Immunity and inflammation Flashcards
What are the different molecules that mediate immune responses?
- Complement- soluable serum proteins
- Cytokines and chemokines- messenger hormones
- Antibodies- secreted molecules which bind pathogens
What are the different types of leukocytes in the innate and adaptive immune processes?
Innate= macrophages, dendritic cells, neutrophils, eosinophils, basophils and mast cells
Adaptive= lymphocytes; B and T cells
What tissues are involved in immune response?
Lymphatics, lymph nodes, spleen, thymus and bone marrow
Where are immune cells made?
Bone marrow and thymus
Where do adaptive immune cells spend most of their time?
In lymph nodes and spleen
What is the name given to swelling of lymphatics during infection?
Lymphadenopathy
What are primary lymphoid organs?
Primary lymphoid organs are where immune cells are made
Immune cells made in bone marrow
T cells mature in the thymus
What are secondary lymphoid organs?
Secondary lymphoid organs are where immune responses are initiated
Lymph nodes and spleen
What do virally infected cells release?
Virally infected cells release IFN-alpha and IFN-beta (cytokines) which induce an antiviral state in neighbouring states.
What two things does the immune system need to recognise to produce an immune response?
Non-self and danger
What are the two types of danger signals?
PAMPS= pathogen associated molecular patterns. Molecules only produced by infectious agents e.g. bacterial wall constituents. Critial for survival of pathogen so cannot lose them
DAMPS= damage associated molecular patterns. Molecules released from injured cells such as DNA, RNA, ATP
What are the two types of cell death and what are their differences?
How does the innate immune system know what is a pathogen and what is not?
Pattern recognition receptors (PRR)
Recognise PAMPs and DAMPs.
They are mainly expressed by antigen presenting cells such as dendritic cells and macrophages, but they are also found in other immune and non-immune cells.
What is an example of pattern recognition receptors?
Toll-like receptors
TLR3 binds double stranded RNA from viruses
TLR4 binds bacterial cell wall
TLR5 binds flagellin
What immune response would stepping on a dirty nail cause?
Full immune response
What immune response would absorbing food molecules cause?
No immune response
What response would a clean scalpel cut cause?
Danger= yes
Non-self= no
Innate response only
What immune response would inhaling flu virus cause?
Full immune response
What are the main causes of cell injury?
- Lack of oxygen
- Physical agents such as temperature and radiation
- Chemicals and drugs
- Infectious agents
- Immune reactions
- Genetic defects
- Nutrition deficiency
How does apoptosis occur?
Apoptosis is usually part of a regulated process, and has been called ‘programmed cell death’ or ‘cell suicide’. It is a carefully regulated event, requiring energy from the dying cell, usually resulting in cell shrinkage and fragmentation. Phagocytosis of the resultant apoptotic bodies ensures there is no associated inflammation and bystander tissue damage.
What are caspases?
They cleave aspartate residue, chops up proteins.
Caspase 8 and 9 lead to the executioner caspases such as caspase 3. the caspases chop around all of the intracellular proteins. The nuclear material gets specifically chopped apart- DNA is cut apart between the histones. Very ordered
What is necrosis?
Uncontrolled cell death where the cell swells up, the membrane swells up and spillage occurs. Does not require energy to die.
What are the different types of necrosis?
- Coagulative
- Liquefactive
- Caseous
- Gangreous
What is coagulative necrosis?
big areas of tissue, no automatic cleanup. The structural proteins of the cells still remain but the nucleus and DNA has degraded. The proteins can glue together and coagulate
There is a ghost outline of cells
What is liquefactive necrosis?
Liquefactive= cell protein digested, loss of tissue architecture. There is infiltration by inflammatory cells (neutrophils)- causes pus. There can be a secondary infection by bacteria- wet gangrene. (can use the dead tissue to grow on)
What is caseous necrosis?
Granulomas ward off foreign bodies but they cannot degrade. When these collections get bigger and bigger, cells in the middle start to die off.
TB causes this
What are granulomas?
Large collections of macrophages,
What are the different types of phagocytes?
Neutrophils, macrophages and dendritic cells.
What is the complement system?
It is a cascade of soluble proteins and membrane expressed receptors and regulators, which operates in plasma, in tissues, on cell surface, and even within the cell.
