*Immunology 2 (lectures 3 and 4) Flashcards
What are the 2 distinct mechanisms of communication in the immune system?
Direct contact (receptor: lingered interactions) Indirect (production and secretion of cytokines)
Do immune cells have receptors or ligands on them?
Receptors
What cells tend to produce and secrete cytokines?
Injured tissue cells
Activated immune cells
What is an autocrine signal?
A signal that acts back on the same cell that produced it
What are the physiological symptoms of acute inflammation? (4)
Rubor
Calor
Tumor
Dolor
What are the 3 phases involved in innate immune cells recognising and responding to pathogens?
Recognition
Activation
Effector
What happens in the recognition phase of innate immune cells recognising and responding to pathogens?
Pathogens express signature molecules not found on human cells called |”pathogen associated molecular patterns” -PAMPS (common to many different types of pathogens)
innate immune cells (and some other cell types) express specific receptors for these PAMPS called “pattern-recognition receptors” (PRRs) - found on cell surface and intracellular (detect extra- and intra- cellular pathogens)
Example of PAMPs and PRRs on gram negative bacteria?
PAMPs = lipopolysaccharide (LPS) PRRs = Toll-like receptor 4 (TLR4) - extracellular
Example of PAMPs and PRRs for fungi?
PAMPs = beta-glucans PRRs = dectin 1 (extracellular)
Example of PAMP and PRR for TB?
PAMP = muramyl dipeptide PRR = NOD2 (intracellular)
Example of PAMP and PRR for viruses?
PAMP = ssRNA PRR = toll-like receptor 7 (intracellular)
What role do macrophages play in the homeostasis of the skin?
Induction of programmed cell death (apoptosis)
Specific recognition and removal of dying cells by phagocytes e.g. macrophages
How are apoptotic cells cleared by tissue-resident macrophages? (5)
Apoptotic cells release “find-me” signals to attract and activate macrophages
Macrophages recognise specific “eat-me” signals expressed on the surface of apoptotic cells
Macrophages rearrange their cytoskeleton to internalise apoptotic cells
Digestion of the ingested “cargo”
Secretion of anti-inflammatory mediators e.g. IL-10
What happens when physical barriers are breached by pathogens?
PAMPs of pathogens are recognised and injured tissue cells release “danger” signals
This activates macrophages, mast cells and NK cells
This causes the pathogens to be killed, infected tissue cells killed, production of inflammatory mediators
What happens when macrophages digest a pathogen compared to apoptotic cell debris?
Pro-inflammatory mediators are released compared to anti-inflammatory mediators
How do macrophages kill pathogens? (2)
What enhances its killing ability?
Phagolysosome (acidification, lysosomal hydrolases)
Production of toxic reactive oxygen and nitrogen species
(killing ability (and other functions) are enhanced by pro-inflammatory cytokines e.g. IFN gamma
How do pro-inflammatory cytokines enhance macrophages pathogen killing? (3)
Produced by NK cell (and some T cells) e.g. IFN gamma
Increased production of toxic reactive oxygen and nitrogen species
Increase microbicidal activity
Boost antigen presentation capability
How do mast cells aid in the killing of pathogens?
They produce inflammatory mediators that enhance killing response
Where do mast cells reside?
In tissues and protect mucosal surfaces (play a key role in defence against parasites)
What happens when a pathogen binds to a PRR on a mast cell?
Degranulation occurs (release of pre-formed pro-inflammatory mediators) Gene expression = production of new pro-inflammatory mediators
What is the purpose of NK cells?
They specifically kill virally infected cells and abnormal cancer cells
How do NK cells recognise cells infect with intracellular pathogens or cancer cells?
If they have an MHC class 1 then the NK cells binds and doesnt attack If there is no MHC class 1 (virus or cancer cell), the NK cell attacks it and releases pro-inflammatory mediators
What 3 cells produce inflammatory mediators as part of the innate immune response?
Macrophages
mast cells
MK cells
What are some examples of inflammatory mediators produced by macrophages, mast cells and NK cells?
