOD2, members of the NLRC subfamily, : CARD domain–
containing NOD subfamily
• expressed in the cytosol of several cell types, including mucosal epithelial
cells and phagocytes
• respond to bacterial cell wall peptidoglycans.
• Important in innate immune response to bacterial pathogen in GI tracts ;
H.pylori , L.monocytigenes.
NOD1 :
• Express GI tract epithelial
• Recognizes a glycosylated tripeptide called
DAP (diaminopimelic acid), derived mainly from
gram-negative bacterial peptidoglycan
NOD2 :
•expressed in intestinal Paneth cells
•stimulates expression of defensins
•Recognizes MDP (muramyl dipeptide), derived
from both gram-negative and positive
peptidoglycans.

• Oligomers of NODs recognize their peptide ligands, including bacterial toxins,
• A conformational change occurs that allows the CARD effector domains of NOD
proteins to recruit multiple copies of kinase RIP2, forming a signaling complex that
has been called NOD signalosome.
• The RIP2 kinases in these complexes activate NF-κB, which stimulates production of
cytokines and other molecules involved in inflammation (similar to TLRs that signal
through MyD88)

NLR (NOD-like receptor) and Inflammasome
• nucleotide oligomerization domain-containing protein
• Expressed on several cell types : Mucosal epithelial cells,
Phagocytes
• Response to bacterial cell wall peptidoglycans 2 Groups
• NOD1 (CARD4), NOD2 (CARD15) : similarly to TLRs
• NLRP3: Intracellular microbes and danger signals
– Caspase-1
– Inflammasome
Deficiency/defect
• Autoimmune diseases; DM, IBD, MS
• Crystal-induced arthritis

Defective in NOD2 gene
• NOD2 gene polymorphisms increase the risk for an inflammatory disease of the bowel
“ Crohn’s disease”.
• Gain-of-function mutations of NOD2 that cause increased NOD signaling and NF-κB
activation lead to a systemic inflammatory disease called “Blau syndrome”.
• Early onset sarcoidosis
• Triad : granulomatous arthritis ,
uveitis ,
dermatitis

2.RIG-Like Receptors (RLRs)
• Cytosolic sensors of viral RNA that respond to viral nucleic acid by inducing the
production of antiviral type I IFN.
• Recognize ds RNA and RNA-DNA heteroduplexes, (RNA viruses and RNA transcripts
of RNA and DNA viruses).
• RIG-I (retinoic acid–inducible gene 1) >> 5′ triphosphate moiety, which is NOT
present in mammalian host cell.
• MDA5 (melanoma differentiation-associated gene 5)>> long ds RNA
• Binding viral dsRNA, the RLRs are recruited to the outer mitochondrial membrane.
• Formation of filaments by a prion-like mechanism
• Initiates signaling events that lead to phosphorylation and activation of IRF3 and IRF7 → type I IFN

RIG-Like Receptors
(RLRs)
formation of
filament by prion-
like mechanism

• CDSs (Cytosolic DNA sensors) are molecules that detect microbial dsDNA in cytosol
and activate signaling pathways that initiate antimicrobial responses,
including type 1 IFN production and autophagy.
• The STING (stimulator of IFN genes) pathway is major mechanism of dsDNA induced
activation of type 1 IFN responses .
3.Cytosolic DNA Sensors and the STING Pathway

The STING cytosolic DNA
sensing pathway.
- Important mechanism of dsDNA induced
activation of type 1 IFN responses
1
2
3
4
1

• Inflammasomes are multiprotein complexes form in the cytosol
response to cytosolic PAMPs and DAMPs,
• function is to generate active forms of cytokines IL1β and IL18.
• Inflammasomes can form with different sensor protein include NLRB,
NLRC4, and at least six NLRP proteins
• Proteolytically cleaved by the enzyme caspase-1 to become active cytokines
Inflammasome

