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1781: Measles epidemic in the Faroe Islands
No measles for 65 years
1846: Measles epidemic
Those individuals, who were older than 65 years and were infected in 1781 did not became sick, but some elderly people got the infection
1. Life-long protection can be induced against some viruses
2. Presence of the virus is not needed for the maintenance of immunological memeory
Immunological memory
Inhabitants: 46 000Area: 1400 km2
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CD24CD24
CD38CD38
New bornNew born 1 1 yearyear 5 5 yearyear
TransienTransientt B B cellscells (T1/T2) (T1/T2) maturemature B B cellcell memmemory ory B B cellcell
DEVELOPMENT OF THE ADAPTIVE IMMUNE SYSTEM
memory memory memory
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CD24CD24
CD38CD38
17 17 yearyear 28 28 yearyear 59 59 yearyear
memory memory memory
DEVELOPMENT OF THE ADAPTIVE IMMUNE SYSTEM
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DEVELOPMENT OF PRIMARY – EFFECTOR – MEMORY T AND B LYMPHOCYTES IN THE COURSE OF ANTIGEN – SPECIFIC IMMUNE
RESPONSES
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Presence of specific antibodies during primary and secondary immune responses protects against repeated infections
• A successful primary immune response eliminates the pathogen and results in long-lasting immunological memory• Antibodies produced during the primary immune response protect agaimst re-infection by neutralization and opsonization.
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The amount and quality of antigen-specific antibodies is increasing in the
course of the adaptive immune responseDominance of IgG-type antibodies
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B CELL MEMORY
Affinity maturation
Isotype switch
Th help is needed
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IMMUNOLOGICAL MEMORY – B CELLS
Memory B cells• Perviously activated• Passed through affinity maturation• Present in the circulation• Rapid proliferation and differentiation to plasma cell upon re-activation or entry to the GC reaction again
Plasma cellsProvides serological memory: pre-existing neutralizing Abs to pathogens and/or toxins
Germinal Centre reaction• B cell proliferation• Somatic hypermutation• Affinity maturation
BT
BB
BBBB
BBB
B
BB
B
FDC
FDC T
B
B
plasmacell
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Marginal zone
Arteriola
Germinal centre T cell area – PALS
paracortex
CELLULAR INTERACTIONS IN PERIPHERAL LYMPHOID TISSUES
T
B
DC – T cell contact
DC Proliferating Bcentroblasts
B – T cell interactionsSomatic hypermutation
Further gene rearrangement (editing – L-chain)
Isotype switchDifferentiation to plasma cells
Antibody production
Memory B cell
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B
B
Memory B cell
Bapoptosis
T
CD40
CD40L
Follicular dendritic cell (FDC)
FcR
CD21
AgFcR
No Ag
DEVELOPMENT OF B CELL MEMORY IN THE FOLLICLES
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Follicular dendritic cell
B cell
SELECTION OF HIGH AFFINITY B CELLS UPON INTERACTION WITH FOLLICULAR DENDRITIC CELLS
VLA-4
LFA-1
VCAM-1
ICAM-1
BCR
CD21 C3d
Inhibition of apoptosis
Tight junction
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B cell
EXTRAFOLLICULAR ACTIVATION OF MARGINAL ZONE B CELLS BY DENDRITIC CELLS
GC
GC
Soluble antigenNo direct access of high molecular
weight or particulate Ag to the follicles
SinusesConduits
DENDRITIC CELLS PROVIDE A CELLULAR PLATFORM
Cognate recognition of Ag by rare naive B and T lymphocytes
Membrane tethered Ag facilitates the activation of low-affinity B cells
Dendritic cellIntracellular undegraded Ag
Recirculation to the cell surface
HEV
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DC
T cell
B cell
CELLULAR INTERACTIONS IN THE SUB-CORTICAL AREA
CD40
CD40
CD40L
CD40LB7
B7
CD28
CD28
MHC
MHC
TCR
TCR
Recognition of antigen by B and T lymphocytes
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Ag-FITC Actin-Alexa Red merged
Phalloidin-Alexa red DAPI control
Ag loaded dendritic cells interact with Ag-specific B cells
Ag and actin are reorganized to the contact site
ANTIGEN-LOADED DENDRITIC CELLS INTERACT AND ACTIVATE ANTIGEN-SPECIFIC B LYMPHOCYTES
Ag loaded dendritic cells interact with Ag-specific B cells
Ag and actin are reorganized to the contact site
Huang N-N. et al. J. Immunol. 175:7125, 2005
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Repeated antigen-specific B cell stimulation results in B cell activation and plasma cell differentiation
• How long follicular dendritic cells can store antigen – months or years? • Polio virus: re-infection by Sabin drops • Subclinical infections (Diphteria in 10% of the population)• Cryptic antigens (measles may persist in neurons and may cause Subacute Sclerotizing Panencephalitis
Bystander help:Cross-reacting antigensTLR ligandsCytokines...
