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Immunological regulation. 1. Regulation on molecular level 2. Regulation on cellular level 3. Regulation on systemic level. Regulation on molecular level. 1. Feedback regulation in the signaling transduction of activated immune cells. Protein phosphoration and dephosphoration

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slide1

Immunological regulation

1. Regulation on molecular level

2. Regulation on cellular level

3. Regulation on systemic level

slide2

Regulation on molecular level

1. Feedback regulation in the signaling transduction

of activated immune cells

Protein phosphoration and dephosphoration

Protein tyrosine kinase,(PTK)—Activate the promotion and upstream

protein tyrosine phosphase(PTP)— Dephosphoration, negative regulation

molecules in signaling pathway.

slide3

Anti-BCR antibody

Anti-BCR antibody

Antigen-antibody

complex

Cross-linking of

receptors

Phosphoration

Dephosphoration

Recruit PTP, Syk

Block/ supress

Activation of B cell

Function of inhibitory receptor FcgR II-B

slide4

2. Two opposite receptors

1). Activating receptor:

ITAM(immunoreceptor tyrosine-based activation motif)

Motifs:YxxL/V

2). Inhibitory receptor:

ITIM(immunoreciptor tyrosine-based inhibitory motif)

Motifs:I/Vx YxxL

Activating receptors cross-linking is necessary fornegative regulation of inhibitory receptors

slide5

Antigen

Inhibitory receptor

Activating receptor

B cell

Phosphoration

Dephosphoration

Activate B cell

Inhibit B cell

Immunological regulation of activating and inhibitory receptors

激活性受体和抑制性受体的免疫调节作用

slide6

3. inhibitory receptor on immune cells

1. T cell: CTLA-4 and PD-1

On activated T cells,

Containing ITIM motif in the cytoplasmicdomain .

Use CTLA4-Ig fusion protein and anti-CTLA-4 antibody ,

inhibit or Enhance the function of specific T cell.

Application:anti-tumor, organ transplantation, autoimmune disease

2. B cell: FcgRII-B

Containing ITIM in the cytoplasmic domain of g chain

Associate with autoimmune disease

slide7

Ag-Ab complex

Anti-m chain IgG

B cell

B cell

Inhibition mediated by anti-IgM IgG

Inhibition mediated by anti-Immune complex IgG

Inhibition of B cell function by anti-BCR or anti-immune complex antibody

slide8

3. Killing cells (NK,CTL): KIR and CD94/NKG2A

Type I:Killing cell inhibitory receptor (KIR)

Ligation:HLA-I,HLA-G

Type II:C-type lectin receptorCD94/NKG2A:

Recognize a conservative 9aa peptide presented in leader sequence

of non-classical MHC class I --HLE;

Containing ITIM in the cytoplasmicdomain;

Application :

Physiologically, prevent the mother from rejecting the fetus ;

Pathologically, Excessively activated ,fail to kill virus infected cells ,

escape the immune surveillance

4. Mast cells:FcgRII-B

Cross-link with activating receptor FceRI on mast cells

Negatively regulate the immune response

slide9

Activating and inhibitory receptors on immune cells

Immune cell Activating receptorInhibitory receptor

B cell BCR FcgRII-B

T cell TCR,CD28 CTLA-4, PD-1

NK cell CD16 KIR, CD94/NKG2A

Mast cell FceRI FcgRII-B, gp49B1

slide10

2. Regulation on cellular level

1). T cell subsets and their interactions

2). Immunological regulation of idiotypic network

3). Negative immunological regulation of apoptosis

slide11

1. T cell subsets and their interactions

1)Natural regulatory T cell

CD4+CD25+regulatory T cell

Secret cytokines: TGF-、IL-10

Cell-cell contact :CTLA-4

slide13

2)CD4+ T cell and CD8+ T cell

Normal : CD4/ CD8=1.5-2:1

Upregulation: Positive regulation

Downregulation: < 1,Immunodeficiency

slide14

Naïve CD4+T cell

Activating CD4+T cell

Th0 cell

Th1 cell

Th2 cell

Activate macrophage

Enhance cytotoxicity

Induce delayed

Delayed type hypersensitivity

Cellular immune response

Activate B cell

Production of neutrolizing Ab

Involved in acute hypersensitivity

Humoral immune response

Imunological regulation of Th1/Th2

slide15

Involvement of Th1 ,Th2 cell and cytokines

Interconversion of Th1 and Th2

Lepra:Distinctly proliferation of Th2,

Arrest the conversion of Th0 to Th1,

Use IFN-g to promote Th1 ,and inhibit Th2 cells

slide16

2.Immunological regulation of idiotypic network

Basel Institute for Immunology Basel, Switzerland

1984 The Nobel Prize in Physiology or Medicine

Niels K. Jerne

1911-1994

slide17

IdiotypeId

Anti-idiotype antibodyAId

1) Anti-idiotype antibody and idiotypic network

(1)Idiotype of antibod,induce Anti-idiotype antibody

(anti-idiotype,Aid),Ab2

(2)Large amount of Ab can induce the production of

antibody

slide18

(3)Classification of Anti-idiotype antibody:

