Immunity To Infection Flashcards
What are commensals?
A micro organism that lives continuously in the body without causing disease
When do opportunistic pathogens cause disease
Only when host defence is compromised
What percentage of human genes are involved in defence
10%
Do innate immunity responses vary with the type of micro organism
Yes
The nature of pathogen is recognised and this information is passed on to the adaptive system
Does the adaptive immune system use the innate immune system
Adaptive responses co-opt many of the effective mechanisms of the innate system in a highly specific way to deal with infection
What kind of response is inflammation
What is its purpose
A stereotypic response to tissue injury, which can be sterile
To eliminate the initial cause of cell injury, remove damage/necrotic tissue resulting from injury or the subsequent immune response and to initiate repair of the damaged tissue
How is localised acute inflammation classically recognised
What causes each
Calour (heat) - increases blood flow
Dolor (pain) - stimulation of nerve endings
Rubor (redness) - increased circulation/ vasodilation
Tumor (swelling) - increased fluid in tissues
What are the two important features of epithelial barriers in the immune system
Physical
Secretions
What are the three key components of the immune system
Epithelial barriers
Cellular barriers
Soluble components
Describe the immune function of the physical epithelial barrier
TEpithelial barriers separate the host tissue from external environment
Tight junctions between squamous epithelial cells of the skin and mucosal glandular epithelium of the GI and respiratory tract prevent access to tissues
Describe the immune function of secretions from epithelial barriers (4)
Mucus covers all glandular surface
Stomach acid
Antimicrobial peptides which damage microbial membranes
Enzymes in tears and saliva (lysozyme,) or stomach (pepsin)
Where are white blood cells generated in adults
In the bone marrow by a process called haematopoiesis
What gives rise to B, T and Natural Killer cells
The lymphoid lineage
What does the common myeloid progenitor give rise to (6)
The 3 granulocytes
Mast cells
Circulating monocytes
Dendritic cells
What are the granulocytes
Neutrophil
Basophil
Eosinophil
Which is the most abundant white blood cell
Neutrophil
Where do neutrophils mobilise to
What guides neutrophils
Sites of infection
C5a and fMLF
What is the life span of a neutrophil
Very short lived
They mobilise to the site of infection, phagocytose the microbe and then die
What happens to neutrophils after death
They degranulate, releasing antibacterial proteins into the ECF
What is a NET and how is it made
Neutrophil extracellular trap
They trap microbes (PUS)
made when neutrophils extrude their DNA
What do macrophages do
They are large phagocytic cells that recognise and engulf microbes and dispose of cell debris
What are the two effector sunsets of macrophages
M1 and M2
What do M1 macrophages do
Secrete cytokines and pro inflammatory mediators that stimulate the acute inflammatory response
How do M2 macrophages work
AKA alternatively activated macrophages
They are associated with tissue repair and parasite killing and explosion
What do mast cells contain
What is their overall function
Pre-formed mediators of inflammation such as histamine
To rapidly induce inflammation
How long do mast cells take to degranulate once activated
What causes mast cell degranulation?
Only Seconds
Allergens (IgE)
PAMPs and DAMPS
Complement components (C3a, C5a)
Substance P (neurogenic inflammation)
Where do both mast cells and macrophages reside
Beneath epithelial surfaces where they function as sentinel cells sensing tissue damage
Give a brief description of the function of eosinophils and basophils
Non-phagocytic granulocytes providing defence against hemliths, worms and other parasites
What do you dendritic cells function as
A bridge between innate and adaptive systems
They Recognise pathogen is at the site of infection in the periphery and carry a record of the encounter to the draining lymph-node’s to initiate the adaptive response
What are the three major players in the innate system
NK cells
Phagocytes
Complement
What do natural killer cells do
They moved to circulate in the blood in a partially activated state ready to respond immediately
They move into infected tissue and proliferate
What are NK cells v important for
are very important in viral infections where they kill infected cells and maintain/increase the state of the information of infected tissue
What are the two broad ways NK cells recognise infection
Missing self (loss of molecules that normal cells express)
Induced self (Expression of self molecules that are induced in stress cells)
What does NK cell response depend on
The balance of signalling derived from activating and inhibitory responses
Which NK receptors dominate in healthy cells
Inhibitory receptors
Where does a major inhibitory signal come from on healthy cells
Recognition of Major Histocompatibility Complex (MHC) class 1 molecules
How do MHC Class 1 molecules work
They present peptide fragments, derived from cytosolic pathogens (e.g. viruses) to T cells, signalling the virus-infected cells should be killed
How have viruses evolved mechanisms to escape T-cells
How do we combat this
They have removed MHC class 1 molecules so fragments from the virus can not be presented to the T cells
