bbs2 mb-k24-cellular mediated immune response k-24
TRANSCRIPT
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CELLULAR MEDIATEDIMMUNE RESPONSE
Departemen Mikrobiologi FK USU
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SLO:
Menjelaskan respon imun non spesifik
selular
Menjelaskan respon imun spesifik selular
Menjelaskan interaksi kerja respon imun
non spesifk dan respon imun spesifik
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Kepustakaan
Levinson, W. 2004. Medical Microbiology
& Immunology: Examination & Board
Review, 8th ed. McGraw-Hill.
Paul, W.E., 1998. Fundamental
Immunology, 4th ed. Lippincott Williams &
Wilkins. USA.
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Cell-Mediated Responses
Two intracellular compartments:
1.Cytosolic:
cytosol and nucleus connected via nuclear
pores site of viruses and some bacteria
2.Vesicular:
membrane-bound entities (endoplasmicreticulum, endosomes, lysosomes, Golgiapparatus)
site of some bacteria, some parasites
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Location of Pathogen Determines
Which T Cell Population Responds
1. Cytosolic: cytotoxic T cells (Tc) thatexpress CD8
2. Vesicular: subpopulation of helper Tcells (Th1) that express CD4
3. Extracellular: subpopulation ofhelper T cells (Th2) that express CD4
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Cytotoxic (Tc) T Cells
Virus infects cell
A B
C
Cell expresses
viral antigens
Cytotoxic
T cell
Infected cell is killed by cytotoxic T cell
by activation of nucleases that cleavehost and viral DNA
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Helper (Th1) T Cells
Macrophage MacrophageTh1
cell
lysosome
mycobacteria
antigen
Infected macrophage Activated infected
macrophage
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Specificity of Immune Responses
Resides in Receptors
T cell receptor (TCR) recognizes peptide
associated with major histocompatibility
complex (MHC) and is univalent.
T
cell
B cell receptor (surface immunoglobulin)
recognizes antigen and is bivalent
B
cell
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Diversity of Receptor Specificity
(Repertoire)Historically two different hypotheses
to explain diversity:
Instructional (template)
Clonal selection
Instructional hypothesis, althoughsimpler, does not explain how hostdistinguishes self from non-selfantigens
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Four Basic Principles of
Clonal Selection
1. Each lymphocyte bears a single type of
receptor of a unique specificity.
2. Interaction between a foreignmolecule and a lymphocyte receptor
capable of binding that molecule with
high affinity leads to lymphocyteactivation.
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Clonal Selection
3. Differentiated effector cells derivedfrom an activated lymphocyte will
bear receptors of identical specificity
to those of parental cell from whichthe lymphocyte was derived.
4. Lymphocytes bearing receptors for
self molecules are deleted at an earlystage in lymphoid cell development.
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Class I MHC Molecules
Expressed on surface of all nucleated
cells
Recognized by TCR of cytotoxic T cells
CD8 binds to class I MHC-peptide
complex
Source of peptide is cytosoliccompartment
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Class II MHC Molecules
Expressed on surface of some nucleatedcells, mainly antigen presenting cells(APC)
Recognized by TCR of helper T cells
CD4 binds to class II MHC-peptidecomplex
Source of peptide is vesicularcompartment
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Cells Expressing Class I and
Class II MHC
Class I MHC
Class II
MHC
All nucleated cells
express class I
MHC
Cells expressingclass II MHC also
express class I
MHC
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Non-specific and Specific
Immunity: ContrastsSpecific (acquired, adaptive) immunity
is induced and enhanced by antigen
shows fine discrimination
has memory
The non-specific and specific immune
systems interact with each other!
