Lecture notes
failures of defence
- Module
- Mechanisms of pathology
- Institution
- Aston University, Birmingham (Aston)
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Failures of defenceThere is 3 main lines of defence that we have to protect us from environmental pathogens.
1. Physical barriers- such as skin and our epithelial layers which keep out pathogens
with a physical barrier.
2. Innate immune response- rapid immune response which tries to contain pathogens
as quickly as possible. They have a distinct subset of cells which are involved in this
response. They use pre-formed receptors against pathogenic ligands to drive
activation and release of soluble factors to drive forward that inflammatory
response. They will initiate an inflammatory condition, which activates other cells to
drive forward the recruitment of the adaptive immune response.
3. Adaptive immune response- is the third element of the immune response. This is a
lymphoid specific cell response where we generate antibody and memory cells. This
gives us protection from that particular pathogen for the rest of our life.
We have 3 different forms of protection which try to work together to maintain our
homeostasis and also eliminate those pathogens as soon as possible should they make it
across the first physical barrier.
3 types of failure.
1. Pathogens evade or manipulate immune responses
2. The immune system has a primary genetic defect
3. Pathogens can lead to acquired immune deficiency syndrome
3 different way pathogens have evolved to avoid detection by our immune system and
thereby increase their chances of sustaining their lifespan within a host.
Pathogens evade or manipulate immune responses: antigenic variation.
• How pathogens have evolved different methods to escape the immune response.
• There are different forms of this mechanism depending on the pathogen that we are
talking about.
• Our protective immunity raides antibodies and these are generally to extracellular
pathogens, molecules on the surface of those pathogens. Which the antibodies
combine to and subsequently neutralise the pathogen and remove it.
• One-way pathogens have evolved to avoid detection is by changing surface antigens
on the surface of their cell membranes. Thereby, they do not give the immune
system enough time to generate those protective antibodies against a particular
antigen on the cell surface.
• By changing their antigens on their coat proteins, they can avoid elimination by
those antibodies which have been generated to subsequent coat proteins before
they were changed.
• This is a complex process and there is different variations on how pathogens use this
mechanism of just changing their cell surface proteins to avoid detection.
• There are 3 different types:
• Variable stereotypes
• 2.Antigenic drift and antigenic shift
• 3.Gene conversion.
Pathogens evade or manipulate immune responses: variable serotypes.
, • Variable serotypes
• This is where we are infected with a pathogen, which is a heterogenous mix of
different isoforms of that particular pathogen.
• Example: we have s.pneumoniae, there is different variations of this streptococcus
species that we will get infected with at the same time.
• Each of these different isoforms have different coat proteins, different cell surface
molecules.
• If we were exposed to one particular form of streptococcus, we would generate a
good antibody response using innate and adaptive immune response in the primary
infection and move those antibodies to that one particular serotype of
streptococcus.
• However, when we are challenged with a different serotype of streptococcus, those
antibodies that were made to the first strain will no longer protect us against that
second strain because the second strain has different coat proteins, so those
antibodies that will be generated to the first serotype will not recognise those
antigens and we will not generate an immune response.
• So instead we have to generate a new primary immune response, to the second type
of streptococcus and thereby induce an adaptive response to generate new
antibodies against that new form of streptococcus because it has different molecules
on its surface.
• Even though they are all from the same family, the streptococcus pneumoniae,
because there are several different serotypes we have to make new immune
responses if we are challenged with a slightly different form of that streptococcus
Pathogens evade or manipulate immune responses: antigenic drift.
• Antigenic drift.
• Viruses are able to change their coat proteins on their surface, and avoid detection
by the immune system.
• This is a cartoon of a virus, the coat proteins are organge and red, we have the
capside with the viral DNA in the middle.
• This is the influenza virus and on the coat proteins we have distinct regions where
they will interact with receptors and infect the host cell, if we can generate
antibodies to those receptor binding sites, we will stop the virus attaching to the
host cell and thereby infecting that host cell.
• The virus has an ability to induce random mutations, in these very specific areas
where it binds to the receptors. By mutating these sites very subtly, it will change the
conformation and the antibodies we generate against that particular strain of
influenza will no longer recognise the new strain which has mutated the receptor
binding site.
• This is termed antigenic drift, where we have a virus that we have made antibodies
to and then it will subtly induce these mutations in these very specific binding sites
and those antibodies can no longer block these interactions between these coat
proteins and the receptors on the host cells.
• This is one way viruses have evolved to maintain the lifespan inside a host, by subtly
changing these very specific regions and thereby preventing neutralisation with
antibodies.
, Pathogens evade or manipulate immune responses: antigenic shift.
• Antigenic shift-
• This is a much more wholesale shift in the genome of a virus, this is where we get
two viruses which will infect a host and there will be transfer of genetic material
between the two viruses which will recombine and it produces a completely new
virus.
• We have taken a virus that we can respond to because it recombines with a virus
from a completely different species, we generate a brand new virus which we have
no antibody protection to, and if we are infected with that virus, if that virus is
pathogenic, we cant raise an immune response quick enough and it will cause a lot
of deaths in the population.
• Example- human flu virus crossed with an avian flu virus, within a porcine host (a
pig).
• Recombination event generated a brand new version of H1N1 avian flu, and by
recombining with the human material, it generated a flu virus which killed over 40
million people.
• Recombination event gives us a different form of the virus, which our bodies have
never seen before, so it can be devastating if it is aggressive virus that cannot be
treated quickly enough.
• Antigenic shift is a much more wholesale change of DNA of the genetic material to
generate an entirely new virus.
Pathogens evade or manipulate immune responses: gene conversion.
• Gene conversion –
• Changing the proteins on the surface of the cell continually to avoid the immune
response.
• We have tropanosomes, which can invade the blood and live within the
bloodstream.
• This is a parasite and this parasite puts one set of coat proteins on its surface and
uses these variant surface glycoprotein antigen genes so it will express one form of
this variant surface glycoprotein on the surface of its cell but when it starts to detect
pressure from the immune system in terms of generating antibodies to that .
• If antibodies start to appear against those coat proteins, the parasite will switch that
gene off and switch on the next variant surface glycoproteins on its surface.
• As soon as it begins to detect antibodies are being generated against particular coat
proteins it will switch to the next one and because we have been generating
antibodies to that first coat protein, those antibodies will no longer be effective
against that parasite.
• So we have to generate another immune response to the next coat protein and it
will switch and change its coat proteins on its surface to the next one and so on.
• The tropanosome has thousands of coat proteins, so it can constantly change and
avoid the immune system.
• Good strategy to avoid elimination by these antibody mediated adaptive immune
responses, allowing the parasite to be maintained within the bloodstream of these
individuals for long periods of time.
• Gene conversion- simple change in genes being expressed alter the proteins that the
antibody should be recognising on the cell surface.
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