1781:Measles epidemic in the Faroe Islands No measles for 65 years 1846: Measles epidemic Those...
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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: 46 000 Area: 1400 km 2
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Transcript of 1781:Measles epidemic in the Faroe Islands No measles for 65 years 1846: Measles epidemic Those...
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
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
CD24CD24
CD38CD38
17 17 yearyear 28 28 yearyear 59 59 yearyear
memory memory memory
DEVELOPMENT OF THE ADAPTIVE IMMUNE SYSTEM
DEVELOPMENT OF PRIMARY – EFFECTOR – MEMORY T AND B LYMPHOCYTES IN THE COURSE OF ANTIGEN – SPECIFIC IMMUNE
RESPONSES
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.
The amount and quality of antigen-specific antibodies is increasing in the
course of the adaptive immune responseDominance of IgG-type antibodies
B CELL MEMORY
Affinity maturation
Isotype switch
Th help is needed
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
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
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
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
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
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
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
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.
T-CELL MEMORY
Central
Effector
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
T-cells differentiate into central and effector memory cells
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
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
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
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
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
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
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
AGE
THYMUS PERIPHERY
N
A
I
V
E
IMMUNOLOGICAL EXPERIENCEIMMUNOLOGICAL EXPERIENCE
M
E
M
O
R
Y
