Chapter 10
Immunologic Tolerance
 General Features and Mechanisms
 T Lymphocyte Tolerance
 B Lymphocyte Tolerance
 Tolerance induced by Foreign Protein Antigens
 Homeostasis in the Immune System
What is Immunologic Tolerance?

Immunologic Tolerance——
an antigen induced specific unresponsiveness
 Tolerogens  Immunogens
Failure
 Self-tolerance  Autoimmunity
 Tolerance induced by foreign antigens
General Features and Mechanisms
 Immunologically specific
 A result of antigen recognition by specific
lymphocytes
Studies of graft rejection in inbred mice
Strain A
Neonate
Strain A
Strain A
Adult
Skin graft
rejection
+
_
During lymphocyte maturation in the
generative lymphoid organs, all
lymphocytes pass through a stage in
which encounter with Ag leads to
tolerance
+
 Immunologically specific
 a result of the recognition of
antigens by specific lymphocytes
General Features and Mechanisms
 Immunologically specific
 Central tolerance:
induced in generative lymphoid organs
immature self-reactive lymphocyte
The
repertoire ofofmature
The repertoire
maturelymphocytes
lymphocytescannot
cannotrecognize
recognize
ubiquitous or
antigens
or widely
widelydisseminated
disseminatedself
self
antigens
Burnet: Clonal selection hypothesis
General Features and Mechanisms
 Immunologically specific
 Central tolerance:
generative lymphoid organs
immature self-reactive lymphocyte
The
repertoire ofofmature
The repertoire
maturelymphocytes
lymphocytescannot
cannotrecognize
recognize
ubiquitous or
antigens
or widely
widelydisseminated
disseminatedself
self
antigens
 Peripheral tolerance:
peripheral sites
mature self-reactive lymphocytes
Important for maitaining unresponsiveness to self
antigens that are not expressed in the generative
lymphoid organs.
Peripheral tolerance is induced when mature lymphocytes
recognize antigens without adequate levels of the
costimulators.
The principal mechanisms of lymphocyte
tolerance
Central tolerance
 Deletion:
apoptotic cell death
 Anergy:
functional inactivation without cell death
 Treg
Peripheral tolerance
Apoptosis
Immunologic Tolerance
 General Features and Mechanisms
 T Lymphocyte Tolerance
 B Lymphocyte Tolerance
 Tolerance induced by Foreign Protein Antigens
 Homeostasis in the Immune System
T Lymphocyte Tolerance
 Central T Cell Tolerance
 Peripheral T cell Tolerance
Maturation of T cells in the thymus
Negative selection: Development of central tolerance
Self antigens expressed in the thymus
 ubiquitous self-antigen:
widely expressed in the body
 tissue-specific antigen
autoimmune regulator gene, AIRE
Natural Tregs arise in the thymus
T Lymphocyte Tolerance
 Central T Cell Tolerance
 Peripheral T cell Tolerance
Peripheral T cell Tolerance





Antigen recognition without adequate costimulation
Use CTLA-4 to recognize costimulators on APCs
Activation induced cell death (AICD)
Regulatory T Lymphocytes
Factors that determine the tolerogenicity of self antigens
Peripheral T cell Tolerance





Antigen recognition without adequate costimulation
Use CTLA-4 to recognize costimulators on APCs
AICD
Treg
Factors that determine the tolerogenicity of self antigens
Two Signal model
Sig2
(co-stimulation)
1975 Lafferty & Cunningham
T helper cells die when they see antigen unless rescued
by co-stimulation(signal two) from APCs.
co-stimulatory signal
Gowth factor: IL-2
Figure 8-20
Anergy is induced when mature lymphocytes recognize
antigens without adequate levels of the costimulators.
CTLA-4/B7 initiate the inhibitory signal
Figure 8-12
Anergy may be induced if T cells use CTLA-4 to
recognize costimulators on APCs
Question
Factors
T cells
recognize B7 molecules
with CD28 (active receptor)
Recognize the same B7
with CTLA-4 (inhibitory
receptor)
Tolerance
Immune
response
Making and breaking tolerance
The nature of tissue APCs is an important determinant
of whether self-tolerance or autoimmunity develops.
Peripheral T cell Tolerance