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Cells of the Immune System
All derive from the bone marrow
Two main lineages derive from the bonemarrow hematopoietic stem cells:
1. Lymphoid lineage
T cells, B cells, Natural Killer (NK) cells
2. Myeloid lineage
Monocytes, Macrophages, Dendritic cells,Megakaryocytes, Granulocytes
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Hematopoiesis
NK
Myeloid
progenitorLymphoid
progenitor
Tccell
TH
cell
Hematopoietic
Stem cell
B cell
Granulocyte
Platelets Megakaryocyte
Macrophage Monocyte
Dendritic cell AFC
Plasmacell
Mast cell
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Lymphocyte Recirculation
Secondary lymphoid tissues (lymphnodes, spleen) main sites wherelymphocytes encounter antigen
Frequency of lymphocytes having areceptor specific for a given antigen islow
Recirculation of lymphocytes throughlymphoid tissues optimizes productiveencounters with antigen to initiateresponse
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Lymphocyte Recirculation
Nave lymphocytes
enter lymph nodes
from the blood circulation
Lymphocytes return
to blood
via the thoracic duct
Antigens from infected area
go to lymph nodes
via the lymphatic system
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Leukocyte Migration and
Localization
Bone marrow and thymus (primarylymphoid tissues) produce B cells and Tcells, respectively
B cells and T cells recirculate throughspleen and lymph nodes (secondarylymphoid tissues)
Antigen presenting cells (APC) pick upantigen and migrate to secondary lymphoidtissues and interact with T cells and B cells
k i i d li i
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Leukocyte Migration and Localization
T
cell
Tcell
T
cell
B
cell
Bcell
B
cell
APC
T
cell
B
cell
Naive
lymphocytes
Bone marrow
Thymus
Spleen and lymph nodes Tissues
Primed lymphocytes
Dendritic
cell
Macrophage
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Critical Role of Th Cells in Specific Immunity
Select effector mechanisms
Induce proliferation in appropriate effectors
Enhance functional activities of effectorsAPC
Thcell
B cell
Tc
cellNK
AgAg
Ag
NK cell
Cytokines
Granulocyte Macrophage
Cytokines
Antigen-presenting cell
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Nave Th Cells Can Differentiate
Into Th1 or Th2 Cells
ThPcell
ThOcell
Th1cell
Th2cell
ThMcell
IL-2 IFN
IL-2
IL-4
IL-5
IL-10
IL-4
IL-5
IL-6
IL-10
IL-2
IFN
IL-2
Naive Th cells Short-term
stimulationChronic
stimulation
Long term
Memory cells
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Functions of Th1 and Th2 Cells
Th1cell Th2cell
Macrophage B cell
IFN
Activates
IL-4 IL-5
IL-10
Activates
Inhibits production
Mast cellEosinophil
Antibodies (including IgE)
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Cytokines Regulate Ig Class Switching
Fc region of antibodies determineseffector function in different anatomical
locations
Class (isotype) switching produces classor subclass of antibody most effective in
host defense
Cytokines acting alone or in
combination regulate class switching
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Macrophage Macrophage
Thcell
Macrophage
Cytokines Lymphokines
Cytokines
Anti-microbial functions
Anti-tumor functions
Invading agent Antigen presentation Activated macrophage
Central Role of Macrophages in
Natural and Specific Immunity
Involved in initial defense and antigenpresentation and have effector functions
l d f h
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Detailed Functions of MacrophagesInflammation Fever, Production
of: IL-6, TNF-alpha, IL-1 act as
pyrogen
ImmunitySelection of lymphocytes to be
activated:
IL-12 results in Th1 activation
IL-4 results in Th2 activation
Activation of lymphocytes:
Production of IL-1
Processing and presentation of
antigen
Reorganization of tissues,Secretion of a variety of factors:
Degradative enzymes(elastase,
hyaluronidase, collagenase)
Fibroblast stimulation factors
Stimulation of angiogenesis
Damage to tissues
Hydrolases, Hydrogen peroxide production
Complement C3aTNF alpha production
Antimicrobial action
O2dependent production of:
hydrogen peroxide, superoxide,
hydroxyl radical, hypochlorous acidO2-independent production of:
acid hydrolases, cationic proteins,
lysozyme
Anti-tumor activity produced by:
Toxic factorsHydrogen peroxide
Complement C3a
Proteases, Arginase
Nitric oxide
TNF alpha
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Macrophage Activation
Macrophage activation results fromalterations in gene products thatgovern new functions.
