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

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

3. 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

4. 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

5. 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

6. 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

7. 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

8. Affinity

9. Self-reactivity

10. 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

11. 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

12. 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

13. Affinity
Self
Cross reactivity
High affinity to
non-self Ag

14. In periphery (no infection)

15. Peripheral
tolerance
When Ag exposure to immune system

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

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

18. Normal
Self Ag
Immature DC /migration

19. 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

20. Induction of T cell anergy in periphery
Self Ag

21. Regulation of
signal 2
CTLA4

22. Peripheral tolerance
Treg: CTLA4
Natural
Treg
CTLA4
Self Ag

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

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

25. Function of Treg
Or cell-cell contact
CTLA4

26. 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

27. Th2 >> Th1

28. AICD
FasL
Clonal deletion

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

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

31. 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

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

33. 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

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

35. 成功不一定取決於起跑點
卻常取決於許多轉折點上

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

37. Self tolerance Clearance HLA
Genetic
Polymorphism
or defect
Clearance KO
HLA

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

39. AutoAg presentation

40. Genetic pre-disposition

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

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

43. AICD
FasL

44. 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

45. Molecular mimicry

46. Infection and autoimmune T cell activation

47. Infection could
break self tolerance

48. Infection can
break tolerance

49. TLR signals provide co-stimulation for B cell activation

50. Epitope
spreading
Amplification
Disease severity

51. 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

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

53. 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

54. Pathologic T cells Pathologic B cells Stimulating antibody Blocking

55. Identification of the major immune mechanism for disease

56. Ab:
Cell destruction

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

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

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

60. 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

61. 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

62. 多發性硬化症
Multiple sclerosis

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

64. T cell mediated IDDM
Leukocyte infiltration

65. HLA class II expression on inflammatory tissue
Co-stimulation
Cytokines

66. 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

67. Identification of the major immune mechanism for disease
transfer

68. Self tolerance

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