Inappropriate immune response against self-components Chapter 15 Autoimmunity Inappropriate immune response against self-components

The mechanism of self-tolerance The pre-disposing factors of autoimmune diseases Autoimmune diseases

Autoreactive lymphocytes Humoral imm 胞外 Th1 Th2 Self(Auto) antigen (encoded by the host’s genome) 胞內 CMI: CD8 T CD4 T effectors Immunopathology

B/T lymphocytes Development Central lymphoid organs Activation & differentiation 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 Adaptive immunity Four characteristics 1. Antigen specificity 2. Diversity 3. Immunological memory 4. Self tolerance Impaired (Central + peripheral) Autoimmune diseases

Within central lymphoid organs After BCR/TCR surface expression: Central tolerance Within central lymphoid organs After BCR/TCR surface expression: Self Ag presentation Major epitopes Criptic epitopes

Central B cell tolerance Self Ag presentation Wide variety of self antigens expressed by stromal cells, hematopoietic cells, and macromolecules circulating in the blood plasma Self-reactive immature B cells Receptor editing Clonal deletion (Apoptosis) Clonal anergy Clonal ignorance

Affinity

Self-reactivity

The presence of autoreactive B lymphocytes in periphery Central B cell tolerance Receptor editing Clonal deletion Clonal anergy Clonal ignorance Major epitopes Criptic epitopes The presence of autoreactive B lymphocytes in periphery

Central T cell tolerance Self Ag presentation AIRE expression on thymic medulary cells Natural Treg CD4+ CD25+ Major epitopes Clonal deletion Criptic epitopes: clonal ignorance Clonal anergy The presence of autoreactive T lymphocytes in periphery

Not normally presented Criptic epitopes Normal: without tissue injury and cell death Epitopes that normally hidden from the immune system Not normally presented by MHC molecules at sufficient levels Signal 1

Affinity Self Cross reactivity High affinity to non-self Ag

In periphery (no infection)

Peripheral tolerance When Ag exposure to immune system

DC Ag uptake & migration Signal 1, 2, 3 DC Ag uptake & migration DC maturation

Costimulation (Signal 2) T cell activation Ag (Signal 1) + Costimulation (Signal 2) Clonal expansion IL2 IL2Ra=CD25 Autocrine

Normal Self Ag Immature DC /migration

Lack of signal 2: T cell inactivation Peripheral tolerance Lack of signal 2: T cell inactivation Self Ag (Signal 1 only) Preventing anti-self response Clonal anergy 19

Induction of T cell anergy in periphery Self Ag

Regulation of signal 2 CTLA4

Peripheral tolerance Treg: CTLA4 Natural Treg CTLA4 Self Ag

Induction of Treg through signal 3 Cytokine (Signal 3) Induction of Treg through signal 3 Signal 1, 2, 3

Induction of Treg in periphery Immature Maintenance of peripheral tolerance Preventing anti-self response Adaptive Treg 24

Function of Treg Or cell-cell contact CTLA4

in the absence of infection Maintenance of tolerance by Treg in the absence of infection Adaptive Treg Natural Treg Inhibition of Th17, Th1, Th2, DC maturation

Th2 >> Th1

AICD FasL Clonal deletion

Maintenance of tolerance in infection Apoptosis of effectors Cell death & self tolerance Apoptosis of effectors Effectors ?

Immune privileged sites Tolerance induction Immunosuppressive cytokines: TGFb Treg FasL expression Non-destructive response Th2 >> Th1 Clonal deletion CMI

Maintenance of peripheral tolerance in the absence of infection Clonal anergy (signal 2) Natural Treg (thymus) & adaptive Treg No inflammatory cytokines (signal 3) Apoptosis of effectors Lack of CD4 T helper cells

Activation of autoreactive cells Ag exposure to immune system Tissue injury and cell death Clearance mechanism Activation of autoreactive cells

The breaking of self-tolerance Myocardial infarction Massive tissue injury and death 心肌梗塞 Ag exposure to immune system Autoimmune response against cardiac antigens Clearance mechanism Transient Inadequate or genetically deficient Autoimmune disease

Lymphocyte activation Self tolerance Lymphocyte activation Innate immunity Effector response Anti-nonself

成功不一定取決於起跑點 卻常取決於許多轉折點上

The mechanism of self-tolerance The pre-disposing factors of autoimmune diseases Autoimmune diseases

Self tolerance Clearance HLA Genetic Polymorphism or defect Clearance KO HLA

Genetic pre-disposition: HLA Association of HLA & autoimmune diseases

AutoAg presentation

Genetic pre-disposition

Signal 1 Signal 2 Signal 3 Dead cells Self Ag exposure Activation of autoreactive cells Pathological B, Th1 or Th2

Breaking of self tolerance ? Lymphocyte activation Immunopathology Lymphocyte activation Innate immunity Effector response Infection: foreign Ag Necrosis: Exposure of self Ag

AICD FasL

Activated T cells seem to enter all tissues in very small numbers 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

Intramolecular epitope spreading Clonal ignorance Intramolecular epitope spreading Criptic epitopes Epitopes that normally hidden from the immune system Signal 1 Exposure of T cell epitopes frequently to which the immune system is not tolerant

The mechanism of self-tolerance The pre-disposing factors of autoimmune diseases Autoimmune diseases

loss of normal function Hypersensitivity II-IV & autoimmune disease II: ADCC Cell/organ-specific Systemic III: Immune complex Activation of auto-reactive B/T cells Abnormal infiltration of leukocytes IV: Th1/mac CD8T Inflammation Chronic diseases Interference or even loss of normal function

Pathologic T cells Pathologic B cells Stimulating antibody Blocking

Identification of the major immune mechanism for disease

Ab: Cell destruction

Function-blocking antibody Myasthenia gravis Function-blocking antibody Muscle weakness

Stimulating antibody Graves’ disease Hyperthyroid The need to increase cell metabolism Stimulating antibody Graves’ disease Hyperthyroid

Autoantibodies against commom components of human cells can cause systemic autoimmune disease Cell death dsDNA Nucleoprotein AutoAg exposure Circulation Deposition

Deposition of immune complex SLE: IgG against a wide range of cell-surface and intracellular self Ag that are common to many cell types Deposition of immune complex can cause glomerulonephritis in the kidneys, arthritis in the joints, and a butterfly-shaped skin rash on the face. Skin

Role of pathologic T cells 風濕性關節炎 Rheumatoid arthritis (RA) Role of pathologic T cells (IgM, IgG, IgA specific for the Fc region of human IgG) Rheumatoid factor Th1-Mac

多發性硬化症 Multiple sclerosis

Experimental autoimmune encephalomyelitis (EAE) Brain autoantigen: myelin basic protein Multiple sclerosis Inflammation Alteration of tissue barriers

T cell mediated IDDM Leukocyte infiltration

HLA class II expression on inflammatory tissue Co-stimulation Cytokines

Tertiary lympohid stuructures Hashimoto’s thyroiditis Chronic inflammation Intense leukocyte infiltration Tissue damage Hypothyroid Tertiary lympohid stuructures Activation of thyroid Ag- specific B and T cells

Identification of the major immune mechanism for disease transfer

Self tolerance

What is the biological significance of the survival of auto-reactive clones in the central lymphoid organs.