memory B cell plasma cell
How antigen-specific antibody production is maintained?
Memory B cells continuously differentiate to plasma cells
Long term memory cells in the bone marrow
MODEL 1. MODEL 2.
MODEL 3.
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T-CELL MEMORY
Central
Effector
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DEVELOPMENT OF CELLULAR MEMORYNegative regulation of the immune system
Days5 10 15 20 25 30
Naive lymphocytes
Az antigen-specific cell number
Primary effector cells
Secunder effector cells
Memory
DIFFERENTIATION
AICD
EXPANSION
AICD
MEMORY
Days
Activation Induced Cell Death
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T-cells differentiate into central and effector memory cells
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Naive T Effector T
Cytokines/cytotoxicity
AICD
Central memory T
Effector T
Cytokines/cytotoxicity
PERIPHERAL LYMPHOID ORGANS
PERIPHERAL TISSUESSkin dermis, gut lamina propria,
alveolar space
Tissue-specific migration
Effector memory T
Effector T
Cytokines/cytotoxicity
ANTIGEN/ SITE OF INFLAMMATION
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IMMUNOLOGICAL MEMORY MEDIATED BY T LYMPHOCYTES
Naive T cell Effector T cell
cytokine productioncytotoxicity
Central Memory T cell Effector T cell
• 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
EffectorMemory 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
Maintained by cytokines:IL-7, IL-15
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NON LYMPHOID TISSUES PERIPHERAL LYMPHOID TISSUES
BLODD
Naive T cells
Activated DCINFLAMMATION
EFFECTOR CELLS MIGRATE TO THE SITE OF INFECTIONSEFFECTOR CELLS MIGRATE TO THE SITE OF INFECTIONS
Effector/memoryT cells
DC + TDC + T
LYMPH
DENDRITIC CELLS
TISSUE ANTIGENS
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GENERAL ENTRY SITES LIMITED ENTRY SITES
Brain
Alveoli
Peritoneum
Lamina propria
Skin
Lung parenchyma
Lymph node
Spleen
Liver
Bone marrow
WHERE MEMORY T CELLS HAVE ACCESS
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Resting Activated Resting Activated
Tissue effector memory T cells Lymphoid central memory T cells
PRODUCTION OF EFFECTOR
MOLECULES
CYTOTOXIC MEMORY T LYMPHOCYTESCYTOTOXIC MEMORY T LYMPHOCYTES
Proliferation
Cytotoxicity
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DEPENDENCE OF ANTIGEN IN THE MAINTENANCE OF MEMORY T LYMPHOCYTES IN AIRWAYS
MONTHS AFTER INFECTIONMONTHS AFTER INFECTION
11 33 66
After successful elimination of viral infections the number of antigen presenting DC and the newly activated memory T cells is decreased
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Secondary antigen-specific effector T cells developing from effector memory (TEM ) cells
LYMPH NODE
Memory T cells
Antigen-specific
Non antigen-specific24 – 72 hrs
Secondary antigen-specific effector T cells developing from
central memory (TCM ) cells
Woodland DL & Kohlmeier JR 2009 Nat Rev 9:153
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AGE
THYMUS PERIPHERY
N
A
I
V
E
IMMUNOLOGICAL EXPERIENCEIMMUNOLOGICAL EXPERIENCE
M
E
M
O
R
Y