According to the distribution, Ab2a,Ab2b etc。

Ab2b (antigen internal image)

Similar structure with antigen epitope ,

Competitively bind to Ab1 with antigen

(4)Negative regulation of Anti-idiotype antibody

(5) Idiotypic network:Ag—Ab---Ab2----Ab3----

slide20

2)Immunointerference of Idiotypic network

(1) Utilize internal image to enhance Ag-specific immune response through inducing Ab1 and Ab3

(2) Induce the production of Ab2 in vivo,decrease or eliminate Ab1, prevent autoimmune disease

slide21

3. Negative immunological regulation of apoptosis

1)activation-induced cell death and specific immune response

(1)Fas 和FasL

Fas: Extensively expressed on tissue cells involving lymphocytes

FasL:Expressed on activated T cells(CTL,Th1),NK cell

AICD (activation-induced cell death):

FasL can bind to Fas on the same cell ,and induce self-apoptosis

Fas—DD—FADD—caspase 8—caspase cascade —cell death

slide22

death effector domain

Death domain

Apoptosis

Death effector

domain

Apoptosis signaling pathway mediated by Fas-FasL

slide23

(2)Caspase and cell apoptosis

Cysteine (c)

Aspartic acid (asp)

Caspase( exist in the form of zymogen)

Activated Lysis Induce cascade

slide24

Lack of cytokines

radiation

Mitochondria

Cyclin C

Caspase cascade

Cell apoptosis

Two apoptotic pathways of caspase

slide25

(3)Significance of AICD

Mutations of Fas and FasL

Autoimmune lymphoproliferative syndrome(ALPS)

slide26

T cell

proliferation

Ag repeat stimulation

Lack of Ag and

other necessory factors

Mitochondria

Autocrine

Cyclin C

T

cell

Activation-induced cell death

(AICD)

Passive cell death (PCD)

Negative immunological regulation by cell apoptosis

slide27

4.Immunological regulation on Systemic and group level

  • Regulation of nerve-endocrine-immunological network
  • 1)Nerve-endocrine factors
  • Corticosterone , androgen --- Downregulate immune response
  • Estrogen , rowth hormone, thyroxine, Insulin --- Upregulate immune response
  • 2)Antibody and cytokines act on nerve-endocrine system ----competitive combination
slide28

Central nerve system

Hypothalamus

Adenohypophysis

Cardiac sympathetic nerve

Cardiac sympathetic nerve

Endocrine hormone

Cytokines

Immune system

Thyroid gland

Thyroxine

Endocrine system

Thymic hormone

Thymus

Cytokine

Pancreas

Insulin

Gonad

sex hormone

Adrenal gland

Corticosterone

Regulation of nerve-endocrine-immunological network

神经-内分泌-免疫网络调节

slide29

2、Immunological regulation on group level

1)MHC polymorphism and group level of immunoregulation

2)Enhance the group flexibility

slide30

Immunological Tolerance

  • Formation and characteristics
  • Mechnism
  • Immunological Tolerance and diseases
slide31

Basic Concepts

Immunological tolerance is a state of unresponsiveness that is specific for a particular antigen ;it is induced by prior exposure to that antigen.

Differ from the universal immune suppression caused by immunodeficiency or drugs.

slide32

1. Formation and characteristics

  • Tolerance induced in fetal and neonatal stage ----
  • Natural immunogical tolerance
  • Immature T, B cell contact self and foreign Ag
  • Last for lifetime
  • 2. Tolerance induced in postnatal stage ----
  • Acquired immunogical tolerance
  • T、B cells Tolerance to Ag which they respond in normal condition
  • Not lifetime
slide33

1. Tolerance induced in fetal and neonatal stage

Natural immunogical tolerance

1)Owen's discovery

1945, Fraternal twin cattle:chimeras,

readily accept skin grafts from each other.