NK cells can recognise a lack of MHC as “missing self” and killing is activated
What is induced self
When cells are infected/stressed, they respond by expressing cell-surface ligands for NK activating receptors, pushing the signalling balance towards activation
What do they cytokines (type 1 IFNs) produced by viruses cause in the host’s immune system
Induced resistance in surrounding cells (anti-viral state)
Increase in expression of ligands recognised by indicate receptors
Activate NK cells to kill
Which cytokines do local macrophages produce
What do these cytokines do
CXCL8
IL-12
They recruit and activate NK cells and cause their proliferation
Do NK cells produce cytokines
What do these do
Yes (IFNγ)
Activate macrophages and up regulate killing capacity
3 effector functions of NK cells
1) release perforin
2) ADCC
3) macrophage activation
What does perforin do
Released by NK cells and Forms pores in the cell membrane allowing apoptotic granzymes into the cell
Describe ADCC
Antibody Dependant Cell Cytotoxicity
NK cells have receptors for the Fc portion of antibodies and will kill cells that are bound by that antibody
Signalling through this activating Fc receptor is very strong and is enough to activate Nk cell by itself
Innate Lymphoid Cells are similar to which group of T cells
CD8 cytotoxic T lymphocytes (CTLs)
What do ICLs do
The ILCs help orchestrate the early innate response
They derive from the common lymphoid progenitor but do not possess B or T cell antigen receptors
They do not directly control infection (like NK cells) but instead function to amplify signals produced during innate recognition
What are the three major types of ILCs
ILC1s
ILC2s
ILC3s
What do ILC1s
They protect against viruses and intracellular pathogen is
They help activate M1 macrophage responses and may assist TH1 polarisation
What do ILC2s do
Assist mucosal and barrier immunity against parasites
They indirectly help TH2 and M2 macrophage polarisation
What do ILC3s do
Protect against extracellular bacteria and fungi
What are cytokines
What is their life span
Small protein messengers which regulate immune responses
Short lived
True or false
Cytokine action is autocrine
True but it can also be paracrine and endocrine-like
Give for traits of cytokines
Redundancy
Pleiotropism
Antagonism
Synergy
What is redundancy in cytokines
What about antagonism
Pleiotropism
Several different cytokines have the same function
1 cytokine May block the action of another
A single cytokine may have a variety of different effects
Name a central communication system for the immune system
Name a type of molecule that works through this pathway
Jak/ STAT signal transduction pathway
Cytokines
What was IL-8 renamed
It is a member of which subgroup of cytokines? What is this subgroup involved in
CXCL8
Chemokines
Chemotaxis
What are the 5 soluble components of the innate system
Cytokines
Histamine
Acute phase proteins
Arachidonic acid metabolites
Soluble inter-related plasma protein systems
What is histamine generated from
Where is it stored
Histidine
In granules in mast cells, basophils and eosinophils
What does histamine do
Acts on local blood vessels causing immediate capillary vasodilation
What does IL-6 do
Stimulates hepatocytes to release acute phase proteins
What do acute phase proteins include
C-reactive protein (opsonin and complement activation) and fibrinogen
What is fibrinogen converted to
How does that help with immunity
Insoluble fibrin strands
This can entrap bacteria limiting growth and dissemination and support the recruitment and activation of host cells, facilitating elimination of infecting microbes
What are prostaglandins and leukotrienes examples of
Potent inflammatory mediators generated after tissue damage
What are arachidonic acid metabolites derived from
Cell membrane phospholipid’s
Where are many of the components of the soluble inter-related plasma protein systems formed
How are these systems activated
Liver
Name 4 of the soluble interrelated plasma protein systems
Clotting system
Kinin system
Fibrinolytics system
Complement system
What does the clotting system involve
Thrombin which converts fibrinogens into fibrin and fibrinopeptides which form clots to limit the spread of infection
Other than fibrinogen, what does thrombin cleave
Both C3 and C5
What does tissue damage resulting in the kinin system
Which complement components does this system interact with
Generation of bradykinin which increases vascular permeability, vasodilation, pain, smooth muscle contraction
Activates C3 and C5
What does tissue damage resulting in the fibrinolytic system
Which complement components does this system interact with
Generation of plasmin, which degrades fibrin into products that recruit neutrophils
Plasmin activates complement C3
Name 3 results of the complement system
Opsonisation
Membrane attack complex formation
Generation of anaphylatoxins (C3a, C4a, and C5a)
What do fibrinopeptides induce
Vascular permeability
Neutrophil chemotaxis
Define the acute inflammatory response
a stereotypical response to tissue damage or infection
How long does the immediate immune response to infection last
What are the 4 key parts of this stage
Immediate innate response: 0 - 4hr
complement
Phagocytes
Natural antibodies
Antimicrobial peptides
Describe the complement response to the primary infection (4)
activation of the alternative (and lectin) pathway rapidly opsonises microbes for phagocytosis.