• After binding of a ligand,
multiple identical NLRP3
proteins interact to form
oligomer
• Each NLRP3 protein in
oligomer binds ASC adaptor
protein
• Triggers conformational
changes of other ASC
molecules in the cytosol by a
prion-like
• The filaments of ASC that can
cluster and recruit inactive
caspase-1
• The recruitment and
consequent clustering of pro-
caspase-1 proteins result in the
generation of active caspase-1.
Inflammasome
Sensors respond to PAMPs, DAMPs,
induce pro IL-1B.
1
Caspase-1 cleaves cytosol
pro–IL-1β , pro IL-18, pro IL-33
→ IL-1β, IL-18, IL-33 (active form)
→ inflammation
2
3

• Associated with infections and cell stress, including microbial products,
environmentally or endogenously derived crystals, and reduction in
cytosolic K+.
• NLRC4 recognizes cytosolic flagellin
• NLRP1 recognizes anthrax lethal toxin.
• NLRP3 senses many DAMPS and PAMPS, including uric acid crystals,
aluminum hydroxide crystals used in vaccine adjuvants, ATP released from
mitochondria, silica, bacterial products, bacterial toxins, bacterial DNA-RNA
hybrids, and influenza virus.
• NLRP12 senses PAMPS from Yersinia species and is required for control of
Yersinia.
Inflammasomes

• Programmed cell death of macrophages and DCs : called pyroptosis.
• Pyroptosis, characterized
swelling of cells, loss of plasma membrane integrity, and
release of mediators including IL1β, IL-18, TNF, IL-6, and IL-8.
• A key feature is caspase-mediated cleavage of a protein called gasdermin D,
which leads to formation of membrane pores.
• The amplification of inflammation provided by pyropotosis enhances
bacterial clearance but also may contribute to septic shock.
Inflammasomes

Gout
• Painful ,Inflammatory condition of the joints caused by deposition of
monosodium urate crystals in joint.
• urate crystals activate the inflammasome
• Treatment : IL-1 antagonists (effectively for severe cases ,resistant to
conventional therapy)
Inflammasome activation of caspase-1

Cryopyrin Associated Periodic Syndromes (CAPS) >> NLRP3 GOF
• Subset of a larger group of periodic fever syndrome
• Fever, rash, joint pain ,eye redness/pain and fatigue
• Dysregulated activation of the inflammasome due to autosomal
gain-of-function mutations of the NLRP3 gene
• Leads to inappropriately excess IL-1 production.
• Treatment : IL-1 antagonists (Anakinra)
Familial Mediterranean Fever (mutation of the MEFV gene which encodes pyrin)
Autoinflammatory syndromes

Characteristics of Immunodeficiency Due to Defective Recognition by
Pattern- Recognition Receptors (PRRs)
Netea MG, new England journal med ,2011 N Engl J Med 2011; 364:60-70

1. C-type lectin receptors for microbial Carbohydrates
• Mannose receptors
• Dectins
• Other dendritic cell carbohydrate receptors include langerin (CD207)
2. Scavenger Receptors
3. Formyl-Peptide Receptors
Other Cell-Associated Pattern Recognition Receptors

• Cellular receptors recognize carbohydrates on the surface of microbes
facilitate the phagocytosis of the microbes → secretion of cytokines
promote inflammation and subsequent adaptive immune responses
• C-type lectins with specificities for different carbohydrates, including
mannose, glucose, N-acetylglucosamine, and β-glucans.
• Found on surfaces of macrophages, DCs, and some tissue cells.
• Other Lectins are soluble proteins in the blood and ECFs → complement
1.Receptors for Carbohydrates ( C-type lectin
receptors)

Mannose receptor (CD206)
• Involved in phagocytosis of microbes
• first step : ingestion microbes by macrophages
• Recognizes certain terminal sugars on microbial surface carbohydrates;
including d-mannose, l-fucose, and N-acetyl-glucosamine
[ These terminal sugars are often present on the surface of microorganisms ]
Receptors for Carbohydrates ( C-type lectin receptors)