Antigen recognition without adequate costimulation
Use CTLA-4 to recognize costimulators on APCs
AICD
Treg
Factors that determine the tolerogenicity of self
antigens
Activation induced cell death
Repeated stimulation of T cells by persistent antigen
results in death of the activated cells by a process of
apoptosis
Fas-mediated activation-induced cell death
AICD is a form of
apoptosis
induced by
signals from
membrane death
receptors
activation
activation
The net effect is that the population of mature lymphocytes is
depleted of antigen specific lymphocytes by repeated stimulation.
Peripheral T cell Tolerance





Antigen recognition without adequate costimulation
Use CTLA-4 to recognize costimulators on APCs
AICD
Regulatory T Lymphocytes (Treg)
Factors that determine the tolerogenicity of self antigens
Treg cell development
Immunity 2009; 30: p626
T cell-mediated suppression
Mechanisms of action of regulatory T cells
Peripheral T cell Tolerance





Antigen recognition without adequate costimulation
Use CTLA-4 to recognize costimulators on APCs
AICD
Regulatory T Lymphocytes (Treg)
Factors that determine the tolerogenicity of self antigens
Factors That Determine the Immunogenicity and
Tolerogenicity of Protein
Factor
Factors that favor stimulation of Factors that favor
immune response
tolerance
Amount
Optimal doses that vary for
different antigens
High doses
Persistence
Short-lived
(eliminated by immune
response)
Prolonged
(AICD)
Portal of
entry;
location
Subcutaneous, intradermal;
absence from generative
organs
Intravenous, oral;
presence in
generative organs
Presence of
adjuvants
Antigens with adjuvants:
stimulate helper T cells
Antigens without
adjuvants:
Properties of
APCs
High levels of costimulators
Low levels of
costimulators and
cytokines
Immunologic Tolerance
 General Features and Mechanisms
 T Lymphocyte Tolerance
 B Lymphocyte Tolerance
 Tolerance induced by Foreign Protein Antigens
 Homeostasis in the Immune System
B Lymphocyte Tolerance
 Central B Cell Tolerance
 Peripheral B cell Tolerance
B cell development in bone marrow
Central tolerance in B cells
•
•
Immature B cells that recognize self antigens in the
bone marrow with high affinity are deleted or
change their specificity.
multivalent self antigens:
cell membrane molecules、polymeric molecules
What is the result of self antigen recognition in
generative lymphoid organ?
HEL transgenic
 Down-regulation of antigen receptor expression
 Change in receptor specificity (receptor editing)
B Lymphocyte Tolerance
 Central B Cell Tolerance
 Peripheral B cell Tolerance
CD28
T-B
Collaboration
Peripheral tolerance in B cells
•
Mature B cells that recognize self antigens in
peripheral tissues in the absence of specific helper
T cells may be rendered functionally unresponsive.
If anergic B cells do encounter any
antigen-specific helper T cells, what
happened?
The B cells maybe killed by FasL on the T
cells engaging Fas on the B cells.
脑 Brain
头发 Hair
脱发 alopecia
癫痫 seizures
精神病 psychosis
头痛 headache
脸 Face
肺 Lungs
胸膜炎 pleurisy
间质性肺炎 interstitial pneumonia
颊部红斑 malar rash
盘状红斑 discoid rash
心 Heart
血液、血管 Blood & Vessels
血管葱皮样改变 onion-skin like artery
贫血 anemia
血栓 thrombosis
心包炎 pericarditis
心肌炎 myocarditis
心内膜炎 endocarditis
肺动脉高压 pulmonary hypertension
小肠 Intestines
血管炎 vasculitis
肾 Kidneys
蛋白尿 proteinuria
管型 casts
手 Hands
雷诺氏现象 Raynauds
phenomenon
Jaccoud关节病
关节 Joints
关节炎 arthritis
足 Feet
血管炎 vasculitis
systemic lupus erythematosus
蝶型红斑 （Butterfly rash）
Homogenous pattern
Peripheral pattern
