Autoimmunity Inappropriate immune response against self-components Chapter 15.
69
Autoimmunity Inappropriate immune response against self-components Chapter 15
-
Upload
derick-gordon -
Category
Documents
-
view
223 -
download
0
Transcript of 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
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.