If natural or specific antibody is present the classical pathway can be used.
Formation of the membrane attack complex (MAC) can destroy pathogens directly.
Complement activation rapidly activates the acute inflammatory response.
Describe the phagocytes’ role in the immediate innate response (4)
Tissues and mucous membranes contain large numbers of resident macrophages.
These are immediately available to phagocytose pathogens.
They recognise pathogens via an array of complement, scavenger and other
receptors that induce activation and phagocytosis.
Ultimately phagocytes will kill most bacteria.
What is the main natural Ab implicated in the immediate innate response to infection
What is it produced by
Is it selected?
IgM (reactive against pathogens without prior antigen exposure)
B-1 cells
Possibly selected by self-antigen but is reactive against antigens present on a range of viral, bacterial, fungal and parasitic pathogens
What are defensins
What do they do
A major group of antimicrobial peptides in humans
disrupt membranes and are effective against Gram-positive and negative bacteria, fungi, parasites and enveloped viruses
What produces defensins (5)
epithelial cells in skin, respiratory and urogenital tracts (β-defensins) and by Paneth cells
in the small intestine (α-defensins)
neutrophils
What happens if an infection is not cleared after 4 hours by the immediate innate response
the induced innate immune response begins - this lasts for up to 4 days
What are macrophages essential for in the induced innate response to infection
recruitment of additional effector cells/molecules;
They possess an array of PRRs that once activated signal production of the proinflammatory cytokines IL-1, IL-6, IL-12 and TNF-α and the chemokine CXCL8.
Give 6 things that TNF-α does in the induced innate response to infection
induces adhesion molecule expression on vascular endothelium (neutrophil recruitment)
- increases vascular permeability (inflammatory exudate)
- triggers platelet activation and blood clotting
- stimulates dendritic cell maturation and migration to lymph nodes
- stimulates the acute phase response (in combination with IL-1 and IL-6)
- primes newly recruited neutrophils
When are neutrophils recruited to the site of infection in the induced innate response
What is their role
within 6-12 hours
phagocytosis
activation also releases ROS and catabolic enzymes
What do the ROS and catabolic enzymes released from neutrophils in the induced innate response to infection do
inactivate micro-organisms but can also damage normal tissue (bystander effect)
Are monocytes recruited before or after neutrophils in the induced innate response to infection
What do they do when they reach the site of infection
recruited later
mature into macrophages which will phagocytose microbes and cellular debris (janitorial role)
What are RLRs
What do they do
RIG-I-like
receptors
detect the presence of viral nucleic acid in the cytoplasm of infected cells and induce expression of type 1 interferons (IFN-α and IFN-β).
What do interferons do after being released from RLRs in the induced innate response to a viral infection (3)
induce an antiviral state in surrounding cells by interfering with virus replication (e.g. PKR, OAS and Mx).
Interferons also work indirectly by activating NK cells
IFN-γ plays a major
role in macrophage activation.
Where are NK cells present in the body
present in most tissues and abundant in blood (5-25% of lymphocytes).
What do NK cells do in the induced innate response to infection
kill infected host cells and secrete cytokines that act mainly on macrophages to upregulate phagocytosis and inflammatory cytokine expression
What activates NK cells at the site of infection
What does this do
Which cells do NK cells interact with after activation (2)
IL-12
induce proliferation
macrophages (work in partnership and activate each other)
DCs (may signal the need for initiation of an adaptive immune response)
Where are ILCs present
in barrier tissues where they respond rapidly to pathogens to eliminate or hinder their spread.