NO Prostaglandins/ leukotrienes Histamines Cytokines e.g. TNFalpha, IL-1, IL-6, IFNgamma Chemokines
What systemic effect do cytokines have (IL-1, IL-6, TNFalpha)? (3)
Cause the release of prostaglandins from the hypothalamus causing fever
Cause the release of acute phase response proteins from the liver
Cause creased neutrophil production (leukocytosis) in the bone marrow)
What is the acute phase response?
A group of physiological processes that occur soon after the onset of infection due to the release of a class of proteins whose plasma concentrations increase (positive acute-phase proteins) or decrease (negative acute-phase proteins) in response to inflammation (this is stimulated by IL-2, IL-6 and TNFalpha) causing the alteration in protein synthesis in the liver
What are examples of acute phase proteins? (7)
CRP Serum amyloid protein (SAP) Complement proteins Fibrinogen Haptoglobin Manganese superoxidase dismutase Proteinase inhibitors
What biological role does CRP, SAP and complement proteins have?
Preventing the spread of infection
Diagnostic marker
What role does fibrinogen have?
Coagulation
Wound healing
What role does CRP, haptoglobin, manganese superoxidase dismutase and proteinase inhibitors have?
Preventing systemic inflammation
How many subunits is CRP made up of?
5 identical subunits
What does high levels of CRP mean?
There is inflammation/ infeciton
How does CRP enhance phagocytosis?
CRP opsonises bacteria, facilitating their clearance by phagocytes
What are the 3 purposes of CRP?
Diagnosis
Enhance phagocytosis
Complement system activation
What anti-inflammatory cytokine is produced when apoptotic cells are phagocytes by macrophages?
Anti-inflammatory IL-10
What are the 3 tissue resident innate immune cells that are involved in the early responses to pathogens?
Macrophages
NK cells
Mast cells
What role does macrophages have in the early innate immune reopens to pathogens? (2)
Phagocytosis and pathogen killing
Pro-inflammatory cytokines (TNFalpha, IL-1, IL-6)
What role does NK cells have in the early innate immune response to pathogens?
Release of pro-inflammatory cytokines (IFNgamma) which enhances macrophage killing ability
Specific killing of virally infected tissue cells
What role do mast cells have in the early innate immune response to pathogens?
Release of pro-inflammatory cytokines
What effects do nitric oxide, prostaglandins, leukotrienes and histamines have? (4)
Cause vasodilation
Increase vascular permeability
Cause smooth muscle contraction
Cause pain
What local effects do cytokines released from macrophages, mast cells and NK cells have?
Increase vascular permeability
Endothelial cell activation
What is released from macrophages that causes increased vascular permeability? (3)
TNF alpha
IL-1
Nitric oxide
What is released from mast cells that causes increased vascular permeability? (4)
Histamine
TNF alpha
Leukotrienes
Prostaglandins
What is released from macrophages that causes vasodilation?
TNF alpha
What is released from mast cells which causes vasodilation?
Histamine
What is released from macrophages that causes endothelial cell activation (expression of cell adhesion molecules)? (2)
TNFalpha
IL-1
What cell adhesion molecules are express on the epithelium?
Selectins (receptors)
ICAM-1, VCAM-1 (ligands)
What is released from mast cells that causes endothelial cell activation in the vasculature?
Histamine
How do neutrophils get out of the vasculature during inflammation and to the damaged cells?
What other cells do this? (5)
Transendothelial migration and chemotaxis of neutrophils
Monocytes
NK cells
Basophils
Eosinophils
T cells (during the adaptive immune response)
What releases chemokines causing chemotaxis of neutrophils?
Macrophages
Mast cells
When do neutrophils stop rolling along the endothelial wall?
When they come into contact with ICAM or VCAM
What on the neutrophil allows it to bind to selections and ICAM/ VCAM?
Integrins
What is the name for the movement or passage of blood cells, especially white blood cells, through intact capillary walls into surrounding body tissue?
Diapedesis
What is the purpose of neutrophils once inside infected tissue?
