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

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….

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! ! 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

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

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

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.

Memory can provide protection against pathogens for decades, Inhabitants: 46 000 Area: 1 400 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

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.

T-CELL MEMORY Central memory cells Effector memory cells

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

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

The differences between central and effector memory T cells.

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

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 100-1000X 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.

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

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

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

A TERMÉSZETES ÉS SZERZETT IMMUNITÁS EGYÜTTMŰKÖDÉSE IDŐBEN

Active and passive immunization

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

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

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

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.

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

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

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

IRF-interferon regulatory factor

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

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