Two major mechanisms that activatemacrophages:
IFN- produced by Th or Th1 cells plusbacterial endotoxin (LPS)
IFN- produced by Th or Th1 cells plusTNF-
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Mechanism of Macrophage Activation
Macrophage Activated
Macrophage
Bacterial endotoxin
(lipopolysaccharide)
triggers cytokineproductionTh1
cell
1
IFN gamma
IFN gamma
2Macrophage
Activated
Macrophage
TNF alpha
Various
products
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Cytolytic T (Tc) Cells
Tc exiting the thymus are pre-Tc cells,i.e. have TCR that can recognizeantigen, but are not mature and cannot
kill until armed To become armed requires two signals:
1. Recognition by TCR of specific antigen
associated with class I MHC, and
2. Exposure to cytokines (IL-2 and IFN-)
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Mechanism of Arming Tc Cells
Pre-Tc cell
Tc cell
T helpercell
Class IMHC
Class II MHC
APC
1. Cell expressing class I MHC
presents antigen ( )to a pre-Tc cell
IFNIL-2
2. Antigen-presenting
cell presents antigen in
association with
class II MHC to Th cell3. Th cell
makes cytokines
4. Pre-Tc cell
differentiates to
functional Tc cell
5. Tc recognizes antigen on
class I MHC-expressing target cell
6. Target cell
is killed
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Features of Tc Killing
Antigen-specific
Requires cell-cell contact
Each Tc capable of killing many target
cells
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Main Mechanism of Tc Killing
Tc granules contain perforin and granzymes
Upon contact with target cell, granule
contents released, perforin polymerizes andforms channel in target cell membrane
Granzymes (serine proteases) enter target
cell through channel, activate caspases andnucleases, lead to apoptosis of target cell
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Mechanism of Tc Killing
Tccell
Ca++
Perforin
monomersPerforin
polymerizes
Polyperforinchannels
Tccell
Target cell
Granzymes
Targetcell
St i T Killi
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Steps in Tc Killing
Tc cell
1. Tc recognizes antigen on
target cellTarget cell
Tc cell
2. A lethal hit is delivered by
the Tc using agents such asperforin or granzyme B
Target cell
Tc cell
3. The Tc detaches
from the target cellTarget cell
4. Target cell dies
by apoptosis
Target cell
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Natural Killer (NK) Cells
Derived from bone marrow Lack most markers for T and B cells (do not
haveTCR)
Do not undergo thymic maturation
Express CD56, a specific NK marker
Express a receptor for Fc portion of IgG,called FcRIII (CD16)
Cytokines (IL-2) promote differentiation intolymphokine-activated killer (LAK) cells
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NK Cell Effector Mechanisms
Mechanism of killing similar to those of Tccells
Not MHC-restricted
Susceptibility of target cell to killing is
inversely proportional to expression of
class I MHC (killer inhibitory receptors(KIR) on NK cells recognize class I MHC and
prevent killing)
NK Effector Mechanisms
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NK Effector Mechanisms
(continued)
IgG-coated target cells recognized by FcRIII
(CD16) are killed by antibody-dependentcell-mediated cytotoxicity (ADCC)
Lymphokine-activated killer cells (LAK) kill
broader range of cells than do NK cells
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Mechanism of Hapten-Carrier
Hapten recognized by Ig receptor on Bcell
Hapten-carrier endocytosed
Carrier processed and presented onclass II MHC to Th cell
Activated Th cell produces cytokines
Cytokines enable B cell to be activatedto produce anti-hapten antibodies
Antigen
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CD40
Immunoglobulin
receptor
MHC II
B7 CD28
TCRT helpercell
g
1. Antigen presentation toTh cell
2. B7 expressed3. Th cell is
activated
and expresses
CD40 ligand,
Cytokines
secreted
CD40
ligand
Cytokine
Cytokine
receptor
B
cell
Bcell
Bcell
T helpercell
4. Cytokine
binds tocytokine
receptor,
CD40 ligand
binds to CD40
Bcell
Bcell
Bcell
5. B cell activated
6. B cells proliferate, differentiate, secrete Ig
