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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?.

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Chapter 10 Immunologic Tolerance

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Chapter 10 immunologic tolerance

Chapter 10Immunologic Tolerance

  • General Features and Mechanisms

  • T Lymphocyte Tolerance

  • B Lymphocyte Tolerance

  • Tolerance induced by Foreign Protein Antigens

  • Homeostasis in the Immune System


Chapter 10 immunologic tolerance

What is Immunologic Tolerance?

Immunologic Tolerance—— an antigen induced specific unresponsiveness

Tolerogens Immunogens

Self-tolerance  Autoimmunity

Tolerance induced by foreign antigens

Failure


General features and mechanisms

General Features and Mechanisms

  • Immunologically specific

  • A result of antigen recognition by specific lymphocytes


Chapter 10 immunologic tolerance

Studies of graft rejection in inbred mice

Strain A

Strain A

Strain A

Neonate

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 mechanisms1

General Features and Mechanisms

  • Immunologically specific

  • Central tolerance: induced in generative lymphoid organs immature self-reactive lymphocyte

The repertoire of mature lymphocytes cannot recognize ubiquitous or widely disseminated self antigens

The repertoire of mature lymphocytes cannot recognize ubiquitous or widely disseminated self antigens


Chapter 10 immunologic tolerance

Burnet: Clonal selection hypothesis


General features and mechanisms2

General Features and Mechanisms

  • Immunologically specific

  • Central tolerance: generative lymphoid organs immature self-reactive lymphocyte

  • Peripheral tolerance: peripheral sites mature self-reactive lymphocytes

The repertoire of mature lymphocytes cannot recognize ubiquitous or widely disseminated self antigens

The repertoire of mature lymphocytes cannot recognize ubiquitous or widely disseminated self antigens

Important for maitaining unresponsiveness to self antigens that are not expressed in the generative lymphoid organs.


Chapter 10 immunologic tolerance

Peripheral tolerance is induced when mature lymphocytes recognize antigens without adequate levels of the costimulators.


The principal mechanisms of lymphocyte tolerance

The principal mechanisms of lymphocyte tolerance

  • Deletion: apoptotic cell death

  • Anergy: functional inactivation without cell death

  • Treg

Central tolerance

Peripheral tolerance


Chapter 10 immunologic tolerance

Apoptosis


Chapter 10 immunologic tolerance

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

T Lymphocyte Tolerance

  • Central T Cell Tolerance

  • Peripheral T cell Tolerance


Chapter 10 immunologic tolerance

Maturation of T cells in the thymus


Chapter 10 immunologic tolerance

High affinity

High concentration

Negative selection: Development of central tolerance


Self antigens expressed in the thymus

Self antigens expressed in the thymus

  • ubiquitous self-antigen: widely expressed in the body

  • tissue-specific antigenautoimmune regulator gene, AIRE


Natural tregs arise in the thymus

Natural Tregs arise in the thymus


T lymphocyte tolerance1

T Lymphocyte Tolerance

  • Central T Cell Tolerance

  • Peripheral 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 tolerance1

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


Chapter 10 immunologic tolerance

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

co-stimulatory signal


Figure 8 20

Figure 8-20

Gowth factor: IL-2


Chapter 10 immunologic tolerance

Anergy is induced when mature lymphocytes recognize antigens without adequate levels of the costimulators.


Figure 8 12

Figure 8-12

CTLA-4/B7 initiate the inhibitory signal


Anergy may be induced if t cells use ctla 4 to recognize costimulators on apcs

Anergy may be induced if T cells use CTLA-4 to recognize costimulators on APCs


Question

?

?

?

?

?

?

?

Question

Factors

T cells

T cells

T cells

recognize B7 molecules with CD28 (active receptor)

?

Recognize the same B7 with CTLA-4 (inhibitory receptor)

Immune response

Tolerance


Chapter 10 immunologic tolerance

Making and breaking tolerance

The nature of tissue APCs is an important determinant of whether self-tolerance or autoimmunity develops.