Dectins = dendritic cell–associated C-type lectin
• Dectins are expressed on DCs and macrophages play important roles in
antifungal immunity
• Dectin-1 (CD369): binds β-glucan, which is a major cell wall component of
many fungal species→ immunity to various pathogenic fungal species,
including candida, aspergillus, and pneumocystis.
• Dectin-2: recognize high-mannose oligosaccharides on the hyphal form of
some fungi and bacteria
• Tail: ITAM-> signal to NF-kB
• In response to ligand binding to dectin-1, dectin-2→ promote the
development of Th17

• Langerin (CD207): mainly expressed by epidermal Langerhans cells
• DC-SIGN (CD209): expressed on the majority of dendritic cells
associated hepatitis C virus and HIV-1.

• Structurally and functionally diverse collection of cell surface proteins
• Some of these scavenger receptors, including SR-A and CD36, are expressed
on macrophages and mediate the phagocytosis of microorganisms
• CD36 functions as a coreceptor in TLR2/6 recognition and response to
bacteria
• Wide range of molecular structures bind to each scavenger receptor,
including LPS, lipoteichoic acid, nucleic acids, β-glucan, and proteins.
2.Scavenger Receptors

• Formyl peptide receptor-1 (FPR1), expressed on leukocytes, recognizes
bacterial peptides containing N-formylmethionyl residues .
• The bacterial peptide ligands are the most potent known chemoattractant
for leukocytes.
• FPR1 and all other chemoattractant receptors belong to GTP –binding
protein–coupled receptor superfamily that are responsible for the
increased cell motility.
3.Formyl-Peptide Receptors

Turvey SE, Broide D, J Allergy Clinical imm, 2010
Components of Innate immunity
1.Anatomical barrier
- Physical barriers
- Chemical barriers
2.Cellular
- Phagocytic cells
- Dendritic cell
- NK cells, ILC
- Mast cell
3.Soluble proteins
- Complement
- Cytokines, Chemokines
- Antimicrobial peptides (AMPs)

1.Epithelial Barriers
▪ Skin and the mucosal surfaces of the GI, respiratory, and GU tracts.
▪ Loss of the integrity of these epithelial layers by trauma → risk of infection
▪ Tight junctions and outer layer of keratin (block microbial penetration)
▪ Mucins is produced by respiratory, gastrointestinal, and urogenital epithelial
(physically impairs microbial invasion).
▪ Ciliary action in bronchial tree and peristalsis in gut (elimination of microbes)
physical and chemical defenses at epithelial barriers
which block microbial entry.

2 structurally distinct families of antimicrobial peptides are defensins and
cathelicidins.
1. Defensins (α and β)
- produced by epithelial cells of mucosal surfaces ,neutrophils, NK cells and
cytotoxic T cell.
- Direct toxicity to microbes(bacteria, fungi ,enveloped viruses) and activation of cells.
Epithelial Barriers : antimicrobial peptides
2. Cathelicidin
- Produced by neutrophils and barrier epithelial cells in
skin, Gl tract (colon), and respiratory tract,
- direct toxicity and activation cells.
- Can bind and neutralize LPS, the toxic component of the
outer wall of gram-negative bacteria
- e.g. C-terminal fragment (LL-37)

Summary of human antimicrobial peptides
Gallo et al. J Allergy Clin Immunol 2002;110:823-31.