Speckled pattern
•
•
Normal individals do not produce autoantibodies against
self protein antigens, and this may be due to deletion or
tolerance of helper T lymphocytes even if functional B
cells are present.
Defects in the maintenance of T cell tolerance may result
in autoantibody production
Feature
T lymphocyte
B lymphocyte
Principal sites
Thymus (cortex);
peripheral
Bone marrow;
peripheral
ToleranceCD4+CD8+ thymocyte
sensitive stage
Stimuli for
tolerance
induction
Principal
mechanisms
of tolerance
Immature B lymphocytes
Central:
high-avidity recognition of Ag in
thymus
Central:
high-avidity recognition of
multivalent Ag in bone marrow
Peripheral:
Ag presentation by APCs lacking
costimulators; repeated
stimulation by self Ag
Peripheral:
Ag recognition without T cell
helper
Central tolerance:
clonal deletion (apoptosis)
Central tolerance:
clonal deletion (apoptosis),
receptor editing
Peripheral tolerance:
anergy, AICD, suppression
Peripheral tolerance:
block in signal transduction
(anergy); failure to enter FC
Immunologic Tolerance
 General Features and Mechanisms
 T Lymphocyte Tolerance
 B Lymphocyte Tolerance
 Tolerance induced by Foreign Protein Antigens
 Homeostasis in the Immune System
Factors That Determine the Immunogenicity and
Tolerogenicity of Protein
Factor
Factors that favor stimulation of
immune response
Factors that favor
tolerance
Amount
Optimal doses that vary for
different antigens
High doses
Persistence
Short-lived
(eliminated by immune response)
Prolonged
(AICD)
Portal of
entry;
location
Subcutaneous, intradermal;
absence from generative organs
Intravenous, oral;
presence in generative
organs
Presence of
adjuvants
Antigens with adjuvants:
stimulate helper T cells
Antigens without
adjuvants:
Properties
of APCs
High levels of costimulators
Low levels of
costimulators and
cytokines
Immunologic Tolerance
 General Features and Mechanisms
 T Lymphocyte Tolerance
 B Lymphocyte Tolerance
 Tolerance induced by Foreign Protein Antigens
 Homeostasis in the Immune System
Termination of normal immune response
Mechanisms of the decline of normal immune response
(homeostasis)
CTLA-4、Fas、FasL
Ag
TCR
B7
B7
CD28
CTLA-4
I TAM
ITIM
24 h
Inhibitory
signal
Active
signal
T cell
Antibody feedback
Niels Jerne: Network hypothesis
Ab1
Ab2
Ab3
Ab2
Ag
Ab1
threshold
The repertoire for TCR and BCR (Ab)
Idiotype and anti-idiotypic
Reach a steady state at which the immune system is
at homeostasis
Summary
 What is immunologic tolerance?
 Central and peripheral tolerance
 Tolerance in T and B cells
 Homeostasis
What is Immunologic Tolerance?
 Tolerance——
an antigen induced specific unresponsiveness
 Tolerogens  Immunogens
 Self-tolerance  Autoimmunity
 Tolerance induced by foreign antigens
Feature
T lymphocyte
B lymphocyte
Principal sites
Thymus (cortex);
peripheral
Bone marrow;
peripheral
ToleranceCD4+CD8+ thymocyte
sensitive stage
Stimuli for
tolerance
induction
Principal
mechanisms
of tolerance
Immature B lymphocytes
Central:
high-avidity recognition of Ag in
thymus
Central:
high-avidity recognition of
multivalent Ag in bone marrow
Peripheral:
Ag presentation by APCs lacking
costimulators; repeated
stimulation by self Ag
Peripheral:
Ag recognition without T cell
helper
Central tolerance:
clonal deletion (apoptosis)
Central tolerance:
clonal deletion (apoptosis),
receptor editing
Peripheral tolerance:
anergy, AICD, suppression
Peripheral tolerance:
block in signal transduction
(anergy); failure to enter FC
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