32. Innate immune system Flashcards
CELLULAR MEDIATORS in innate immune system
Macrophages
Neutrophils
Dendritic cells
Mast cells
(have Epithelium barrier)
SOLUBLE MEDIATORS / extra-cellular mediators in innate immune system
Cytokines
Complement
Acute phase protein
Antimicrobial factors
(have mucus antimicrobial factors barrier)
major INTERFACES between the body and external environment include… (4)
- SKIN
- GASTROINTESTINAL TRACT
- RESPIRATORY TRACT
- GENITOURINARY TRACT
Microbes come into contact with INTERFACES via… (4)
- PHYSICAL CONTACT
- INGESTION
- INHALATION
- SEXUAL ACTIVITY
what forms a MECHANICAL BARRIER against Microbes
continuous EPITHELIA
-consisting of TIGHTLY ADHERENT CELLS
SKIN is made of
STATIFIED SQUAMOUS EPITHELIUM
(several stacked layers of cells)
How do OUTERMOST LAYERS of SKIN act as a BARRIER against MICROBES
- DRY and INHOSPITABLE to microbes
- regular sloughing (SHEDDING) helps reduce microbial load
how does SKIN act as a BARRIER to MICROBES (5)
- WATER-RESISTANT (lipids in inner-layer provide additional waterproof barrier)
- SWEAT: HIGH SALT content and LOW PH INHIBITS BACTERIAL GROWTH
- contains ANTI-MICROBIAL PROTEINS
- outermost layer DRY and INHOSPITABLE
- regular SHEDDING helps reduce microbe loading
keratinocytes in skin produce keratin which protects epithelial cells from..
damage, stress
MUCOUS MEMBRANES of EPITHELIAL surfaces consist of…
one or more LAYERS of EPITHELIAL CELLS OVERLYING a LOOSE LAYER of CONNECTIVE TISSUE
where are MUCOUS MEMBRANES found (3)
- GASTROINTENSTINAL (GI) TRACT
- RESPIRATORY TRACT
- UROGENITAL TRACT
what does MUCUS do in mucous membranes
ADHESIVE BARRIER that TRAPS PATHOGENS
- produced by Goblet cells in epithelium or specialised Submucosal Glands
in RESPIRATORY tract, what happens to PATHOGENS TRAPPED in MUCUS
Expelled by movement of CILLIA
How does GI TRACT act as a BARRIER against PATHOGENS
- LOW PH of GASTRIC SECRETIONS
INHIBIT BACTERIAL GROWTH - PERISTALSIS MOVES PATHOGENS
through GI tract - NORMAL FLORA (microbiota) may
OUTCOMPETE pathogens.
how do NORMAL FLORA of GI TRACT act against PATHOGENS
- COMPETE with pathogens (outcompete)
compete for NUTRIENTS or physical SPACES that would otherwise be occupied by pathogens,
strengthen epithelial barriers,
PRODUCE ANTI-MICROBIAL FACTORS of their own.
- stimulate DEVELOPMENT of the IMMUNE SYSTEM.
EPITHELIAL CELLS secrete soluble mediators that contribute to HOST DEFENCE: (3)
- produce ANTIMICROBIAL substances
- release CHEMOKINES
chemotactic signals to RECRUIT IMMUNE CELLS - release CYTOKINES
to COMMUNICATE with IMMUNE CELLS
examples of ANTIMICROBIAL PROTEINS produced by EPITHELIAL CELLS
(enzymes)
- Lysozyme
- Secretory
Phospholipase A2
(Antimicrobial Peptides)
- Defensins
- Cathelicidins
- Histatins
besides epithelial cells what also PRODUCE ANTIMICROBIAL PROTEINS
PHAGOCYTIC CELLS
STEM cells in the GUT are responsible for…
protected by…
the ability of the epithelium to RENEW and REPAIR itself
- PROTECTED by PANETH CELLS
what are OPSONINS
the PROTEINS that decorate the SURFACE of the PATHOGEN
PHAGOCYTES have SPECIFIC RECEPTORS for the OPSONINS,
allowing them to ATTACH to the
pathogen, and ENGULF and DESTROY it
what is OPSONISATION
COATING of an infectious agent with HOST PROTEIN which makes
it more easily RECOGNISED by PHAGOCYTES
what are CHEMOKINES
FAMILY of CYTOKINES
- DIRECT the MIGRATION of IMMUNE CELLS (CHEMOTAXIS)
how do CHEMOKINES DIRECT the MIGRATION of IMMUNE CELLS
UP a CONCENTRATION GRADIENT
TOWARDS the SOURCE of the chemokine
- CHEMOTAXIS
The ABILITY of a cell to RESPOND to a particular CHEMOKINE GRADIENT depends on…
the EXPRESSION of CHEMOKINE RECEPTORS on the cell surface.
where are ACUTE PHASE PROTEINS produced..