• Atopic dermatitis
• reduction cathelicidin , β- defensins 2,3
• IL-4 and IL-13 production: suppress production of cathelicidin, β- defensins 2,3
• More susceptible to herpes viruses and Staphylococcus aureus
• Vitamin D: promote production of cathelicidin via TLR-2-dependent manner
Clinical implication

• Intraepithelial T lymphocytes are present in the epidermis of the skin
and in mucosal epithelial.
• Several subsets:
• αβ form of TCR : lymphoid tissue, circulation
• γδ form of TCR : epithelial
• Common characteristic of intraepithelial T cells is limited diversity of their
antigen receptors
• Recognize a small number of commonly encountered microbial structures
• Activated NOT by antigen recognition but by cytokines and other molecules
produced by epithelial cells
Intraepithelial T lymphocytes

• Primarily macrophages and neutrophils, are the first line of defense against
microbes that breach epithelial barrier
• The essential role that phagocytes is demonstrated by the high rate of lethal
bacterial and fungal infections in patients with low blood neutrophil counts
• Function – Phagocytosis , Cytokine production
1.Phagocytes (phagocytic cell)
CELLULAR COMPONENTS OF THE INNATE IMMUNE SYSTEM
• Neutrophils:
– Short lifespan (2-3days)
• Monocytes/Macrophages:
– Longer lifespan (several months)
– Main source of inflammatory cytokines: initiates inflammation

1.Phagocytes (phagocytic cell)
Cytokine
production
NETosis (NET formation)
– Another form of programmed cell death
by releasing of decondensed chromatin
bound to cytosolic contents .
• The fibrous structure contains:
– Histone, chromatin and DNA structure
– Antimicrobial substances: neutrophil
elastase, cathepsin G, lactoferrin,
myeloperoxidase

• Dendritic cells (DCs) rapidly and efficiently detect invading microbes because
of their location in tissues
• Expression of numerous pattern recognition receptors for PAMPs and DAMPs
• The plasmacytoid subset of DCs is a major source of the antiviral cytokines,
type I interferons produced in response to viral infections
• Express abundant amounts of the endosomal TLRs (TLRs 3, 7, 8, 9)
• Direct naïve T cell differentiation (adaptive immunity)
2.Dendritic Cells : Antigen presenting cell

• Mast cells are sentinel cells present in the skin, mucosal epithelium, and
connective tissues
• Rapidly secrete proinflammatory cytokines and lipid mediators in response to
infections and other stimuli
• Contain abundant cytoplasmic granules (histamine) filled with various
inflammatory mediators (prostaglandins) and cytokines (such as TNF)
3.Mast cells

• Innate lymphoid cells (ILCs): bone marrow–derived cells with lymphocyte
morphology that serve diverse antimicrobial functions
• Produced cytokines similar to those made by T cells but lacked TCRs
• There are different subsets of ILCs that arise from the same common
lymphoid precursor T cells
4.Innate Lymphoid Cells

Cytokine producing innate
lymphoid cell subsets

• LC1s are likely important for defense against intracellular microbes.
• LC2s are important for defense against parasites, allergic diseases.
• ILC3s are found at mucosal sites and in defense against extracellular fungi
and bacteria, as well as in maintaining the integrity of epithelial barriers.
• Early host defense is that they are always resident in epithelial barrier tissues
Cytokine-Producing Innate Lymphoid Cells (ILCs)

• Important roles in innate immune responses, mainly against viruses and
intracellular bacteria
• 5-15% of the mononuclear cells in blood and spleen.
• Major function is killing infected cells, similar cytotoxic T lymphocytes (CTLs),
also secrete IFN-γ
• Expression of CD56 , CD16 (involved in recognition of antibody-coated cells)
and absence CD3.
5.Natural Killer Cells

• Kill infected cells and to produce IFNγ → activates macrophages to destroy
phagocytosed microbes
• NK cells are activated, granule exocytosis releases these proteins adjacent to
the target cells (Perforin, Granzymes (proteolytic enzymes ).
• Early in the course of a viral infection (few days in CTL)
• Killing infected cells that have escaped by reducing expression of class I MHC
Natural Killer Cells

Functions of NK cells
NK cells recognize ligands on infected cells
Activates the macrophages to kill phagocytosed
microbes.

Functions of NK cells
Inhibitory receptors of NK cells recognize class I MHC molecules
protein tyrosine kinases
(PTKs),
protein tyrosine phosphatases
(PTP).

