The document discusses immunological memory, which allows the adaptive immune system to remember specific pathogens and provide long-lasting protection against reinfection. Memory is maintained through periodic reexposure to pathogens, the production of antibodies by long-lived plasma cells and memory B cells, and the persistence of memory T cells in the absence of antigen through cytokines like IL-7 and IL-15. Studies in humans show antibody and T cell memory can last decades after vaccination or infection.
2. Immunological Memory
• The adaptive immune system can learn and
remember specific pathogens, and it can
provide long-lasting defense and protection
against recurrent infections.
• When the adaptive immune system is exposed
to a new threat, the specifics of the antigen
are memorized so we are prevented from
getting the disease again.
• The concept of immune memory is due to the
body’s ability to make antibodies against
different pathogens.
3. • The most important and effective mechanism for
maintaining immunity is the periodic re-exposure
to the pathogen.
• Such re-infections are usually asymptomatic or
produce only mild symptoms and act as a natural
booster to the immune system.
• The importance of this mechanism is shown in
epidemiological studies demonstrating that
protective immunity is maintained for longer
periods in people living in areas where a given
disease is endemic.
• Individuals that live in regions where, for
example, malaria is endemic have higher
malaria-specific antibody titers than those who
have intermittent exposures.
4. • It is well established that protective immune
memory can persist for many years after the
initial antigenic exposure. Examples include
Measles
Immunity
• Faroe Islands
• 65 years
Yellow Fever
Immunity
• Virginia
• 75 years
Polio
Immunity
• Eskimo
villages in
Alaska
• 40 years
5. • It is well accepted that people who have had
diseases such as measles and mumps as
children are unlikely to have severe
symptoms to the infection upon re-exposure.
6. History
• The first documentation of immune memory
dates back to the time of the Greek historian
Thucydides who recorded that the “same man
was never attacked twice” while describing the
plague of Athens in 430 B.C.
• It is remarkable that nothing was known about
the immune system or about microbes when
Thucydides made his observations on immune
memory; it would be more than 2000 years
before we gained an appreciation of the immune
system and learned that microbes cause
infectious diseases.
7. Example
• A good example of immunological memory is shown in
vaccinations.
• A vaccination against a virus can be made using either
active, but weakened or attenuated virus, or using
specific parts of the virus that are not active.
• Both attenuated whole virus and virus particles cannot
actually cause an active infection.
• Instead, they mimic the presence of an active virus in
order to cause an immune response, even though
there are no real threats present.
• By getting a vaccination, you are exposing your body to
the antigen required to produce antibodies specific to
that virus, and acquire a memory of the virus, without
experiencing illness.
8. Two Components of Immunological
Memory
• It includes preexisting
antibody, memory B
cells and plasma cells.
Humoral
Immunity
• It includes memory CD8
and CD4 T-cells.
Cellular
Immunity
9. • Humoral and cellular immunity are important in
protection against re-infection .
• Pre-existing antibodies can directly bind virus
particles, extracellular bacteria, and parasites.
• Their role is to provide the first line of defense
by neutralizing or opsonizing invading
pathogens.
10. Basic studies in immunological
memory
• During the past decade, major advances have
been made in identifying antigen-
independent mechanisms of maintaining
immunological memory.
• Using a combination of approaches a variety
of immune responses are analyzed in mice.
• It is now clear that memory CD4+ T cells,
memory CD8+ T cells, and memory B cells can
persist in the absence of antigen.
11. Memory B cells
• Performed Cell adoptive transfer studies of B cells
into irradiated animals
• Indicated memory B cells have an extremely short
lifespan in the absence of antigen
Gray and
Skarvall
• Performed memory B cell adoptive transfers into
unirradiated animals
• B cells were maintained
Bachmann and
coworkers
• Observed that the B cells persisted in an antigen-
independent manner
Rajewsky and
coworkers
12. Long-lived plasma cells
• These are a central part of immune memory
• These cells are largely responsible for the long
term continuous secretion of antibody.
• In contrast to memory B cells, plasma cells are
terminally differentiated and cannot be
stimulated by antigen to either divide or
increase their rate of antibody production.
13. Traditional View about Plasma cells
• The traditional view was that all plasma cells
(antibody secreting cells) are short-lived cells.
• Their half-life estimates ranging from 3 to 14
days .
• Continuous antigenic stimulation of memory
B cells was necessary to replenish the pool of
rapidly dying plasma cells and thereby
maintain antibody production.