It assists the immune system by releasing anaphylotoxins, causing opsonisation of pathogens and forming membrane attack complexes
What are the 3 different complement pathways?
- Classical
- Mannose-binding lectin
- alternative pathway
When does the classical complement pathway occur?
Only occurs when there are antibodies present specific to a foreign antigen. E.g. on a bacteria. Antibody complexes bound by complement component C1q which then triggers the cascade.
How is the mannose binding lectin complement pathway triggered?
Activation through mannose binding lectin binding mannose, or a similar carbohydrates on bacteria. Mannose is not present on the surface of host (human) cell.
How is the complement complement pathway triggered?
Most common pathway, based around complement component C3 which is spontaneously activating. When it activates it binds to nearby membrane. Host cells have control proteins on their surface to prevent further complement activation, whilst bacteria cells do not- thus is activates the complement.
What are the 3 ways in which complement helps the immune response?
- Forms membrane attack complexes
- Mediates anaphylatoxins
- Causes opsonisation
What are membrane attack complexes?
They are barrel-like structures that form on membrane of bacteria
Causes water to rush in, and ions to rush out causing the bacteria to swell and burst
How does the complement pathway help immune response through anaphylatoxins?
Soluable compenent complements are released on complement activation known as anaphylotoxins.
Their release results in blood vessels becoming leaky, causing oedema and allows recruitment of immune cells
What is opsonisation?
Where bacteria is coated to make it visisible to innate immune cells.
It encourages phagocytosis and killing
What are the differences between neutrophils, macrophages and dendritic cells?
What is the process of neutrophils moving from the circulation to the site of inflamation called?
Extravasation
How do neutrophils move from blood vessels to tissue?
During inflammation local inflammatory cytokines are released- this alters the endothelium of blood vessels and the junctions between cells become leaky.
Neutrophils start to roll along the endothelium, then firmly adhere and exit between endothelial cells (diapedesis). They follows a chemokine gradient to the site ofinflammation.
What is the pathogen called when a phagocyte engulfs it?
Phagosome
What happens when lyosomes fuse with phagosome and what is it called?
Lysosomes fuses with a phagosome and the toxic products kill/ degrade the pathogen
Called a phagolysosome
How are macrophages activated?
Activation can come from danger signalling or cytokines, especially IFN gamma
What is netosis?
Neutrophils can extrude their DNA, acting like a net which traps pathogens that it is struggling to kill.
What is antigen specificity?
Antigen= a molecule that is recognised by the adaptive immune system. Adaptive immune cells are randomly generated to express a unique receptor which recognises a specific antigen
Antigens can be self or non-self
Why do dendritic cells migrate to lymph nodes?
When they are in the periphery they are constantly taking up antigens. If they sense danger they mature.
They upregulate different chemokine receptors
This results in their migration to the lymphatics and into the draining lymph node, where they will present the antigen to lymphocytes.
What cell do dendritic cells present their antigen to?
T cells
How doe B cells and T cells recognise antigen?
The B cell receptor BcR can recognise soluble antigen in its normal for,
The T cell receptor TcR has to have antigen ‘presented’ to it on the major histocompatibility complex. Antigens must be chopped up into peptides which are then loaded onto MHC molecules and presented on the surface of the cell
What signals do dendritic cells need to give to activate T cells?
Signal one= MHC + antigen
Signal 2= costimulation
What will happen to a T cell if there is no stimulation singal from dendritic cells?
Anergy/death
Anergic= they cannot be activated again
What is the third signal from dendritic cells to activate T cells?
The third signal is a release of cytokines which tells T cells what type of cell to become.
What is inducible immunity?
An alert response to mounting danger that disrupts and damages tissue. Caused by:
PRRs over a threshold, triggering inflammtion
Antigen specific receptors after an antigen encounter tigger adaptive immunity
What are the main factors that maintain immune health?
Physical activity
Sleep
Microbiota
How does having healthy skeletal muscle moderate immunity?
Skeletal muscle is a major source of cytokines in homeostasis.
Myokines support immunity and regulate inflammation, also causes adaptive responses to new and recall antigens in the elderly and causes innate functions such as boosting NK and macrophages.
What are tissue-resident sentinel cells and sentinel cells?
Tissue resident monitor near surfaces like skin and GI mucosa- mast cells, macrophages, dendritic cells
Sentinel cells monitor inside blood vessels- monocytes, NK cells
What is the decline of immunity that comes with older age called?