NK cells induce target cell apoptosis by the release of
toxic granules containing granzymes and perforins :
disrupt cell membranes.
Express apoptosis-inducing FAS ligand (FASLG) &TRAIL
that interact with their counterparts on target cells.
IFN γ augment cytotoxic T lymphocyte
and Th1 immune
Natural killer (NK) cells recognize and target infected or malignant cells in an antigen-independent manner.

Structure and ligands of activating and
inhibitory receptors of NK cells
Activating receptors:ITAMs
Inhibitory receptors:ITIMs
Ab-dependent cell-mediated
cytotoxicity (ADCC)
• CD16 (FcγIII): bind Fc region of Ab
(IgG1,IgG3: produce during
infection) >> cell apoptosis
• Perforin , Granzyme B
NKG2D:
• C-type lectin
• Bind class 1 MHC like protein
(MIC-A, MIC-B) on viral infected cell,
tumor cells
FcγIII

• Cytokines can enhance the functional responses of NK cells.
• The major cytokines of the innate immune system that stimulate NK function
are IL-12, IL-15, IL-18, and type I interferons.
• IL-15 are important growth factors for NK cells
Cytokines & Functional responses of NK cells

• Small populations of lymphocytes express antigen receptors that are
structurally the same as those of T and B cells, but these receptors have
very little diversity.
• T cell : Invariant NK T cells (iNKT), γδ T cells, MAIT cells,
and intraepithelial T cells with αβ TCRs
• B cell : B-1 cells and marginal-zone B cells
6.T and B Lymphocytes with Limited Antigen
Receptor Diversity

Soluble effect
molecules of the
innate immunity

• Recognize microbes and promote innate responses exist in soluble form
in the blood and extracellular fluids.
• 2 major function
• Opsonins:
binding to microbes, enhance the ability of
macrophages and neutrophils to phagocytose microbes
• Promote inflammatory responses : bring more phagocytes to sites of
infections, directly kill microbes
Soluble effect molecules of the innate immunity
The major components:
• Complement system
• Collectins
• Ficolins
• Pentraxins

Pathways of complement activation.
C3 convertase

• Plasma protein prominent members: Short pentraxins, C-reactive protein
(CRP) and serum amyloid P (SAP), and the long pentraxin PTX3.
• All activate complement by binding C1q and
initiating the classical pathway
• Increased levels of CRP are result of increased synthesis
by liver induced the cytokines IL-6 and IL-1
→ “acute phase reactants”
Pentraxins

• Collectin:
• The collectins are a family of trimeric or
hexameric proteins, contains a collagen-like tail
• There are mannose-binding lectin (MBL) and
pulmonary surfactant proteins SP-A and SP-D
• Ficolin:
• The molecular ligands of the ficolins include N-acetylglucosamine
and the lipoteichoic acid component of the cell walls of
gram-positive bacteria
Collectins and Ficolins
Ficolin

Bacterial phospholipids
(phosphorylcholine)
Functions
Opsonization, complement
activation, microbial cell lysis,
chemoattraction, phagocytosis
activation
activation, microbial cell lysis,
chemoattraction, phagocytosis
Opsonization,killing,phagocytosis,
proinflammatory and
Anti-inflammatory mediator release
Microbial mannan
Bacterial cell wall lipids;
viral coat proteins

• The major proinflammatory cytokines
• Recruitment of Leukocytes to infection sites → Activated phagocytes
Inflammatory response
• Innate immune system deals with infections and tissue injury to stimulate
acute inflammation -> accumulation of leukocytes, plasma proteins, and
fluid derived from the blood
• Chronic inflammation : takes over from acute inflammation if the infection is
not eliminated or the tissue injury is prolonged

• Mainly by tissue macrophages and dendritic cells
• Three of the most important proinflammatory cytokines of the innate
immune system are TNF, IL-1 and IL-6
• TNF,IL-17, IL-5, IFN-ɣ -> from both innate and adaptive
The Major Proinflammatory Cytokines

