Autoimmunity Inappropriate immune response against self-components Chapter 15

Autoimmunity

Inappropriate immune response against self-components

Chapter 15

1. The mechanism of self-tolerance

2. The pre-disposing factors of autoimmune diseases

3. Autoimmune diseases

CMI: CD8 T

Humoral imm

胞內

胞外

Self(Auto) antigen

(encoded by the host’s genome)

Th2Th1

Immunopathology

Autoreactive lymphocytes

CD4 T effectors

B/T lymphocytes

Development

Activation & differentiation

Central lymphoid organs

Peripheral lymphoid organs

Effector function Inflamed sites

In healthy individuals the immune system is tolerant of self antigens

1. Antigen specificity

2. Diversity

3. Immunological memory

4. Self tolerance

Adaptive immunity

Four characteristics

Autoimmune diseases

(Central + peripheral)

Impaired

Major epitopes

Criptic epitopes

Self Ag presentation

Central tolerance Within central lymphoid organs

After BCR/TCR surface expression:

Wide variety of self antigens expressed by stromal cells, hematopoietic cells, and

macromolecules circulating in the blood plasma

Central B cell tolerance

Self Ag presentation

Clonal anergy

Clonal ignorance

Self-reactive immature B cells

Receptor editing

Clonal deletion (Apoptosis)

Affinity

Self-reactivity

Central B cell tolerance

Major epitopesClonal anergy

Clonal ignorance Criptic epitopes

Receptor editing

Clonal deletion

The presence of autoreactive B lymphocytes in periphery

Central T cell tolerance

AIRE expression on thymic medulary cells

Major epitopes

The presence of autoreactive T lymphocytes in periphery

Criptic epitopes: clonal ignorance

Self Ag presentation

Clonal deletion

Clonal anergy

Natural Treg

CD4+ CD25+

Not normally presented by MHC molecules at sufficient levels

Criptic epitopes

Epitopes that normally hidden from the immune system

Normal: without tissue injury and cell death

Signal 1

Cross reactivity

High affinity to non-self Ag

Affinity

Self

In periphery (no infection)

Peripheraltolerance When Ag exposure to immune system

DC maturation

Signal 1, 2, 3

DC Ag uptake & migration

IL2

Clonal expansion

Autocrine

Costimulation (Signal 2)

T cell activation

Ag (Signal 1) +

IL2Ra=CD25

Self Ag

Immature DC /migration

Normal

Preventing anti-selfresponse

Clonal anergy

Lack of signal 2: T cell inactivation

Peripheral tolerance

Self Ag (Signal 1

only)

Induction of T cell anergy in periphery

Self Ag

Regulation of signal 2

CTLA4

Peripheral tolerance

CTLA4

Treg: CTLA4

Natural Treg

Self Ag

Cytokine (Signal 3)

Signal 1, 2, 3

Induction of Treg through signal 3

Immature

AdaptiveTreg

Preventing anti-selfresponse

Maintenance of peripheral tolerance

Induction of Treg in periphery

Function of Treg

CTLA4

Or cell-cell contact

Maintenance of tolerance by Treg

in the absence of infection

Natural Treg

Inhibition of Th17, Th1, Th2, DC maturation

AdaptiveTreg

Th2 >> Th1

AICD FasL

Clonal deletion

Cell death & self tolerance

Maintenance of tolerance in infection

Effectors ?Apoptosis of effectors

Tolerance induction

Non-destructive response

Immunosuppressive cytokines: TGFb

Th2 >> Th1

Immune privileged sites

CMI

FasL expression

Treg

Clonal deletion

1. Clonal anergy (signal 2)

2. Natural Treg (thymus) & adaptive Treg

3. No inflammatory cytokines (signal 3)

4. Apoptosis of effectors

Maintenance of peripheral tolerance in the absence of infection

Lack of CD4 T helper cells

Tissue injuryand cell death

Ag exposure to immune system

Clearance mechanismActivation of

autoreactive cells

Autoimmune response against cardiac antigens

Massive tissue injury and deathMyocardial infarction

Transient Clearance mechanism

Inadequate or genetically deficient Autoimmune disease

Ag exposure to immune system

The breaking of self-tolerance

心肌梗塞

Innate immunity

Effector response

Self tolerance

Anti-nonself

Lymphocyte activation

成功不一定取決於起跑點

卻常取決於許多轉折點上

1. The mechanism of self-tolerance

2. The pre-disposing factors of autoimmune diseases

3. Autoimmune diseases

Self tolerance

Clearance

KO

Genetic Polymorphism

or defect

HLA

Genetic pre-disposition: HLA

Association of HLA & autoimmune diseases

AutoAg presentation

Genetic pre-disposition

Signal 1Signal 2Signal 3

Pathological B, Th1 or Th2

Dead cells

Self Ag exposure

Activation of autoreactive cells

Innate immunity

Effector response

Breaking of self tolerance ?

Immunopathology

Lymphocyte activation

Necrosis:Exposure of self Ag

Infection:foreign Ag

AICDFasL

Activated T cells seem to enter all tissues

in very small numbers

44

But accumulation of cells is seen only when

antigen is recognized in the site, triggering the

production of cytokines that alter tissue barriers

Molecular mimicry

Infection and autoimmune T cell activation

Infection could break self tolerance

Infection can break tolerance

TLR signals provide co-stimulation for B cell activation

Epitope spreading

Amplification

Disease severity

Criptic epitopes

Epitopes that normally hidden from the immune system

Clonal ignorance

Signal 1

Intramolecular epitope spreading

Exposure of T cell epitopes frequently to which the immune system is not tolerant

1. The mechanism of self-tolerance

2. The pre-disposing factors of autoimmune diseases

3. Autoimmune diseases

Chronic diseases

Activation of auto-reactive B/T cells

Abnormal infiltration of leukocytes

Inflammation

Interference or even loss of normal function

Cell/organ-specificSystemic

Hypersensitivity II-IV & autoimmune disease

II: ADCC

III: Immune complex

IV: Th1/mac CD8T

Stimulatingantibody Blocking

antibody

Pathologic B cells

Pathologic T cells

Identification of the major immune mechanism for disease

Ab:

Cell destruction

Function-blocking antibody

Myasthenia gravis

Muscle weakness

Stimulatingantibody

Hyperthyroid

The need to increase cell metabolism

Graves’ disease

Autoantibodies against commom components of human cells can cause systemic autoimmune disease

Cell death

AutoAg exposure

Deposition

Circulation

dsDNANucleoprotein

Deposition of immune complex

Skin

SLE: IgG against a wide range of cell-surface and intracellular self Ag that are common to many cell types

can cause glomerulonephritis in the kidneys, arthritis in the joints, and a butterfly-shaped skin rash on the face.

Rheumatoid arthritis (RA)

(IgM, IgG, IgA specific for the Fc region of human IgG)Rheumatoid

factor

Th1-Mac

Role of pathologic T cells

風濕性關節炎

Multiple sclerosis

多發性硬化症

Brain autoantigen: myelin basic protein

Experimental autoimmune encephalomyelitis (EAE)

Multiple sclerosisInflammation

Alteration of tissue barriers

T cell mediated IDDM Leukocyte infiltration

HLA class II expression on inflammatory tissue

Co-stimulation Cytokines

Hashimoto’s thyroiditis Intense leukocyte infiltration

Chronic inflammation

Tissue damage

Hypothyroid

Activation of thyroid Ag-specific B and T cells

Tertiary lympohid stuructures

Identification of the major immune mechanism for disease

Disease transfer

Self tolerance

What is the biological significance of the

survival of auto-reactive clones in the central

lymphoid organs.