1. Immunological Tolerance and Autoimmune Diseases

2. Immunological Tolerance
a state of specific immunological unresponsiveness to a particular antigen in a fully immunocompetent person
- Immunogen
- tolerogen

3. Immunological Tolerance
Types of tolerance:
Naturally acquired (Neonatal, self ,auto tolerance)
Tolerance to self is initially induced during embryonic life, and is maintained by antigen , continues to occur at some level throughout life (as new lymphocytes are produced from bone marrow stem cells)
Specifically Induced

4. Induced Tolerance Low Zone Tolerance High Zone Tolerance
Therapeutic Inducing tolerance may be exploited to prevent graft rejection, treat autoimmune and allergic diseases
-T cells becomes tolerance quicker & last longer than B cells
-The simpler the Ag gets Better Tolerance because has less epitopes
Can be achieved by
Low Zone Tolerance
High Zone Tolerance

5. Mechanisms of Immunological Tolerance - Overview
Central Tolerance through Clonal Deletion
Clones of cells that have receptors for self-antigens are deleted during development
Peripheral tolerance

6. Peripheral Tolerance
1- Immunological ignorance to some self antigens (anatomical barrier)
2- T-cell anergy a- signal block: failure of APC to deliver a second signal during antigen presentation (example: B7-CD28 interaction)
b- engagement of inhibitory receptors (CTLA-4)

7. Peripheral Tolerance
3- Suppression of responses by regulatory T- cells (CD4+ CD25+) : secretion of immunosuppressive cytokines (IL-10 & TGF-B)
4- Deletion (activation-induced cell death):
T- cell apoptosis by engagement of death receptors (Fas-Fas L)

8. Central Tolerance

9. Foreign Ag + second signal
Central Tolerance
DEVELOPMENT MATURITY
Clonal Deletion
Anti-self
Lymphocyte
Self Ag
Activation
Differentiation
Anti-non-self
Lymphocyte
Foreign Ag + second signal

10. Peripheral tolerance Normal T cell response Anergy Apoptosis
APC
CD28
Normal T cell
response
Activated
T cells
TCR
APC
Functional
unresponsiveness
Anergy
Off signals
TCR
Activated
T cell
APC
Apoptosis
(activation-induced
cell death)
Deletion
APC
Suppression
Block in
activation
Regulatory
T cell

11. Pathways to Peripheral Tolerance

12. Pathways to Peripheral Tolerance
Activated T cells
Normal Response
CD28 B7
Proliferation & differentiation
Antigen Recognition without co-stimulation
Anergy
CTLA4 B7
Functionally Unresponsive
CTL4-B7 interaction
Fas
Activation induced cell death
Fas-FasL interaction
Adapted From:   Van Parijs: Science, Volume 280(5361).April 10,
Apoptosis
FasL
Inhibition of proliferation &
effector action
Cytokine-mediated suppression
Cytokine regulation
cytokines

13. Properties of regulatory T cells Th 3 (T reg)
Phenotype: CD4, high IL-2 receptor (CD25), low IL-7 receptor, other markers
Mechanisms of action: multiple
secretion of immune-suppressive cytokines (TGF, IL-10, ),
inactivation of dendritic cells or responding lymphocytes

14. Functionally Unresponsive T cell
Regulatory T cells
Production of IL-10 or TGF-b
Functionally Unresponsive T cell
Regulatory T cell

15. The Two Signal Hypothesis for T-cell Activation
Mature
Dendritic
cell
APC
Activated
TH cell TH
cell
MHC II
TCR
CD28 B7
Signal 2

16. Hypothetical mechanism of tolerance in mature T cells
Signal 1
CD28
Resting
B-cell
APC
TH0 cell
Tolerant
T cell
Tolerance (anergy or apoptosis)
from lack of signal 2

17. Functionally Unresponsive (Anergic) T cell
Regulation by CTLA-4
CTLA4
CTLA4-B7 interaction
Functionally Unresponsive (Anergic) T cell B7
Activated T cell