Cytokine of
innate immunity

Dendritic cell

Cytokine of innate immunity
Homologous to IL-2

2.Recruitment of Leukocytes to sites of infection
express E-selectin
secrete chemokines
(CXCL8 and CCL2)

• Neutrophils and macrophages that are recruited into sites of infections
ingest microbes into vesicles by the process of phagocytosis and destroy
these microbes
• Signals from various receptors, including
PRR :such as TLRs
Opsonin receptors : Fc and C3 receptors
Receptors for cytokines :mainly IFN-γ and CD40,
function cooperatively to activate phagocytes to kill ingested microbes.
• Fusion of phagocytic vacuoles (phagosomes)
Ingestion and Killing of Microbes by Activated Phagocytes

Ingestion and Killing of Microbes by
Activated Phagocytes
1
Activated neutrophils and macrophages kill
phagocytosed microbes by the action of microbicidal
molecules in phagolysosomes

• Neutrophils also kill microbes by extruding their DNA and granule contents,
which form extracellular threads on which bacteria and fungi are trapped
and killed.
• The extruded contents, which are called neutrophil extracellular traps (NETs)
• NETs: composed of strands of DNA and histones to and of antimicrobial
granule contents, including lysozyme, elastase, and defensins.
• NET formation leads to neutrophil cell death
NETosis

Functions of
macrophages.
Promote tissue repair and fibrosis

Local and systemic
actions of cytokines in
inflammation.
Septic shock

• The major way by innate immune system blocks viral infections is to induce
the expression of type I interferon → action to inhibit viral replication
• The most important type I interferons in viral defense are IFN-α and IFN-β
• Signaling through the type I interferon receptor → confer on cells a
resistance to viral infection called “an antiviral state”
The Antiviral Response

Biologic action of
type I interferons
paracrine action

Stimulation of adaptive immunity by innate immune responses
Two-signal hypothesis
- Antigen recognition by
lymphocytes provides signal 1
- innate immune responses to
microbes provide signal 2.
- DCs activated by microbes produce cytokines
and costimulators : enhance T cell activation and
differentiation into effector T cells.
- Complement fragments generated by the
alternative pathway : provide second signals for B
cell activation and antibody production.

Innate immune instruction of adaptive immunity

HOMEOSTASIS IN THE INNATE IMMUNE SYSTEM
▪ Innate immune responses are regulated by negative feedback mechanisms
▪ Macrophages have an essential role in maintaining immune homeostasis
▪ Classic activation of macrophages
- Proinflammatory : TNF-α
- Anti-inflammatory mediators : IL-10, TGF-β, and PGE2 (downregulate macrophage and DC functions)
anti-inflammatory mediators
1
2
3
IL-10 : inhibits activation of macrophages and DCs.

1.Which of the following statements is accurate?
a. MyD88/TRAM pathway is required for all TLR signaling.
b. The TRIF/TRAM pathway leads to activation of NF-κB.
c. Inflammasome activation and the generation of mature IL-1B is
elicited by TLR signaling.
d. Viral nucleic acid is recognized by both NLRs and RIG-I.
e. Endocytosis is the primary function of C-type lectin receptors.

2. Which neutrophil granule product exploits a structural
difference in the cellular membrane organization between
bacterial and mammalian cells for its microbicidal activity?
a. Myeloperoxidase
b. Human α-defensins
c. Neutrophil elastase
d. Cathepsin G

3. Which cytokine is released by necrotic epithelial cells but has
also been shown to play a role in restoration of epithelial
integrity and thermogenesis?
a. IL-33
b. IL-25
c. Thymic stromal lymphopoietin (TSLP)
d. IL-8

4. Which is a bacterial metabolic by-product with anti-inflammatory
properties linked to dietary fiber breakdown in the intestine?
a. Long chain fatty acids
b. Butyrate
c. Alpha ketoglutarate
d. Citric acid

Innate immunity

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