How do ILCs and T cells interact
What is the aim
The major sunsets of ILCs and CD4 T cells (ILC1/TH1, ILC2/TH2 and ILC3/TH17) work cooperatively.
coordinate adaptive responses with different arms of the myelomonocytic pathway to generate responses appropriate for the particular pathogen
Which cells are activated by which t cells
monocyte and macrophage being enhanced by TH1 cells;
eosinophils, basophils and mast cells by TH2 cells;
neutrophils by TH17 cells
Why does the adaptive response to infection take 4 days to kick in (4)
because it requires:
dendritic cell activation and migration to secondary lymphoid organs
• activation of low frequency T cells
• activation and proliferation of antigen-specific B cells by activated T cells
• B cell differentiation into plasma cells for antibody production, B cell isotype switching and affinity maturation
How do the 4 different types of T cell act in an infection during the adaptive response
- CTLs are MHC class I restricted and kill cells harbouring intracellular viruses, bacteria and parasites
- TH1 cells (IFN-γ) are MHC class II restricted and their main role is to activate macrophages
- TH2 cells (IL-4) direct IgE production and help eosinophils, basophils, mast cells and B cells respond to parasite infections.
- TH17 cells (IL-17) help neutrophils respond to extracellular fungal and bacterial infections.
How long after infection do specific antibodies appear
5 days after (this varies and can be longer)
What is the first Ig isotype to be produced in the immune response to infection
what does it do (2)
IgM
recruits complement very efficiently and can compensate for low affinity through high avidity
What is a common theme for all of the 3 types of response to infection
innate sentinel cells such as macrophages, dendritic cells, tissue-resident mast cells or epithelial cells sense the presence of pathogens using arrays of pattern recognition receptors and respond by producing cytokines and chemokines
what does the production of chemokines and cytokines from innate sentinel cells do during infection
What is the purpose of this early response
initiates local inflammation and activates
innate lymphoid cells (ILCs)
helps to contain the infection until an appropriate adaptive response involving dendritic cells, effector T cells and class switched antibody can be made
Do ILCs require priming
no - they act immediately to enhance the function of resident and recruited innate effector cells
What does the type 1 response to infection focus on
Which immune cells does it use (5)
n intracellular pathogens such as intracellular bacteria, viruses and parasites.
involve the group 1 ILC1 cells, TH1 cells, NK cells, CTLs, and M1 macrophages
What does the type 2 immune response to infection focus on
Which immune cells does this response involve (6)
large multicellular parasites e.g. helminths
group 2 ILC2 cells, TH2 cells, IgE, basophils, tissue-mast cells, eosinophils (which express FcεRI and can be prebound by IgE) M2 macrophages
What does type 3 response to infection focus on
Which cells are involved (4)
extracellular bacteria and fungi
group 3 ILC3 cells, TH17 cells, opsonising antibody isotypes and neutrophils.
What happens after macrophages and DCs recognise intracellular pathogens
produce IL-12, which stimulates ILC1 and NK cells to produce IFN-γ which induces
macrophages to upregulate their killing capacity
DC cells travel to regional lymph nodes to activate CD4 and CD8 T cells
What is the purpose of the production of IFN-γ from ILC-1 and NK cells in response to intracellular pathogens in a type 1 response to infection
upregulates macrophage killing capacity
polarises towards Th1 response
In the type 1 response to viral infection, how are CTLs activated
How are macrophages induced to increase killing capacity
Some viral infections may directly activate CTLs without additional T cell help but many require help from TH1 cells.
by IFN-γ (classical or M1 macrophage
activation)
How do NK cells and CTLs kill infected cells in the type 1 response to infection
directly kill infected cells by release of perforin and granzyme.
How are chronically infected bacteria laden macrophages dealt with in the type 1 response to infection
perforin from NK cells and CTLs
or by Th1 cells via Fas/Fas dependent apoptosis , which releases the bacteria to be killed by fresh macrophages
Describe the steps involved in controlling a viral infection using the Type 1 response
- Interferon initiates an antiviral state
- NK cells a) kill virally infected cells and b) secrete inflammatory cytokines, which act on macrophages to enhance phagocytosis of viral particles and induce macrophage cytokine secretion
- NK killing is enhanced 20-100 fold by IFN-β, IFN-α or IL-12. This contains infection until adaptive immunity is generated.