LIVER
ACUTE PHASE PROTEINS are produced in response to…
INFLAMMATION
release of ACUTE PHASE PROTEINS from liver is stimulated by…
CYTOKINES (IL-6) from sentinel cells
(which are activated in response to PAMPS/DAMPS)
FUNCTIONS of ACUTE PHASE PROTEINS: (4)
- RECRUITMENT of immune cells
- Pattern recognition (bind to bacterial and fungal polysaccharides and
glycolipids) and activation of COMPLEMENT CASCADE - Binding to pathogens and enhancing UPTAKE by PHAGOCYTIC cells =
OPSONISATION - BINDING to, and KILLING pathogens.
what are COLLECTINS
- ACUTE PHASE PROTEINS
- Molecules that ACT AS Soluble PATTERN RECOGNITION RECEPTORS
- BIND OLIGOSACCHARIDES or LIPIDS on MICROBIAL SURFACES (PAMPs)
what are EXTRA-CELLULAR INNATE MEDIATORS and their functions
- A wide variety of soluble mediators
- Some are constitutive, some inducible: e.g. acute phase proteins
- Bind to pathogens and BLOCK their CELLULAR RECEPTORS
- Bind to pathogens and KILL them directly
- Bind to pathogens and ENHANCE their UPTAKE by phagocytic cells
(opsonisation) - RECRUIT immune cells (CHEMOTAXIS)
- ACTIVATE immune cells and SYSTEMIC INFLAMMATORY RESPONSE
(cytokines)
what is the COMPLEMENT SYSTEM
Family of abundant SERUM PROTEINS
- involved in DETECTION and DESTRUCTION of pathogens
C1-C9
(can be considered as an extracellular innate mediator)
3 ways the COMPLEMENT SYSTEM can be ACTIVATED
- CLASSICAL
via ANITBODY - ALTERNATIVE
via direct contact with PATHOGEN - LECTIN
via CARBOHYDRATE BINDING MEDIATORS
each COMPLEMENT PATHWAY starts with…
RECOGNITION of the surface of a MICROBE
every COMPLEMENT PATHWAY results in…
CLEAVAGE OF C3
into C3b and C3a
what is C3a
an ANAPHLATOXIN
increases VASODILATION and VASCULAR PERMEABILITY
plays a role in RECRUITMENT of INNATE immune cells
(smaller)
what is C3b
OPSONIN
enhances DEGRADATION of pathogens by PHAGOCYTES
CLEAVAGE of C3 in complement system relies on the GENERATION of…
C3 CONVERTASE
in COMPLEMENT activation, the COVALENT BINDING of C3b to other molecules results in the formation of…
C5 CONVERTASE
-generates C5a & C5b
C5a acts as… (2)
ANAPHYLATOXIN &
CHEMOATTRACTANT
C5b becomes part of/forms the…
MEMBRANE ATTACK COMPLEX
(binds with C6,C7,C8,parts C9)
which results in CELL LYSIS
(make ion channels that allow water movement but not protein)
ACTIVATION of COMPLEMENT is referred to as..
the COMPLEMENT CASCADE
examples of Pathogen-associated Molecular Patterns (PAMPs)
(molecular signatures shared across groups of bacteria, fungi or viruses, but not commonly found on host cells)
Flagellin
LPS
Peptidoglycan
ds RNA (viral)
ss RNA (viral)
Unmethylated CpG
DNA (bacterial)
examples of Damage (danger)-associated Molecular Patterns
(DAMPs)
(host proteins released from cells or generated from tissues following injury)
Extracellular DAMPs:
Hyaluronic Acid
Heparan sulfate
Collagen-derived peptides
Fibrinogen
Intracellular DAMPs:
HMGB1
Uric Acid
Chromatin
Heat-shock proteins
N-formyl peptides
what is HMGB1 - High mobility group box 1 protein
INTRACELLULAR DAMP
Involved in CHROMATIN REMODELLING and REGULATION of TRANSCRIPTION
Released into extracellular space by NECROTIC cells,
or secreted by immune cells in INFLAMMATION
Pattern Recognition Receptor Families:
- TOLL-LIKE receptors (TLR)
- NOD-LIKE receptors (NLR)
- C-TYPE LECTIN receptors (CLR)
- RETANOIC ACID-INDUCIBLE GENE-1 LIKE RECEPTORS (RLR)
TOLL-LIKE receptors (TLR)
location?
