The document discusses autoimmunity, focusing on T and B cell tolerance and the mechanisms that contribute to autoimmune diseases. It outlines two types of immunological tolerance: central and peripheral, as well as the pathogenesis involving factors such as molecular mimicry and environmental triggers. Additionally, it highlights the role of genetic predisposition and provides examples of various autoimmune disorders.

1. Autoimmunity
Autoimmunity
Dr. Al-Farah

2. Learning objectives
Learning objectives
• Define T & B cell tolerance, autoimmunity
• Discuss the pathogenesis of autoimmune disease
• Discuss various clinical presentations of autoimmune
diseases

3. Immunological tolerance
Immunological tolerance

4. Immunological tolerance
Immunological tolerance
• The mechanisms of self-tolerance can be broadly
classified into two groups:
1. Central tolerance and
2. Peripheral tolerance

5. Immunological tolerance
Immunological tolerance
Central Tolerance
•In this process, immature self-reactive T and B lymphocyte
clones that recognize self antigens during their maturation in the
central (primary) lymphoid organs (the thymus for T cells and
the bone marrow for B cells) are killed or rendered harmless.
Mechanism:
•Negative selection or clonal deletion
•Receptor editing
•Development of regulatory T cells (CD4 lineage)

6. Immunological tolerance
Immunological tolerance

7. Immunological tolerance
Immunological tolerance
Peripheral Tolerance
•In this process, immature self-reactive T and B lymphocyte
clones that escapes central tolerance, are deleted or muzzled in
the peripheral tissues.
Mechanisms:
•Clonal Anergy (a state of inactivation in which the lymphocytes remain
alive but are unable to respond to antigen)
•Suppression by regulatory T cells (Tregs)
•Deletion by apoptosis

10. Autoimmunity is a problem of
self/non-self discrimination.
Autoimmunity

11. Autoimmunity
Autoimmunity
Disorder in which tissue injury is
caused by an immunologic reaction
of the host to its own tissues.

12. Failure of Immune Tolerance
(Development of
Autoimmunity)

13. Characterstics of Autoimmune
Characterstics of Autoimmune
diseases
diseases
• Ideally, at least three requirements should be met
before a disorder is categorized as truly caused by
autoimmunity:
(1) Presence of an immune reaction specific for some
self antigen or self tissue;
(2) Evidence that such a reaction is not secondary to
tissue damage but is of primary pathogenic
significance; and
(3) Absence of another well-defined cause of the
disease.

14. Mechanisms of Autoimmunity
Mechanisms of Autoimmunity

15. Mechanisms of Autoimmunity
Mechanisms of Autoimmunity

16. Mechanisms of Autoimmunity
Mechanisms of Autoimmunity
Role of Susceptibility Genes
Many autoimmune diseases exhibit a marked familial incidence
suggesting a genetic predisposition to these disorders
• However, that whether a person develops an autoimmune
disease or not is clearly multifactorial.
EXAMPLE
 Rheumatoid arthritis occurs predominantly in individuals carrying the HLA-DR4
gene.
 Ankylosing spondylitis is 100 times more likely to occur in people who carry
HLA-B27.
 Polymorphisms in the gene for NOD2 are associated with Crohn disease

17. Mechanisms of Autoimmunity
Mechanisms of Autoimmunity
Role of Infections and Other Environmental Factors
There are several environmental agents that trigger
autoimmune diseases, most of which are either bacteria
or viruses.
EXAMPLE
 Pharyngitis caused by Streptococcus pyogenes predisposes to rheumatic fever.
 Some viruses, such as EBV and HIV, cause polyclonal B-cell activation, which may
result in production of autoantibodies.
 Ultraviolet (UV) radiation causes cell death and may lead to the exposure of
nuclear antigens, which elicit pathologic immune responses in lupus.
 Smoking is a risk factor for rheumatoid arthritis, perhaps because it leads to
chemical modification of self antigens.

18. Pathogenesis
of
autoimmunity

19. Induction of Autoimmunity
Induction of Autoimmunity
“Proposed Mechanisms!”
“Proposed Mechanisms!”
1. Molecular mimicry
2. Alteration of Normal Proteins
3. Sequestered antigens
4. Epitope Spreading
5. Failure of Regulatory T Cells
6. Polyclonal B cell activation

20. 1. Molecular Mimicry
1. Molecular Mimicry
(Cross-reacting Antigens)
(Cross-reacting Antigens)
• Viruses and bacteria possess antigenic
determinants that are very similar, or even
identical, to normal host cell components.
• This phenomenon, known as molecular
mimicry, occurs in a wide variety of
organisms.
• Molecular mimicry may be the initiating step
in a variety of autoimmune diseases.

21. Examples of Molecular Mimicry
Examples of Molecular Mimicry

22. 1. Molecular Mimicry
1. Molecular Mimicry
(Cross-reacting Antigens)
(Cross-reacting Antigens)

23. 2. Alteration of Normal Proteins
2. Alteration of Normal Proteins
• Surface antigens on host altered by chemical,
biological or physical means.
• This new antigenic determinant may be recognized
as foreign by the host.
EXAMPLE
• Procainamide-induced systemic lupus erythematosus is an
example of this mechanism.
• Citrullination of vimentin, collagen, fibrillin lead to
Rheumatoid arthritis

24. 3. Sequestered antigens
3. Sequestered antigens
• Some self-antigens are sequestered (hidden) in
specialized tissues.
• These are not seen by the developing immune
system – will not induce self-tolerance.
• Exposure of T cells to these normally
sequestered/tissue-specific self-antigens in the
periphery results in their activation.

25. Examples of
Examples of Sequestered
Sequestered Antigens
Antigens
1. Myelin basic protein (MBP), associated with
Multiple sclerosis
2. Lens and corneal proteins of the eye following
infection or trauma

26. Sympathetic ophthalmia

27. 4. Epitope Spreading
4. Epitope Spreading
• Epitope spreading is the term used to describe the new
exposure of sequestered autoantigens as a result of damage
to cells caused by viral infection.
EXAMPLE
• a multiple sclerosis–like disease was caused by infection with
an encephalomyelitis virus.

28. 4. Failure of Regulatory T Cells
4. Failure of Regulatory T Cells
• An important function of Tr cells is to produce IL-10,
which inhibits proinflammatory Th-1 cells. Patients
with a mutation in the FoxP3 gene have an increase
in autoimmune diseases
Example
• In systemic lupus erythematosus, the function of
their regulatory T cells is lost.

29. 1) Tissue destruction
• Diabetes: CTLs destroy insulin-producing b-cells in pancreas
2) Antibodies block normal function
• Myasthenia gravis: Ab binds acetylcholine receptors
3) Antibodies stimulate inappropriate function
• Graves’ disease: Ab binds TSH receptor mimics thyroid-stimulating hormone
Activates unregulated thyroid hormone production
4) Antigen-antibody complexes affect function
• Rheumatoid arthritis: IgM specific for Fc portion of IgG IgM-IgG
complexes deposited in joints inflammation
Effects of autoimmunity

30. General Features of Autoimmune
General Features of Autoimmune
Diseases
Diseases
• Autoimmune diseases tend to be chronic,
sometimes with relapses and remissions, and the
damage is often progressive.
• The clinical and pathologic manifestations of an
autoimmune disease are determined by the extent
of tissue involvement (organ-specific disease OR
systemic disease) and nature of the underlying
immune response (auto-antibody mediated OR T
cell mediated).

31. Examples of autoimmune disease
Examples of autoimmune disease

32. Examples of autoimmune disease
Examples of autoimmune disease

33. Examples of autoimmune disease
Examples of autoimmune disease

35. Thank you