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Class II MHC
APCTh cellB
cellTh cell
Bcell
Bcell
B cell takes up and
presents antigen
Th cell Th cell
B
cell
Th cells are primed by antigen-
presenting cell
B-T cell cooperationB cells receive signals from T cells
B cells divide
Bcell
Bcell
Bcell
Bcell
Antibody formingcell Antibody formingcell Antibody formingcell
B
memorycell
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B Cells In Secondary Responses
Memory cells created during primaryresponse
Have high-affinity Ig receptors Can therefore take up antigens at
much lower concentrations than other
antigen presenting cells that lack Igantigen receptors
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Cytokines
Non-antibody proteins acting as
mediators between cells, termed:
Monokines mononuclear phagocytes Lymphokines activated T cells, especially
helper T cells
Interleukins abbreviated IL with a
number
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Properties of Cytokines
1. Produced by cells involved in bothnatural and specific immunity
2. Mediate and regulate immune
responses
3. Secretion brief and limited - not stored
pre-formed - synthesis initiated by
gene transcription - mRNA short-lived
- cytokines produced as needed
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Properties of Cytokines
(continued)
4. Can be produced by many cell types and act on
many cell types (pleiotropic)
5. Can have similar actions (redundant)
IL2
R
IL2
R
IL2
R
IL15R
IL2
R
IL2
R
IL7R
IL2
R
?
IL9R
IL2
R
IL4R
IL2
R
IL-2 IL-15 IL-7 IL-9 IL-4Receptor for:
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Properties of Cytokines (continued)
6. Can influence synthesis of other cytokines
- produce cascades
- enhance or suppress production of othercytokines
- exert positive or negative regulatory
mechanisms for immune responses
7. Influence action of other cytokines - can be
antagonistic, additive, synergistic
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Properties of Cytokines (continued)
8. Bind to receptors with high affinity
9. Cells responding to cytokine can be:
- same cell (autocrine)
- nearby cell (paracrine)
- distant cell by circulation (endocrine)
10. Cellular responses to cytokines are slow,
require new mRNA and protein synthesis
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Tumor Necrosis Factor-alpha (TNF-)
Interleukin-1 (IL-1)
Chemokines (Chemotactic cytokines)
Type I Interferons (IFN- and IFN-)
Interleukin-12 (IL-12)
Interleukin-10 (IL-10)
Mediators and Regulators of
Natural Immunity
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Tumor Necrosis Factor (TNF-)
Produced by activated macrophages Most important mediator of acute
inflammation in response to microbes,
especially Gram-negative bacteria (LPS) Mediates recruitment of neutrophils and
macrophages to site of inflammation
Acts on hypothalamus to produce fever
Promotes production of acute phaseproteins
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Interleukin-1 (IL-1)
Produced by activated macrophages
Effects similar to those of TNF-
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Chemokines
Produced by many different
leukocytes and tissue cells
Large family of >50 substances
Recruit leukocytes to sites of infection
Play a role in lymphocyte trafficking
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Type I Interferons (IFN- and )
IFN- a family of many proteinsproduced by macrophages, IFN- a
single protein produced by many cells Both IFNs inhibit viral replication
Both increase expression of class I
MHC Both activate NK cells
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Interleukin-12 (IL-12)
Produced by activated macrophages and
dendritic cells
Stimulates production of IFN-
Induces differentiation of Th cells to
become Th1 cells
Enhances cytolytic functions of cytotoxic T
cells and NK cells
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Interleukin-10 (IL-10)
Produced by activated macrophages,Th2 cells
An inhibitory cytokine Inhibits cytokine production by
activated macrophages
Inhibits expression of class II MHC andcostimulatory molecules onmacrophages