ligands?
ligand sources?
recognise..
PLASMA MEMBRANE (Including vesicular membranes/endosomal membranes)
Ligands: LPS, DNA, RNA, peptidoglycan, flagellin, DAMPs
Ligand Sources: Bacteria, viruses, parasites, self
recognise NUCLEIC ACIDS of ingested microbes
NOD-LIKE receptors (NLR)
location?
ligands?
ligand sources?
recognise..
CYTOPLASM
LIgands: DAMPs, muramyldipeptides (fragments of
peptidoglycan)
Ligands Source: Self, bacteria
recognise BACTERIAL CELL WALL LIPIDS
and PRODUCTS of DAMAGED HOST CELLS
C-TYPE LECTIN receptors (CLR)
location?
ligands?
ligand sources?
recognise..
PLASMA MEMBRANE
Ligands: Beta-glucans
Ligands Source: Fungi
recognise MICROBIAL POLYSACCHARIDE
RETANOIC ACID-INDUCIBLE GENE-1 LIKE RECEPTORS (RLR)
location?
ligands?
ligand sources?
recognise..
CYTOPLASM
Ligands: double-stranded RNA viruses
Ligand Source: RNA viruses
recognise VIRAL RNA
TOLL-LIKE RECEPTOR family has how many members…
9
TOLL-LIKE RECEPTORS are specific to either…
GRAM-POSITIVE BACTERIA
GRAM-NEAGATIVE BACTERIA
(TLR-1, TLR-4)
or viruses (3,7,8)
where are TLR-1, TLR-2, TLR-3, TLR-4, TLR-5, TLR-6 found
CELL SURFACE
where are TLR-3, TLR-7, TLR-8,TLR-9 found
ENDOSOME
why do we have so many different PRRs
- We are up against a vast range of different bacterial, viral and fungal pathogens with a great VARIETY of antigenic EPITOPES
- Many pathogens can AVOID RECOGNITION by the host immune response hence we need several BACKUP MECHANISMS should one or more be evaded
DENDRITIC CELLS express which TLR
TLR-4
what happens when TLR-4 is ACTIVATED on DENDRITIC CELLS
- to enhance ADAPTIVE immune response
(by PAMPs/DAMPs)
- Induces production of PROINFLAMMATORY CYTOKINES
- Induces UPREGULATION of costimulatory molecules
CD80/CD86 required for T-CELL ACTIVATION - Leads to UPREGULATION of CLASS II MHC
Recruitment of neutrophils to the site of infection:
At the site of infection, cells that have encountered microbes can produce…
CYTOKINES eg. TNF alpha, Interleukin-1
Recruitment of neutrophils to the site of infection:
Cytokines produced by cells at site of infection ACTIVATE ENDOTHELIAL CELLS to EXPRESS…
- SELECTINS
- INTEGRIN RECEPTORS
- SECRETE CHEMOKINES
Recruitment of neutrophils to the site of infection:
SELECTINS, INTEGRIN LIGANDS and CHEMOKINES produced by endothelial cells causes…
- selectins activate: ROLLING of neutrophils from blood
- integrins activate: stable ADHESION of neutrophils to venule (integrin activation by chemokines)
- chemokines activate: neutrophil MIGRATION THROUGH ENDOTHELIUM to site of infection
what is the result of Recruitment of neutrophils to the site of infection
PHAGOCYTOSIS and destruction of pathogen
activated when cell surface receptors bind to opsonins of the pathogen
when PHAGOSOME releases its contents in the PHAGOLYSOSOME what happens
OXIDATIVE BURST
- generating oxidative species
what does the PHAGOSOME FUSE with
- NEUTROPHIL GRANULES
- LYSOSOMES
phagolysosome
what leads to pathogen destruction in phagosome
combined activities of REACTIVE OXYGEN SPECIES and GRANULE CONTENTS (nuclear proteases)
6 steps of PHAGOCYTOSIS
- Phagocytosis is initiated when CELL SURFACE RECEPTORS BIND to components of the PATHOGEN surface, or OPSONINS (e.g. antibodies, complement proteins).