To find and kill pathogens
What is another name for neutrophils?
Polymorphonuclear cells
What are neutrophils?
Phagocytic cells that circulate in the blood and are rapidly recruited into inflammatory sites by cytokines and other pro-inflammatory mediators
What are the functions of neutrophils? (2)
To kill extracellular pathogens
To produce pro-inflammatory cytokines e.g. TNFalpa
Characteristic features of neutrophils?
Intracellular granules
Multi-lobed nucleus
What are the 3 possible neutrophil killing mechanisms?
Phagocytosis
Degranulation
NETs
What are the 2 possible killing mechanisms that neutrophils use once they have encapsulated the pathogens in phagosomes?
Anti-microbial proteins
NADPH oxidase-dependent mechanisms
What are examples of anti-microbial proteins in the granules of neutrophils that are used i phagocytosis? (4)
Cathepsins
Defensins
Lactoferrin
Lysozyme
What is another name for NADPH oxygenate-dependant killing mechanisms?
The respiratory burst
How does the respiratory burst kill pathogens?
Through the production of toxic reactive oxygen species e.g. superoxide, hydrogen peroxide, NO
What type of killing mechanisms do neutrophils use to kill extracellular pathogens (bacteria and fungi)?
Degranulation - causes tissue damage and systemic inflammation
What does NETs stand for?
neutrophil extracellular traps
How do NETs work?
They are released by activated neutrophils into the extracellular environment and immobolise pathogens (prevents them from spreading, facilitates their phagocytosis)
Are neutrophils long or short lived?
Short (die by apoptosis and are phagocytes by macrophages)
What is pus made up from?
Neutrophils, NETs, dead bacteria, cellular debris
Why is pus fellow/ green?
Lactoferrin binds iron, iron is green
What pathological consequences does excess amounts of TNF alpha have?
Ailments suc as IBD, psoriasis, autoimmune conditions, rheumatoid arthritis, asthma and cancer are linked to too much of this
As well as leukocytes, what else leaks out of the vasculature during inflammation?
Complement proteins (kinins, coagulation factors, fibrinolytic system)
How many complement proteins are there?
Where are they produced?
Where are they found?
Approx. 30
Liver
Circulate in blood and are recruited into infected and inflamed tissues
What activates complement proteins?
Pathogens
What is an acute acute phase protein that is synthesised during early events of inflammation?
What is it cleaved to?
What pathways activate the cleaving of this?
C3 C3b and C3a Classical pathway Mannose-binding lectin pathway Alternative pathway
What does activation of downstream complement proteins cause?
Pathogen killing
Pathogen opsonisation
Leukocyte recruitment and inflammation
What is the mannose-binding lectin pathway of complement activation?
Mannose-binding lectin (an acute phase protein) binds to mannose on bacterium
This causes C4b joined to C2a to convert C3 to C3a and C3b stimulating downstream events
What is the alternative pathway of complement activation?
C3 spontaneously breaks down to C3a and C3b
C3b is then either rapidly degraded or binds to bacterium via ligands
Factor B then binds to the C3b attached to the bacterium which then causes factor D to join on too
This then causes more C3 to breakdown in an amplification loop leading to downstream events
What does C3b do?
Converts C5 to C5b and C5a (C5a causes killing, etc. whist C5b assembles on the surface of the pathogen with C6, C7, C8 and C9 to form the membrane attack complex)
This causes osmotic cell lysis
What complement protein acts as an opsonin?
C3b
What are C3a and C5a also known as?
Why?
How do they do this?
Anaphylatoxins
Act directly on blood vessels causing increased permeability
Act on mast cells causing release of pro-inflammatory mediators and chemokines
What type of complement proteins are active?
Cleaved complement proteins
Half life of cleaved complement proteins?
Very short
What do dendritic cells act as?
The bridge between the innate and adaptive immune systems?
What do dendritic cells do?
Present in peripheral tissues in an immature state
Phagocytose antigens, cell debris, particles, mature and migrate into secondary lymphoid tissues where they play a key role in antigen presentation