Peripheral t cell tolerance2

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

Activation induced cell death

Repeated stimulation of T cells by persistent antigen results in death of the activated cells by a process of apoptosis


Chapter 10 immunologic tolerance

Fas-mediated activation-induced cell death

AICD is a form of apoptosis induced by signals from membrane death receptors


Chapter 10 immunologic tolerance

activation

activation

The net effect is that the population of mature lymphocytes is depleted of antigen specific lymphocytes by repeated stimulation.


Peripheral t cell tolerance3

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


Chapter 10 immunologic tolerance

Treg cell development

Immunity 2009; 30: p626


T cell mediated suppression

T cell-mediated suppression


Mechanisms of action of regulatory t cells

Mechanisms of action of regulatory T cells


Peripheral t cell tolerance4

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

Factors That Determine the Immunogenicity and Tolerogenicity of Protein


Chapter 10 immunologic tolerance

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

B Lymphocyte Tolerance

  • Central B Cell Tolerance

  • Peripheral B cell Tolerance

Checkpoints during B cell maturation and activation at which encounter self Ags may abort these process


Chapter 10 immunologic tolerance

B cell development in bone marrow


Central tolerance in b cells

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


Chapter 10 immunologic tolerance

HEL transgenic

What is the result of self antigen recognition in generative lymphoid organ?

  • Down-regulation of antigen receptor expression

  • Change in receptor specificity (receptor editing)


B lymphocyte tolerance1

B Lymphocyte Tolerance

  • Central B Cell Tolerance

  • Peripheral B cell Tolerance


Chapter 10 immunologic tolerance

CD28

B7

T-B Collaboration


Peripheral tolerance in b cells

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.


Chapter 10 immunologic tolerance

脑 Brain癫痫 seizures精神病 psychosis头痛 headache

头发 Hair脱发 alopecia

脸 Face颊部红斑 malar rash盘状红斑 discoid rash

肺 Lungs胸膜炎 pleurisy间质性肺炎 interstitial pneumonia

心 Heart心包炎 pericarditis心肌炎 myocarditis心内膜炎 endocarditis肺动脉高压 pulmonary hypertension

血液、血管 Blood & Vessels血管葱皮样改变 onion-skin like artery贫血 anemia血栓 thrombosis

小肠 Intestines血管炎 vasculitis

手 Hands雷诺氏现象 Raynauds phenomenonJaccoud关节病

肾 Kidneys蛋白尿 proteinuria管型 casts

关节 Joints关节炎 arthritis

足 Feet血管炎 vasculitis

systemic lupus erythematosus 


Butterfly rash

蝶型红斑 (Butterfly rash)


Homogenous pattern

Homogenous pattern

Peripheral pattern

Speckled pattern


Chapter 10 immunologic tolerance

  • 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


Chapter 10 immunologic tolerance

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 protein1

Factors That Determine the Immunogenicity and Tolerogenicity of Protein


Chapter 10 immunologic tolerance

Immunologic Tolerance

  • General Features and Mechanisms

  • T Lymphocyte Tolerance

  • B Lymphocyte Tolerance

  • Tolerance induced by Foreign Protein Antigens

  • Homeostasis in the Immune SystemTermination of normal immune response


Mechanisms of the decline of normal immune response homeostasis

Mechanisms of the decline of normal immune response (homeostasis)

CTLA-4、Fas、FasL


Chapter 10 immunologic tolerance

Ag

TCR

B7

CD28

B7

CTLA-4

ITIM

ITAM

24h

Inhibitorysignal

Active signal

T cell


Antibody feedback

Antibody feedback


Chapter 10 immunologic tolerance

Ab1

Ag

Ab2

Ab2

Ab1

Ab3

Niels Jerne: Network hypothesis

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

Summary

  • What is immunologic tolerance?

  • Central and peripheral tolerance

  • Tolerance in T and B cells

  • Homeostasis


Chapter 10 immunologic tolerance

What is Immunologic Tolerance?

Tolerance—— an antigen induced specific unresponsiveness

Tolerogens Immunogens

Self-tolerance  Autoimmunity

Tolerance induced by foreign antigens


Chapter 10 immunologic tolerance

THANK YOU


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