1. IMMUNOLOGICAL MEMORY
The immune system seems to „remember” previous infections,
Which cells do it and how?
Why?
For how long?
How can we use this to fight infectios diseases?
The concept of immune protection by immune memory memory has
probably been known for a few thousand years…..
Parents can take care of sick children if they already had the disease and recovered

2. History of infection with a pathogen.
Consider a student’s history of infection with a pathogen. The student’s first infection with the pathogen was not stopped by innate immunity, so a primary adaptive immune response developed. Production of effector T cells and antibodies terminated the infection. The effector T cells were soon inactivated, but antibody persisted, providing protective immunity that prevented reinfection despite frequent exposure to infected classmates. A year afterward, antibody levels had dropped and the pathogen would now be more likely to establish an infection. When a second infection did occur, a much faster and stronger secondary immune response was made; this eliminated the pathogen before it had a chance to disrupt tissue or cause signicant disease. This strong response was mediated by long-lived, pathogen-specific B cells and T cells that had been stockpiled during the primary immune response. The student’s immune system had retained a ‘memory’ of that first infection.
Some infections are stopped by the innate immunity… Adaptive immune response is
not induced
Many pathogens are seasonal, repeated infections with viruses during wintertime.
Antibodies produced in response to an infection are present for several months.
Virus neutralization….

3. !

4. ! ! B cell memory: Quicker response
Increase in the number of specific B cells
The amount of antibody are higher
Higher affinity antibodies (‘more specific’)
Isotype switch
In case of T dependent B cell activation

5. B cell memory is provided by:
Memory B cells
proliferation and differentiation to plasma cell upon re-activation or entry to the GC reaction again
and
Long-lived plasma cells
Plasma cells generated during GC reaction migrate to bone marrow and
survive for years, producing antibody Much of circulating IgG is produced by long-lived plasma cells, provides initial protection

7. Both effector B and T cells and memory B and T cells are produced during a primary immune response.

8. This figure shows the results of an experiment on mice that mimics the development of specific antibodies when a person is given a course of three immunizations (1�, 2�, and 3�) with the same vaccine. The upper panel shows how the amounts of IgM (green) and IgG (blue) present in blood serum change over time. The lower panel shows the changes in average antibody affinity that occur. Note that the vertical axis of each graph has a logarithmic scale, because the observed changes in antibody concentration and affinity are so large.

9. Memory can provide protection against
pathogens for decades,
Inhabitants:
Area: km2
1781: Measles epidemics in the Faroe islands
after the epidemics the island has remained measles free for 65 years
1846: Another epidemic
Those, who were elder than 65 years and were sick in 1781 were not re-infected
Life long protection against some viruses exists
Maintenance of memory does not require the sustained or intermitting presence of the virus
5000 inhabitant , 98 survivors were protected

10. Memory B cells and T cells provide protection against
pathogens for decades,
75 years after inoculation (vaccination) with
vaccinia virus, vaccinia-specific
antibodies are still present.
Retention of vaccinia-specific antibodies and T cells after vaccination against smallpox virus.
Specific anti-vaccinia antibodies continue to be made for as long as 75 years after the last exposure to vaccinia virus, the smallpox surrogate that is used for vaccination (top panel). The numbers represent international units (IU) of antibody, a standardized way of measuring an antibody response. Many vaccinated individuals retain populations of vaccinia-specific CD4 T cells and CD8 T cells (bottom panel). Only small differences are observed for individuals who received one (blue bars) or two (pink bars) vaccinations.
75 years after inoculation (vaccination) with
vaccinia virus, CD4+ and CD8+ T cells are still present.

11. T-CELL MEMORY
Central memory cells
Effector memory cells

12. ! ! T cell memory: Quicker response
Increase in the number of responding cells

13. Citokines/Cytotoxicity Naive T
Effector T
Citokines/Cytotoxicity
AICD
Naive T
Central memory T
Effector T
Citokines/cytotoxicity
PERIPHERAL LYMPHOID ORGANS
Effector memory T
Effector T
Cytokines/cytotoxicity
ANTIGEN/SITE OF INFECTION
PERIPHERAL TISSUES
Skin dermis, gut lamina propria, alveolar space
Tissue-specific migration