Immunosenescence
Why does the immune system decrease in old age?
Thymus and marrow atrophy reduced lymphocyte diversity
DNA methylation reduces survival factor for memory cell generation
Exhausted T cells from chronic infection
Scars from severe infection
What is inflammaging?
It is chronic low grade inflammation which lasts for decades and contibutes to age-related multisystem morbidity e.g. atheroma.
What is metaflammation?
Inflammation in metabolic disease
How can does type II diabetes arise from obesity?
Nutrient stress (volume/quality in obesity) causes mitochondrial dysfunction with increased oxidative stress
The stressed adipocytes release more inflammatory cytokines (danger signals) such as pro-inflammatory adipokines. This causes an influx of inflammatory monocytes and T cells, a senescent immune cell accumulation and adipokines cause insulin resistance in myocytes- poor glucose control.
In the intenstine, what secrete mucous?
Goblet and Paneth
What are the causes of inflammatory bowel disease?
Dysfunctional barriers, dysbiosis and inflammation
Genetic/ environmental factors alters the ecosystem subtly. Reduced diversity plus the accumulation of a microbes causes inflammation.
Once there is inflammatory damage, causes danger signals which causes a breakdown of barrier and recruitment of other immune cells.
What is dysbiosis?
A disruption to the microbiota homeostasis caused by an imbalance in the microflora
What are the two different cell metabolic programs?
Dormancy associated- catabolic
Growth associated- anabolic
What are catabolic state cells?
Cells not directly involved in defence
They are resource converting- maximising energy yield from carbon resources such as glucose
What are anabolic cells?
Activated immune and repiar cells that are resource demanding. They are involved in proliferation, differentiation and pathogen clearance
What is the name given to cells allocating resources for defence and survival?
Immunometabolism
What is the central hub for switching between anabolic and catabolic states?
Mitochondria of the cell
Metabolic reprogramming is signalled by oncogene proteins
How does T cell metabolism change during immune response?
In a naïve T cell there is only a basal nutrient uptake to sustain itself. Very little biosynthesis is occuring. After activation there is a ramp up of glycolysis and nutrient uptake- switches itself to require glucose fuel. The mitochondria is no longer burning fuel but are exporting intermediates to produce biomass- cell proliferation and growth.
Once the stimulus that activated these cells is finished, they return to quiescence- slightly different to that of naïve cells- more mitochondrial mass- better able to respond faster the next time
What are the symptoms of acute inflammation?
Swollen, warm, painful, red and loss of function
What happens when innate immune cells recognise danger signals from PAMPs and DAMPs?
The signals converge and inflammatory cytokines and chemokines, type I interferon is released and there is cell death
What are the changes in the small blood vessels that drive inflammation?
- dilitation of the arterioles
- water uptake into connective tissue matrix
- junction breaks between endothelial cells
What changes neutrophil’s cell adhesion molecule expression?
Circulating neutrophils near injured tissue are activated by DAMP or cytokines and chemokines from DAMP activated cells.
What causes the endothelial cells to exposure adhesion molecules?
Histamine, DAMPs and cytokines such as TNF and IL-1 cause endothelium to shed glycoalyx and exposure sticky adhesion molecules e.g. selectins on its surface.
What guides out transmigrating neutrophils?
Pericytes
What seals the transmigration site of a neutrophil?
Platelets
What is chemotaxis?
Orientation or movement of an organism or cell in relation to chemical agents.
What attracts neutrophils to site of injury?
SELF= coagulation products, complement and IL-8
NON-SELF= bacterial endotoxins
How do resident macrophages stop neutrophils from causing inflammtion in minor damage?
Minor damage is cloaked by resident macrophages and so is concealed from neutrophils
How does oedema reduced local immunity in tissue?
It is harder for immune cells to patrol the extravascular tissue when the connective tissue fibres are seperated by fluid- they need something to adhere to for patrolling tissues
What is exudate and gangrene?
Exudate is fluid that leaks out of blood vessels into nearby tissues
Gangrene is a dangerous and potentially fatal condition that happens when the blood flow to a large area of tissue is cut off
Why does fever occur?
Pyrogens can bind to receptors in the hypothalamus, increasing temperature
Once pyrogen is IL-1 produced by macrophages