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Mediators and Regulators of Specific
Immunity
Interleukin-2 (IL-2)
Interleukin-4 (IL-4) Interleukin-5 (IL-5)
Interleukin-10 (IL-10)
Interferon-gamma (IFN-)
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Interleukin-2 (IL-2)
Produced by Th>>Tc Main growth factor for T cells
IL-2
secretion
T cell
NKIncrease in NK
Cell activity
B cell Stimulationof division
T cell
Stimulation
of division and IFN gamma
release (and other
mediators)
Monocyte
Activation
Autocrine Function of IL 2
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Autocrine Function of IL-2
Activated
T cell
Resting
T cell
Class II MHC
APC
T cell
T cell T cell T cell T cell
T cell T cell T cell T cell
IL2 IL4 IL7
Binds to IL-2 receptor
Receptor
decay
Division
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Interleukin-4 (IL-4)
Produced by Th2 cells
Stimulates Ig class switching to IgE
isotype Stimulates development of Th2 cells
from nave Th cells
Promotes growth of differentiated Th2cells
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Interleukin-5 (IL-5)
Produced by Th2 cells
Promotes growth and differentiation
of eosinophils Activates mature eosinophils
IL-4 and IL-5 can work together
Helminths opsonized with IgE can bekilled by activated eosinophils
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Interleukin-10 (IL-10)
Produced by activated macrophages,
Th2 cells
Inhibits production of IFN- by Th1
cells needed to activate macrophages
Interferon gamma (IFN )
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Interferon-gamma (IFN-)
Produced by Th cells >> Tc and NK cells
Numerous functions in both natural and specificimmunity
Bcell
MacrophageNK
T cell
Th1 cell >
Tc cell
NK
Many cell types Many cell types
Induction of class I
and class II MHC
Increase in
NK
cell activity
Differentiation,
Stops cell divisionT cell activation
Weak anti-viral activity,
Stops cell division,Sto s hemato oiesis
Activation
Granulocyte
Activation
Endothelial cellActivation
IFN gamma
secretion
Stimulators of Hematopoiesis
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Stimulators of Hematopoiesis
Granulocyte-macrophage CSF (GM-CSF)
promotes growth and differentiation of
bone marrow progenitors
Macrophage CSF (M-CSF) is involved in
development and function of monocytes
and macrophages Granulocyte CSF (G-CSF) stimulates
production of polymorphonuclear
leucocytes (PMN)
Colony-Stimulating Factors (CSF)
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Cytokine Network
Many cytokines have effects on many
cells and organ systems in addition to
functions in immune systems
Referred to as the cytokine network
Effects on Cells of Immune System
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Effects on Cells of Immune System
LymphocyteMacrophage
Bcell T cell NK LAK
Proliferation,
Differentiation,
Ig secretion
and selection
Proliferation,
Differentiation,
Cytokine
production
Activation of cells of
immune system Cytokine production
cytokines
Cytokine Effects on Organ Systems
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Cytokine Effects on Organ Systems
Lymphocyte Macrophage
Hypothalmus
ACTH
Adrenal
gland
Corticosteroid
Liver
Acute phase proteins
Pituitary
Fever
cytokines
Cytokine Effects on Various Cells
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Cytokine Effects on Various Cells
Lymphocyte Macrophage
Fibrogenesis
Extracellular
matrix
cytokines
Endothelial cell
Fibroblasts
FibrinogenPermeability change
adhesion
Endothelial cells
cytokines
Hematopoiesis
Bone marrow
cytokines
Angiogenesis
Fibroblast
Extracellular
matrix
Osteoclasts
Tissue
remodelingTissue repair
IL1TNF
Anti-viral
state
Many cell types
IL1 TNF IFN
IFN IFN
Reg lation of Imm ne Responses
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Regulation of Immune Responses
Magnitude determined by balance between the
extent of lymphocyte activation and tolerance
induced by an antigen
Nature determined by specificities and
functional classes of lymphocytes activated
Regulatory mechanisms may act at the
recognition, activation, or effector phases of an
immune response