RECEPTORS AND CELL-SURFACE MOLECULES OF MACROPHAGES ! ! TLR4 + CD14 Scavenger receptor Mannose receptor MHCI TLR – pattern recognition Rs FcRI (CD64) Ag + IgG complex FcRII (CD32) MHCII Mϕ FcRIII (CD16) CR1 (CD35) LFA1 (CD11a/CD18) CR3 (CD11b/CD18)

IRF-interferon regulatory factor

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

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

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

IMMUNOLOGICAL MEMORY Life long protection against some viruses exists 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 epidemics Those, who were elder than 65 years and were sick in 1781 were not re-infected, but some elderly got sick Life long protection against some viruses exists Maintenance of memory does not require the sustained or intermitting presence of the virus

! ! THE TWO ARMS OF THE IMMUNE SYSTEM has memory Differentiation between harmless and harmful impacts DETECTION OF STRESS AND DANGER SIGNALS INNATE IMMUNITY Differentiation between self and non-self structures Antigen-specific recognition ADAPTIVE IMMUNITY Neutralization and elimination of foreign and harmful structures EXECUTIVE FUNCTIONS COORDINATED AND REGULATED ACTIONS INNATE IMMUNITY immediate reaction not antigen-specific no memory ADAPTIVE IMMUNITY developes in several days specific has memory communication Humoral immunity Cellular immunity

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

Activation of specific B cells ! Antigen recognition by specific BCR induces clonal expansion and differentiation of the sepcific B cells. Plasma cells, antibody production 2.Differen tiation Activation of specific B cells 1. Clonal expansion MEMORY B CELLS

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

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.

! Repeated immunization primary response against B antigen days

!

NEUTRALIZATION

PRODUCTION OF IMMUNOGLOBULINS

IMMUNOLOGICAL MEMORY – B CELLS SUMMARY Germinal Center reaction B cell proliferation Somatic hypermutation Affinity maturation Memory B cells Perviously activated Passed through affinity maturation Present in the circulation proliferation and differentiation to plasma cell upon re-activation or entry to the GC reaction again Plasma cells Provides serological memory by pre-existing neutralizing Abs to pathogens and/or toxins B B FDC B FDC B T B B B B B B plasma cell B B B B B B – T cell collaboration T B

T-CELL MEMORY Central memory cells Effector memory cells

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

DEVELOPMENT OF CELLULAR MEMORY Negative regulation of the immune system AICD Activation Induced Cell Death DIFFERENTIATION Naive lymphocytes Memory Az antigen-specific cell number Secondary effector T cells Primary effector cells EXPANSION AICD MEMORY Days

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

Maintained by cytokines: IMMUNOLOGICAL MEMORY MEDIATED BY T LYMPHOCYTES Naive T cell Effector T cell 2X107 cytokine production cytotoxicity Central Memory T cell Effector T cell Maintained by cytokines: IL-7, IL-15 Previously activated, partially differentiated cell type Circulating CCR7+ cells in blood, lymphoid tissues High proliferation rate induced by activation signals Rapid differentiation to effector cells 2X105 Effector Memory T cell Effector T cell Previously activated, partially differentiated cell type Closest to the effector state Circulating CCR7- cells in blood and tissues Slow proliferation, rapid effector functions

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

IMMUNOLOGICAL EXPERIENCE AGE THYMUS PERIPHERY M E O R Y N A I V E IMMUNOLOGICAL EXPERIENCE

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)

! !

PASSZÍV IMMUNIZÁLÁS ENDANGERED SUBJECT mouse monoclonal antibodies immunization mouse monoclonal antibodies Human immunoglobulin transgenic mouse humanized mouse monoclonal antibodies immunization human monoclonal antibodies PROTECTED SUBJECT serum antibody ENDANGERED SUBJECT This is a case of PASSIVE IMMUNIZATION Immune system is not activated prompt effect temporary protection/effect Immunoglobulin degradation

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

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

PRODUCTION OF IMMUNOGLOBULINS

Pathological consequences of placental transport of IgG (hemolytic disease of the newborn) Passive anti-D IgG anti-Rh IgM

Host itself produce preformed antibodies Immunization Active Passive Host itself produce preformed antibodies antibodies and cells are imported to the host biotic biotic artificial artificial

Immunitás Természetes Aktív: betegség, immunizálódás (sorozatos találkozás az adott kórokozóval) Passzív - in utero, placentán át, maternális (anyai IgG, folyamatos, homológ) - születés után, colostrális, anyatej útján IgG, IgA