Transcript The Immune System Second Edition

Peter Parham
The Immune System
Second Edition
Chapter 9
Failures of the Body’s Defenses
Copyright © 2005 by Garland Science Publishing
Failures of the body’s defenses.
Two general ways in which the body’s defenses fail to protect against
infection:
1. Microorganism can escape immune response.
2. The immune system itself can fail (immunodeficiency
disease).
Pathogens can evade the immune system through antigenic variation.
There are three main forms of antigenic variation used by pathogens.
1. existence as multiple serotypes
2. antigenic drift and antigen shift
3. gene rearrangements
Streptococcus pneumoniae exists in at least 90 known serotypes
Figure 9-1
Antigenic drift-The development of mutations in an antigen that alters its
ability to be recognized by antibodies.
Figure 9-2 part 1 of 3
Cause of flu epidemics occurring every 2-3 years
Antigenic shift-genetic recombination between different strains generates new
viruses with different epitopes.
Figure 9-2 part 1 of 3
Occurs in influenza type A strains with a wide host range (B is human
specific and doesn’t undergo antigenic shift).
Can cause worldwide pandemics (every 10-15 years)
Gene rearrangements – rearrangement of
DNA to allow expression of different surface
proteins (express different epitopes)
1. Strategy used by trypanosomes.
Protozoan parasites responsible for sleeping
sickness (carried by Tse Tse fly).
2. Salmonella typhimurium – causes food poisoning - expresses 1
of 2 antigenically distinct flagellins.
3. Neisseria gonorrhoeae – causes STD gonorrhea-has several
variable antigen genes. Of particular importance is the pilin
gene-encoded by a family of genes of which only 1 at a time is
expressed. (genetic recombination occurs in a manner somewhat
similar to VSG shown above but occurs mainly within a single
hypervariable region)
Latency-used by many viruses-strategy is to hide in the cell in an inactive state
while the initial immune response dies down.
Normally, a virus infects a cell and, as it replicates, some of the viral
peptides are presented by MHC class I molecules. Cells are killed by CD8
cytotoxic T cells.
virus
infected cell
CD8 T cell
Some viruses enter a quiescent state called latency. Don’t generate enough
virus-derived peptides to elicit a response.
Virus can be reactivated and cause an episode of disease.
Herpes viruses often enter latency.
Herpes Simplex causes cold sores –
infects epithelial cells-infection is
cleared by a normal adaptive
immune response.
Virus spreads to sensory neurons
where it persists in a latent state
(neuronal cells have low levels of
MHC I and the virus is making very
little viral protein.
The virus can be reactivated in response
to stress-travels down nerve axons and
reinfects the epithelial cells.
Varicella-Zoster-causes chicken pox (varicella). Virus can hide in dorsal
root ganglia (cell bodies for sensory branches of spinal neurons (near
spinal cord)). Can be reactivated later in life to cause shingles (Zoster).
Usually only occurs one time per lifetime of an individual.
Epstein-Barr virus. Most people are infected with EBV at a young age,
symptoms are mild, but some virus remains in B lymphocytes in a latent
state for life.
If infected as an adolescent or adult symptoms are much worse-causes
infectious mononucleosis-infection causes the B cells to proliferate and
make new virus until immune system can catch up and eliminate
infected cells.
Subversion of the immune system
lysosome
phagolysosome
phagosome
Mycobacterium tuberculosis – blocks fusion of the phagosome with the lysosome
to protect itself. Lives inside the cell in this vesicular system.
Listeria monocytogenes - escapes from the phagosome to live in the cytoplasm
(makes a virulence factor called lysteriolysin).
Toxoplasma gondii – generates its own vesicle inside the cells that won’t fuse with
the lysosome to protect it and its peptides from being available for presentation
via MHCI.
Over stimulation of immune system
Staphylococci produce toxins that function as superantigens like
enterotoxin or toxic shock syndrome toxin-1. These molecules bind to
TCR’s on many CD4 T cells and, at the same time, bind to MHC II
molecules on APC’s.
Immunosuppression
HIV is a good example, will consider in detail later.
Leprosy is an interesting example. Caused by a bacterium,
Mycobacterium leprae, that infects macrophages. Tends to suppress one
arm of the T cell response, either TH1 or TH2 (depending on what initial
conditions are like during early phase of infection). The outcome of the
infection depends on the type of immune response that is elicited during
the initial infection.
Suppression of the antibody response, leaving a cell-mediated TH1
response leads to a condition known as tuberculoid leprosy. TH1
cells control the infection in macrophages pretty well. Damage is
localized and is largely due to inflammation.
Suppression of the cell-mediated response is much more severe.
The TH2-mediated antibody response is ineffective in controlling the
infection and the bacteria grow in the host macrophages in an
uncontrolled fashion. Causes Lepromatous leprosy.