14. The differences between central and effector memory T cells.

15. Functional differences between lymphoid tcm cells and tissue-resident TEM cells
The localization of effector memory T (TEM) cells in peripheral tissues before infection is clearly an important factor
in their ability to provide protection from a secondary infection. However, several studies have also shown that
TEM cells and central memory T (TCM) cells have different effector functions in response to antigen stimulation51,52
(see the figure). Although both subsets of memory T cells
produce large amounts of effector cytokines such as
interferon‑γ (IFNγ) and tumour‑necrosis factor (TNF)
after antigen stimulation, a greater frequency of TCM
cells also produce interleukin‑2 (IL‑2), which could
increase their ability to proliferate in response to
antigen94. By contrast, TEM cells have more potent lytic
activity ex vivo compared with TCM cells. This is probably
due to the increased expression of perforin by both
resting and activated TEM cells95, and because resting
tissue‑resident memory T cells (that is, TEM cells) can
maintain the expression of mRNA transcripts that
encode cytolytic proteins96. The presence of this
pre‑formed mRNA enables TEM cells to express cytolytic
proteins, such as granzyme B, more rapidly, thereby
increasing their ability to rapidly kill infected cells. In
addition, a small fraction of TEM cells can express the
low‑affinity Fc receptor for IgG IIIa (FcγRIIIa) (not
shown), which allows them to directly mediate
antibody‑dependent cell‑mediated cytotoxicity97.
Proliferation
Cytotoxicity
cytotoxicity
killing
Woodland DL & Kohlmeier JR 2009 Nat Rev 9:153

16. Generation of memory T cells during the response to a virus infection.
After clearing viral infection about 5% of the cells become memory cells. This is about X more than the % of naive virus-specific T cells.
Cytomegalovirus (CMV) is a latent herpesvirus that usually is quiescent but has episodes of activation that are quelled by the immune response. Such an episode is illustrated here for a CMV-carrying patient who underwent immunosuppressive treatment for cancer followed by a hematopoietic stem-cell transplant. The increase in viral load that occurs when the virus is reactivated (lower panel) triggers a rapid increase in the numbers of virus-specific effector CD8 T cells present in the blood (upper panel). This falls back once the virus has been brought under control, leaving a sustained lower level of long-lived, virus-specific memory T cells. Data courtesy of G. Aubert.

17. IMMUNOLOGICAL EXPERIENCE
As we age we rely more on our past experiences with pathogens (Memory cells)
AGE
THYMUS
PERIPHERY M E O R Y N A I V E
IMMUNOLOGICAL EXPERIENCE

18. The original antigenic sin
Highly mutable viruses such as influenza gradually escape from immunological memory without stimulating a compensatory immune response.
A person’s history of infection with influenza is shown here. The first infection is with a strain of influenza virus that elicits a primary antibody response to viral epitopes A, B, C, and D. The next four infections are with viruses that successively lose the epitopes of the first virus and gain in turn the epitopes E, F, G, and H. With each infection the strength of the person’s memory response declines but cannot be compensated for by a new primary response until all the epitopes of the original strain are lost at the fifth infection. Then, no memory response is elicited, disease ensues, and a primary immune response against all the new epitopes is made.
The original antigenic sin

19. Differences between the primary and secondary immune responses.
Summary
Differences between the primary and secondary immune responses.

20. A TERMÉSZETES ÉS SZERZETT IMMUNITÁS EGYÜTTMŰKÖDÉSE
IDŐBEN

21. Active and passive immunization

22. Active: generates memory response
Passive: ensure the protection by premade antibodies
(the adaptive immune system of the person is not activated)

23. ! !

24. ! ! Active and passive immunization active passive
protection slow immediate
(2 weeks)
Time-span long short
(years) ! !
protection
passive
active
injection
time

26. Vaccination with cowpox virus elicits neutralizing antibodies that react with antigenic determinants shared with smallpox virus.
Cowpox is very similar to smallpox, similarity is the basis of protection

27. Most viral vaccines are made of killed or inactivated viruses…
But live, attenuated viruses usually generate effective long-lasting protection
Attenuated viruses are selected by growing human viruses in non-human cells.
To produce an attenuated virus, the virus is first isolated by growing it in cultured human cells. This in itself can cause some attenuation; the rubella vaccine, for example, was made in this way. In general, however, the virus is then grown in cells of a different species, such as a monkey, until it becomes fully adapted to those cells and grows only poorly in human cells. The adaptation is a result of mutation, usually a combination of several point mutations. An attenuated virus grows poorly in the human host: it produces immunity but not disease.

28. The Polio eradication program
A successful vaccination campaign.
Poliomyelitis has been virtually eliminated from the USA, as shown in the graph. The arrow indicates when the vaccination campaign began. Because the polio virus has not been eradicated worldwide and the volume of international travel is so high, immunization must be maintained in much of the population to prevent a recurrence of epidemic disease.
1988: Polio endemic in 125 countries
350,000 deaths / year
By 1990 polio is almost eradicated

29. Time course of the H1N1 influenza pandemic of 2009 and the development of a vaccine against it.

31. Anti-viral immune response!
Anti-viral immune response
Defense:
Innate Immunity: – type I interferons(INFα, β)
– NK cells
Adaptive immunity
B cells – antibody-mediated neutralization
T cells --- cytotoxic T cells, cytokines

32. IRF-interferon regulatory factor

34. Anti-viral immune response Type I INTERFERONs!
Anti-viral immune response Type I INTERFERONs
vírus
IFN és IFN !

35. KINETICS OF VARIOUS ANTI-VIRAL MECHANISMS
IFNα/β, IL-12
NK cells
Cytotoxic T cells
Antibody
Complement
level/activity
VIRUS TITER
days