18. Summary: Lack of co-stimulation can lead to tolerance (anergy)
Activated T cells
CD28 B7
Proliferation &
differentiation
Normal Response
Antigen Recognition without co-stimulation
Anergy

19. Tolerance: Establishment and Failure
Generation of immune repertoires
Bone Marrow
Thymus 
Central Tolerance 
Self-reactive lymphocytes
Deleted by negative selection  
Leakage of self-reactive lymphocytes controlled
Peripheral Tolerance
Wrong environment
(viral infection?)
Wrong genes
or mutations
Tolerance fails
Autoimmune Diseases

20. Autoimmune Diseases Immune reaction against self-antigen which
present in own tissues, they are characterized by tissue damage, disturbed physiological function, chronicity & usually non reversible
Affect female > male
Usually started at years of age

21. Autoimmune Diseases Predisposing Factors: 1- Advancing age
2- Hormonal factors (more common in females)
3- Genetic predisposition
4- Environmental factors (infection, drugs, U.V light, psychological stress, dietary factors)

22. Mechanisms of Autoimmune Disease (Loss of self-tolerance)
1- Emergence of sequestered antigens (e.g., eye, brain ,thyroid , sperm )
2- Molecular mimicry
Microbes share epitopes with self-antigens
Ex. Streptococci and rheumatic heart disease
3- Polyclonal lymphocyte activation (Endotoxin, EBV , AIDS , CMV)

23. 4- Alteration of normal proteins
Procainamide induces SLE
5- Inappropriate expression of class II MHC molecules
Normally only on APC s
After viral infection or trauma the released gamma IFN leads to
expressing class II MHC molecules on some cells like
Pancreatic beta cells ---IDDM or thyroid cells
6- Genetic predisposing (association with MHC gene)
Ankylosing spondylitis (HLA- B27)
SLE DR- 2,3
IDDM DR- 3,4

24. 7-Cytokine dysregulation &Break down (FAILURE) of suppressor mechanisms
8-Thymus defect (Increasing with age)
9-Hormonal factor ( more in females)

25. Pathogenesis of autoimmunity
Environmental trigger
(e.g. infections, chemicals
tissue injury)
Susceptibility genes
Failure of
self-tolerance
Activation of
self-reactive
lymphocytes
Persistence of functional
self-reactive lymphocytes
Immune responses against self tissues

26. -Clinical types of auto immune diseases
Organ specific Graves’ disease
Myasthenia gravis
Systemic SLE
-Ab non specific but organ specific as primary biliary cirrhosis
-Multiple autoimmune diseases can be occurred in the same patient

27. Tissue Damage in Autoimmune diseases can be classified like hypersensitivities
Type II — Antibodies react with cell-surface antigens in specific organs Ex. auto-immune Hemolytic anemia
Type III (Immune Complex) — IgM and/or IgG react with soluble cell material, complexes are deposited, initiate complement activation, inflammation Ex. SLE
Type IV — Mediated by cytotoxic & CD4 + T cells Ex. MS 27

28. Type II autoimmune disease: Graves’ disease
Stimulating auto-antibodies against growth receptors on thyroid gland
Cross reactive autoantigens in the eyes
Patients develop goiter, bulging staring eyes 28

29. Systemic Lupus Erythematosus
Incidence 1:2500
Female: male 10:1
2nd/3rd decade of life
Skin, kidney, serosal membranes, joints, heart
Many autoantibodies
Failure to maintain self-tolerance

30. Anti-Nuclear Antibodies (ANA)
Abs to DNA
Abs to histone
Abs to non-histone proteins bound to RNA
Abs to nucleolar antigens

31. Systemic Lupus Erythematosus
Genetic factors
30% concordance in monozygotic twins
Increased risk in family members
HLA-DQ & DR locus and SLE association
Non-Genetic factors
Drugs: procainamide, hydralazine
Sex hormones (estrogens>androgens)\
UV light

32. Type III autoimmune disease: systemic lupus erythematosus
Auto-antibodies against nuclear components
RBC, Platelets, clotting factors
Immune complexes activate complement
Excess complexes are deposited in small blood vessels
Local inflammation in skin, joints and kidneys, multi-organ damage 32