• CTLs kill virally infected cells
The adaptive cell-mediated response to virus relies mainly on cytotoxic CTL and helper TH1 cells.
What is the time scale for CTL activity against viral infections in a type 1 response to infection
For many virus infections CTL activity arises around days 3-4, peaks at days 7-10 and then declines.
How does protective immunity generated through infection or vaccination mainly work
through neutralising antibodies
What are the steps involved in killing intracellular bacteria
- Neutrophils and macrophages phagocytose pathogen
- Macrophage ->IL-12 -> activates NK cell/TH1 cell -> IFN-γ -> activates macrophages to upregulate killing.
- Adaptive response: CD8-CTLs directly kill infected cells. CD4-TH1 cells express CD40L and activate macrophages more strongly than IFN-γ alone. TH1 cells can induce Fas/Fas ligand-dependent apoptosis of chronically infected cells.
- Generation of a memory T cell response is required to protect against most intracellular bacteria.
What is the main innate response to protozoa
What is a problem with this strategy? Give an example
phagocytosis
resistance to phagocytic killing is
common (e.g. T. gondii limits parasitophorous vacuole acidification and lysosome fusion).
How to epithelial cells respond to helminths early in infection
secreting alarmins, which activate ILC2 cells present in mucosal sites
Name 3 alarmins
When are they produced
What do they do
thymic stromal lymphopoietin (TSLP), IL-25 and IL-33
produced by epithelial cells in an early response to helminth infection
ILC2 cells present in mucosal sites are activated by these alarmins and produce IL-13 and IL-5.
What do the following do in helminth infection
IL-13
IL5
IL13: stimulates smooth muscle contraction, increased
epithelial cell turnover and mucus production by goblet cells.
IL5: stimulates eosinophil recruitment and activation
Which Th response is favoured in the presence of IL13 and TSLP
What else helps drives this
Th2
IL-4 (from an unknown source, maybe basophils, mast cells or iNKT cells)
At the site of helminth infection, what do Th2 cells do?
enhance the recruitment and function of type 2 innate effector cells, eosinophils, basophils, tissue-mast cells and alternatively activated M2 macrophages.
also drive IgE production
What do eosinophils do in helminth infection
When directed by surface bound IgE, eosinophils release cytotoxic molecules stored in secretory granules directly onto the worm surface (e.g. major basic protein, MBP).
What do mast cells do in the type 2 response to helminth infection
What does this lead to
Mast cells armed with helminth specific IgE produce mediators including histamine, TNF-α, prostaglandins & leukotrienes and proteases such as mucosal mast cell protease-1
increased vascular and epithelial permeability, mucus production, intestinal motility and leucocyte recruitment creates a ‘weep and sweep’ environment that helps expel parasites
What do macrophages do in the type 2 response to infection
M2 macrophages increase smooth muscle contraction and control tissue repair and remodelling.
These TH2-activated macrophages are also important in forming granulomas that entrap worm larvae in tissues
What is the type 3 response to infection important for
at barrier sites to control extracellular bacteria and fungi (including components of microbiota that enter when the barrier epithelium is damaged)
What is the sequence of actions that occurs during the type 3 response to infection
ILC3 cells respond rapidly to IL-23 produced by mononuclear phagocytes after recognition of bacterial/fungal PAMPs.
They produce IL-17 and IL-22.
The action of these cytokines may indirectly promote the generation of the subsequent TH17 response by increasing local levels of IL-1β, IL-6 and IL-23.
What does IL-17 do in the type 3 response to extracellular infection
stimulates local stromal cells, epithelial cells and myeloid cells to produce proinflammatory cytokines and chemokines (e.g. IL-1β, IL-6, GM-CSF and CXCL8), which recruit neutrophils
What does IL-22 do in the type 3 response to infection
increases epithelial cell division and shedding to impair bacterial colonisation.
Works with IL-17 to produce antimicrobial peptides (AMP) and promote barrier integrity
How do ILC3 and Th17 work together in the type 3 response to infection
Whilst ILC3 cells respond rapidly TH17 cells amplify and sustain the production of IL-22 giving long lasting protection at sites of infection
What do Tfh cells do in a type 3 response to infection
Is this effective
promote high affinity IgG and IgA responses and plasma cells secreting these localise to barrier tissues.
yes- Antibodies clear
many primary infections with bacteria such as Staphylococcus aureus and Streptococcus pneumoniae which elicit type 3 responses
