preview:First lines of defence
• Barriers-skin, mucosal surfaces (epithelial cells)
• Prevent entry of pathogens
• Mechanical
• Chemical
• Microbiological
• We have got a multi layered defense.
• the first lines of defense are always ready for action these are barriers, th...
First lines of defence
Barriers-skin, mucosal surfaces (epithelial cells)
Prevent entry of pathogens
Mechanical
Chemical
Microbiological
We have got a multi layered defense.
the first lines of defense are always ready for action these are barriers, these are
our skin, these are mucosal surfaces, and these prevent the entry of pathogens.
We have barriers that are mechanical, chemical and microbiological.
For mechanical barriers you can see the different mechanical barriers at each of
these different anatomical sites.
We also have chemical barriers in these sites for example, chemical barriers within
the skin would be the fatty acids that are produced and also the antimicrobial
peptides that are present
Breach of the physical barriers can lead to infection
This activates INNATE IMMUNITY
First response mechanism – instant
Second response – hours-days later
Sequence of events depends on pathogen – type and route of entry
How efficient is innate immunity?
When there is a breach of the physical barriers the pathogens will enter the body
and that will then activate the innate immune system.
The second response is an induced innate immune response which happens hours or
days later after the initial activation.
The sequence of events depends on the pathogen- the type and route of entry so it
is really important for any pathogen that we get absolutely the right sort of response
to help defend us against the challenges that any pathogen will produce.
How important is innate immunity?
We know its one of the two arms of the immune response, the other being the
adaptive response, the adaptive response is super specific but actually the innate
immune response is massively important and we can see that on the graph.
We have along the horizontal axis the duration of infection from an infection starting
at the origin and the number of microorganisms of the Y axis and how they grow.
In normal situations you would get an infection shown in yellow and the pathogen
numbers would increase.
They would eventually plateau and they would turn off as the adaptive immune
response finally cleared the pathogen. If we lack the adaptive immune response we
can see that the slow take off of the pathogen numbers is the same but the adaptive
immune response then cannot get rid of that pathogen completely so it then slowly
continues to increase in its numbers.
If we don’t have any innate immune response however immediately pathogen
numbers are massively increased and rise extremely quickly and the reason for this is
the innate system holds the infection at bay and informs and activates the adaptive
, immune system to come and finish the infection but actually without the innate
immune system, we lose all of those benefits.
Defence depends on what the pathogens produce.
We need to respond in an appropriate way to whatever pathogen we have and
whatever challenge that pathogen presents us.
Vibrio cholera produces a toxin out of the pathogen and that will go and bind to the
cells and cause toxic damage.
We need a response particularly against these soluble factors that are produced and
typically we would want a neturalising antibody response here. So the antibody
would bind to the toxin and inactivate it.
For the case of endotoxin release for yersinia pestis we need a different sort of
response as these pathogens may live within a cell and we need those to be able to
be activated within these macrophages or rather the macrophages to be activated to
kill.
and for a virus that lives within our host cells we actually need a direct cytotoxic
effect on these cells.
These viruses will kill those cells, we need in a controlled manner to kill those cells
containing the virus.
Exotoxin release- produces a toxin out of the pathogen and this will go bind to the
cells and cause toxic damage. We need a response against the soluble factors coming
out of the cell. We will need a neutralizing antibody response. The antibody will bind
to the toxin and inactivate it.
Endotoxin release- pathogens may live within a cell and we need those to be
activated within macrophages, so the macrophages must be activated to kill.
Direct cytopathic effect: for a virus that lives within our host cells, we need a direct
cytotoxic effect on these cells. Virus will kill those cells. We need to kill the cells
which contain virus in a controlled manner.
Defence depends on where the pathogens are
We need to deploy the right sort of immune response in the right place.
It it pointless for us to have for example, the mucosal immune response if the
pathogen isn’t in our mucosa.
So, we need to understand broadly where a pathogen might infect whether its
extracellular or intracellular.
If it is extracellular, it is within the spaces between cells in tissue or it may be in the
blood or in the link or it may be on our mucosal surfaces on our epithelial surfaces.
We have to deploy the appropriate defense mechanism to be able to kill that sort of
or limit that pathogen in that particular site.
The same is true for the intracellular location of the pathogens, if it lives in the
cytosol, we will need NK cells that would be able to kill this virus infected self or if it
lives in vesicles within pathogens we would need activated macrophage which would
then be able to kill
Pathogenicity
Pathogens are usually host-specific
, Swine ‘flu & bird ‘flu
Most human infections are spread by contact with other, infected humans
Ease of infection depends on persistence of pathogen outside the body
HIV – very weak outside the human body
Only spread by very close contact
Anthrax – really tough, heat-resistant spores
Can transmit over long distances
Clostridium difficile
Pathogenicity is the ability to cause disease.
Most human infections are spread by contact with other, infected humans- nature of
this virus is such that we need contact between humans to be able to pass that on
through droplet transmission and probably aerosol transmission so if we keep apart
we limit that infectivity.
The ease of infection depends upon the mode of transmission so how resilient that
organism is on persistence of pathogens outside the body.
HIV- very weak outside the body, so we need to be very close in contact to spread it
from person to person. (R number- is the rate of infection) the higher the number
shows how much of the infection is spreading.
Anthrax- produces spores. The spores are resistant in the environment, this gives
opportunity for spores to be transmitted between people. People do not have to be
close in contact to get that, this is because spores can last a long time on surfaces.
Complement-first line of defence
Complement is a collection of soluble and membrane-bound proteins
Made by the liver constitutively (no stimulus required)
Found in blood, lymph, extracellular fluids
Many complement components are proteases
zymogen (i.e. a pro-enzyme; inactive form)
These require activation – cascade of enzymatic reactions that occur on infection
Once we have an infection the barrier has been breached and the innate immune
system comes into play.
One of the earliest lines of defense is a family of proteins called complement
proteins and these are a huge family of proteins.
Some of them are soluble and some of them are stuck on a membrane- so they are
membrane bound.
They are made by the liver constitutively so they are always present, they’re in our
blood, in the lymph in the extracellular fluids between cells and tissues and many of
these components are proteases ( enzymes that will cut up proteins which are
produced in an inactive form called the zymogen or a pro enzyme and through
cleavage it becomes activated) they work in a cascade where the activation of one
can then activate the next and so on down the line.
C3- most important complement component
There are >30 proteins in the complement system
C3 is the most important
people without this component are really sick
Key complement event
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