14. Modern View about Plasma cells
• A new model suggests that there are two
populations of plasma cells:
Produce antibody
shortly after antigen
exposure
Short –
lived
plasma
cells
Survive
for extended
periods (half-life =
3–4 months in mice)
Long-Lived
Plasma
Cells
15. Fig 1: Memory B cell and plasma cell differentiation
Source: Crotty, S., & Ahmed, R. (2004, June)
16. Memory T cells
• From a number of studies, it is now clear that
memory CD4+ T cells and memory CD8+ T
cells can persist in the absence of antigen.
• It has also been shown that memory T cells
are not static; they regularly undergo
homeostatic proliferation to replenish their
numbers.
• This proliferative renewal does not require
stimulation with antigen or MHC I.
17. • IL-15 and IL-7 are critical for the maintenance
of memory CD8+ T cells.
• But only IL-7 is essential for maintenance of
memory CD4+ T cells.
• It has now been shown that IL-7 is also a
critical factor in the generation of CD4+ and
CD8+ T cell memory.
• Cytokines such as IL-15 and IL-7 may play key
roles in competition between naive and
memory cells and between memory T cells of
different specificities.
18. • Experimental studies done in mice have
shown that memory CD8+ T cells, memory
CD4+ T cells, memory B cells, and long-lived
plasma cells can often persist for the life of
the mouse (≥2 years) in the absence of
antigen.
• What about in humans?
19. Immune memory in humans
• There are classic reports of long term
immunity in humans in the absence of re-
exposure to a pathogen.
• Let us consider an impressive study of
antibody levels in a large cross-sectional study
of poliovirus immunity done in Sweden.
20. Poliovirus
Immunity
Poliomyelitis has
been eliminated
in Sweden since
1962
Only inactivated
poliovirus vaccine
is provided by a
single supplier in
the Swedish
population
Final booster
immunization is
given at the
young age of 5
years old
Enterovirus
infection burden
is extremely low,
and few
opportunities for
introduction of
poliovirus from
Sweden has
excellent health
care records and
public health
surveillance
21. • When the Swedish population was surveyed for
poliovirus immunity in 1991, substantial anti-
poliovirus antibody titers were detected in all
age groups.
• Interestingly, there was virtually no difference in
serum antibody titers among the different age
groups.
• Anti-poliovirus antibody titers are stably
maintained in the absence of additional
immunizations or exposure to live virus.
• Interestingly, declining levels of anti-tetanus and
anti-diptheria antibody titers were observed in
that same study, suggesting that not all immune
memory is created equal.
22. Long-term humoral immunity in
humans
• Memory B cell levels appeared to be stable
from 10 to 60 years post-vaccination,
indicating that antigen-specific memory B cells
are maintained by robust homeostatic
mechanisms.
• There was a 10-fold drop from peak memory
B cell responses that occurred sometime
before 10 years post-vaccination/infection and
then the memory B cell frequency stabilized.
23. • Long-lived plasma cells are crucial for the
maintenance of antibody levels.
• But with a half-life of 3–4 months (as
determined in mice long-lived plasma cells
must still be restocked to maintain antibody
levels for years/decades.
• One proposal is that long-lived plasma cells in
a human may, in fact, live for decades.
• A second proposal is that intermittent
antigen-independent differentiation of
memory B cells to long-lived plasma cells
occurs, possibly linked to homeostatic
proliferation of memory B cells.
24. Long-term T cell memory in humans
• These new studies of anti-smallpox immune memory
also showed that memory T cell responses were long-
lived in the absence of antigen.
• Memory CD4+ T cells and CD8+ T cells were both
generated after smallpox vaccination.
• Slifka and coworkers performed a detailed analysis of
the memory T cell populations and showed that
IFN+,TNF+, CD4+ T cells declined with a half-life of 8–
12 years.
• The IFN+, TNF+ memory CD8+ T cells did not follow
the same pattern. In 50% of individuals CD8+ T cell
memory slowly declined with a half-life of 8–15 years,
but in the other 50% of individuals CD8+ T cell memory
was rapidly lost by some unknown point between 3
and 20 years post-immunization.
25. CD8 T cell memory: generation and
maintenance
• The CD8 T cell response can be divided into three
distinct phases.
• The first is the expansion phase where the initial
activation and clonal expansion of CD8 T cells
occurs.
• The second phase is the contraction or death
phase where 90–95% of the activated effector
CD8 T cells die via apoptosis.
• The final phase is the establishment and
maintenance of CD8 T cell memory.
• Recent studies have suggested that all three
phases may be programmed shortly following
antigenic stimulation.