Reject skin grafts from other cattles

slide35

2)Medawar---Experimental immunological tolerance

1953,Medawar:Acquired immunological tolerance

slide36

Week 0

Week 6

Week 7

Transfuse cells from

strain B neonatal mice

to strain A mice

Skin implant from

strain B and C mice

to strain A

Skin implant

from B survived ,

that from C rejected

B cell

Medawar’s experimental immunological tolerance

slide37

2. Tolerance induced in postnatal stage

1)Antigen factors

2)Antigenic variation

slide38

1)Antigen

Tolerogen — Antigen inducing immune tolerance

1. Dose of Antigen:

High and low dose of TD Ag:

High zone tolerance(T,B cell tolerance)

Low zone tolerance(T cell tolerance)

slide39

2. Type of antigen:

Simple structure , small molecular ,soluble ---readily induce tolerance

Physical chemistry characters: BSA monomer

Polymers easier to be phagocytosed and to be presented )

slide40

3. Ways of Antigen injection:

Induction of tolerance

Oral , i.v. > i.p > s.c

Split tolerance:

Taking Ag orally induce local mucosal immune response ,

but systemic tolerance

slide41

4. Features of Ag epitopes

Hen egg white lysozyme ( HEL) induce tolerance

Ts epitopes and Th epitopes exist in N and C terminus, respectivly

HEL with 3 aa Deletion of N terminus will induce immune response.

slide43

2. Mechanism

1. Central tolerance

2. Peripheral tolerance

slide44

1. Central tolerance

Tolerance to self-antigen

1)T cell clonal deletion theory (negative selection)

2)B cell clone depletion:

slide45

Positive selection

Low expression of TCR ab

Clonal deletion( negative selection)

Mature T cell

High expression of TCR ab

Not bind to

self peptide-MHC I complex,

Survive and mature

Bind to

self peptide-MHC I complex,

apoptosis

Bind to

self peptide-MHC I complex

apoptosis

Not bind to

self peptide-MHC II complex,

Survive and mature

Clonal deletion theory

slide46

2. Peripheral tolerance

1)Clonal deletion and immunological ignorance

T cell anergy

a. Lack the second signal ---CD28-B7

b. Dysfunction of activating and proliferating signal transduction

c. Ag dose : too low to induce immune response

slide47

APC

APC

MHC- II

MHC- II

TCR

TCR

Co-stimulating

molecules

T cell

T cell

T细胞活化

T cell anergy

T cell activation

T cell anergy

Mechanism of clonal anergy

slide48

Clonal ignorance

Co-existence of

self-reactive T cell clones and associated tissue specific Ag ,

physiologically ,will not induce autoimmune disease.

slide49

2)Clonal anergy

no co-stimulatory molecules on immnature DC

3)Immunosupressive cells

Ts produce TGF- to inhibit Th and CTL function

4)Cytokine

5)Dysfunction of cellular signal transduction

slide50

6)Ag in immuno isolation region -----no immune response

brain, anterior chamber of eye, placent

(1) Physiological barrier

(2) Inhibitory cytokines: TGF-b , IL-4/IL-10 inhibit Th1

Produced by placental cytotrophoblast cells and endometrium epithelial cells

slide51

3. Immunological tolerance and clinic medicine

1. Induce immunological tolerance

2. Break immunological tolerance

slide52

1. Induce immunological tolerance

take antigen orally to induce systemic tolerance

Inject antigen in vein to induce systemic tolerance

Transplant bone marrow or thymus to induce or restore immune tolerance

Desensitization therapy prevent the production of IgE

Avoid infection

Induce the production of suppressive immune cells to inhibit the function of effector cells

Antagonistic peptide of self-antigen

slide53

Ag

Low dose

High dose

MHC II molecule

Antagonistic

peptide

Ag peptide

TCR complex

Anergy

T cell

Antagonistic peptide block

the activating signal of Ag

Oral tolerance

Induction of peripheral immunological tolerance

slide54

2.Break immunological tolerance

Usage of immunogen and immune response components

in tumor therapy

Rational utilization of Cytokines and their antibodies

Multiple steps to avoid infection , prevent the production of

Antagonistic molecules by pathogens

slide55

Master T cell subsets and their interaction

  • Master the concepts of idiotypic network and Antigen internal image
  • Master the differences between T and B cell tolerance
  • Familiar with the regulation function of ITAM and ITIM to immne cells activation
  • Familiar with the role of idiotypic network and apoptosis in the process of
  • immune regulation.
  • Familiar with the immune tolerance mechanism and influencing factors
  • Comprehend the inhibitory receptors on other immune cells
  • Comprehend the interaction of nerve-endocrine-immunological network
  • Comprehend the formation , sustenance , termination of immune tolerance,
  • and its biological significances