- The pathogen is engulfed: SURROUNDED BY PLASMA MEMBRANE , and
internalised into a LARGE VESICLE (PHAGOSOME) - The phagosome FUSES with NEUTROPHIL GRANULES and
LYSOSOMES. The CONTENTS are DISCHARGED into the PHAGOSOME. - An OXIDATIVE BURST is initiated in the phagosome, generating
REACTIVE OXYGEN SPECIES (ROS) - Combined activities of REACTIVE OXYGEN SPECIES and GRANULE CONTENTS (neutral proteases) lead to pathogen DESTRUCTION
- EXOCYTOSIS of SOLUBLE DEBRIS
NEUTROPHIL PRODUCTS and their EFFECTS
GELATINASE - Degradation of host tissue
LACTOFERRIN - Binds to IRON (competes with pathogens for iron so limited availability for pathogens)
ELASTASE - Degradation of host tissue/microbes
COLLAGENASE - Degradation of host tissues
MYELOPEROXIDASE - Respiratory Burst
LYSOZYME - Kills Bacteria
DEFENSINS - Kills Bacteria
Bacterial Permeability Inducing Factor - Kills Bacteria
NEUTROPHILS also undergo…
NETOSIS
for NETosis NEUTROPHILS release…
NEUTROPHIL EXTRACELLULAR TRAPS (NETs)
- web of fibres composed of chromatin and anti-microbial factors
what do NETs do in NETosis of NEUTROPHILS
TRAP and KILL extracellular MICROBES
what are required for the formation of NETs in NETosis
reactive oxygen species (ROS)
activation of PROTEASES
first line of defence cells:
neutrophils
INNATE LYMPHOID CELLS are considered to be the INNATE COUNTERPARTS (equivalents) of…
T CELLS
( do NOT express T cell receptors TCRS)
INNATE LYMPHOID CELLS are … resident
TISSUE RESIDENT
INNATE LYMPHOID CELLS stimulated by
CYTOKINES at site of infection / damaged epithelia
INNATE LYMPHOID CELLS RAPIDLY secrete..
CYTOKINES
5 subsets of INNATE LYMPHOID CELLS :
ILC1
ILC2
ILC3
NK CELLS (natural killer)
Lti CELLS
INNATE LYMPHOID CELLS are involved in…
the protective immune response to pathogenic
microbes
/ tissue homeostasis and tissue repair.
ILC DYSFUNCTION is thought to play a role in asthma, autoimmune disease
NATURAL KILLER (NK) CELLS are …. derived LYMPHOCYTES
BONE-MARROW DERIVED lymphcytes
making up around 10% of peripheral lymphocytes
NK cells are bone-marrow derived LYMPHOCYTES lacking…
antigen-specific receptors of T or B cells
NK CELLS are important in PROTECTION against..
VIRAL INFECTION or CANCEROUS CELLS
RECOGNISE and KILL STRESSED cells / INFECTED cells
- release GRANULES that kill target cell
specialised NK cells found in placenta play an important role in pregnancy
NK cells respond to which CYTOKINE
IL-12 (interleukin-12)
- stimulates release of Interferon Gamma
- activates macrophage to kill microbe
NK CELLS express both receptors:
ACTIVATING RECEPTOR
& INHIBITORY RECEPTOR
NK CELLS:
what do HEALTHY HOST CELLS express..
CLASS I MHC MOLECULES
NK CELLS:
CLASS I MHC molecules on HEALTHY HOST CELL is recognised by…
INHIBITORY RECEPTOR of NK CELLS
- inhibitory receptor not engaged
how do we get ACTIVATION of NK CELLS
NO MHC CLASS I on the cell
( not healthy cell - virus inhibits CLASS I expression)
so INHIBITORY RECEPTOR NOT ENGAGED
only ACTIVATING RECEPTOR is ENGAGED
recognitional of microbial components by PRR leads to..
MATURATION of DENDRITIC CELLS
- activates ADAPTIVE immune system
