Tolerance & autoimmunity

1. Immune tolerance & Autoimmunity
Dr Ghada Barakat
lecturer, Med Microbiology & Immunology

2. Contents
Introduction1
2
3 Autoimmunity
Tolerance

3. Tolerance
Our own bodies produce some 100,000 different
proteins and one of the longstanding conundrums of
immunology has been to understand how the
immune system produces a virtual repertoire
against pathogens while at the same time avoiding
reacting to self.
The strict definition of immunological tolerance
occurs when an immunocompetent host fails to
respond to an immunogenic challenge with a
specific antigen.

4. Tolerance

5. Tolerance
Definition:
Immunological non-reactivity to an antigen.
Resulting from a previous exposure.
The most important form is non-reactivity to self Ag
When an antigen induces tolerance, it is tolerogen.

7. Tolerance
ToleranceImmune response
Soluble, smaller, less complexLarge,aggregated, complexPhysical form of Ag
Oral or IVSC or IMRoute of Ag
Very large (sometimes very
small)
Optimal doseDose of Ag
Newborn, immunologicall
immature
Older and immunologically
mature
Age of responding
animal
Relatively undifferen: B, T cells Fully differentiated; memory
T and B
Differentiation state
of cells

8. Tolerance, mechanism
B cell tolerance
•Deletion
•Anergy
•receptor editing
T cell tolerance
•Deletion
•Ignorance
Loss of Ts cells
Anti-idiotype antibody

10. Thymus
•Positive selection: cells that are able to recognize
and bind to self MHC or to peptide + MHC molecules
are selected to grow
•Negative selection: cells that recognize and
efficiently bind self peptides are auto-reactive cells
and undergo apoptotic cell death because they are
harmful to the host
Cells that pass both positive and negative selection
tests “graduate” from thymus ; enter circulation as
mature T lymphocytes
Tolerance, T cell tolerance

11. Mechanism of tolerance
1- Clonal deletion:
Auto-reactive T-cells are eliminated in the thymus
following interaction with self-antigen during their
differentiation (negative selection).
Likewise, differentiating early B cells become
tolerant when they encounter cell-associated or
soluble self-antigen.

12. Mechanism of tolerance
2- Clonal anergy:
Auto-reactive T cells, when exposed to antigenic
peptides lose the second signal, become anergic to
the antigen.
B cells when exposed to large amounts of soluble
antigen down regulate their surface IgM and
become anergic.

13. Mechanism of tolerance

14. Ignorance
It can be shown that there are T cells and B cells
specific for auto-antigens present in circulation.
These cells are quite capable of making a
response but are unaware of the presence of their
auto-antigen. This arises for 2 reasons.

15. Ignorance
The first is that the antigen may simply be present
in too low concentration. Since all lymphocytes
have a threshold for receptor occupancy which is
required to trigger a response then very low
concentrations of antigen will not be sensed.

16. Ignorance
The second possibility is a more interesting one.
Some antigens are sequestered from the immune
system in locations which are not freely exposed
to surveillance.
These are termed immunologically privileged
sites. Examples of such sites are the eye, CNS
and testis.
Pathologically mediated disruption of these
privileged sites may expose the sequestered
antigens leading to an autoimmune response.

17. Mechanism of tolerance
4- Receptor editing:
B cells which encounter large amounts of soluble
antigen, as they do in the body, and bind to this
antigen with very low affinity become activated to
re-express their RAG-1 and RAG-2 genes.
These genes cause them to undergo DNA
recombination and change their antigen
specificity.

19. Mechanism of tolerance
5- Anti-idiotype antibody:
produced during the process of tolerization. They
prevent the receptor from combining with antigen
so inhibit immune response to it.
6- Suppressor cells:
Both low and high doses of antigen may induce
suppressor T cells, which can specifically suppress
immune responses of both B and T cells.

21. Autoimmunity

22. AUTOIMMUNITY- Definition
Immune recognition and injury of self tissues
(autoimmunity) results from a loss of self tolerance.
Autoimmunity is
Breakdown of mechanisms responsible for self
tolerance
Induction of an immune response against components
of the self.

23. Loss of Self Tolerance
Most self peptides are presented at levels
too low to engage effector T cells
those presented at high levels induce clonal
deletion or anergy.
Autoimmunity arises most frequently to
Tissue-specific antigens with only certain MHC
molecules
present the peptide at an intermediate level
recognized by T cells without inducing tolerance.

24. MHC Association with
Autoimmune Disease
The level of presented autoantigenic peptide
Is determined by residues in MHC molecules
These molecules govern the affinity of peptide
binding.
Autoimmune diseases are associated with
particular MHC genotypes.

25. Classification
Table 1. Spectrum of autoimmune diseases, target organs and diagnostic tests
Organ specific
Non-organ
specific
Disease Organ Antibody to Diagnostic Test
Hashimoto's thyroiditis Thyroid Thyroglobulin, thyroid
peroxidase
RIA, Passive, CF,
hemagglutination
Primary Myxedema Thyroid Cytoplasmic TSH receptor Immunofluorescence (IF)
Pernicious anemia Red cells Intrinsic factor, Gastric
parietal cell
B-12 binding to IF
immunofluorescence
Addison's disease Adrenal Adrenal cells Immunofluorescence
Male infertility Sperm Spermatozoa Agglutination,
Immunofluorescence
Insulin dependent juvenile
diabetes
Pancreas Pancreatic islet beta cells
Insulin resistant diabetic Systemic Insulin receptor Competition for receptor
Myasthenia graves Muscle Muscle, acetyl choline
receptor
Immunofluorescence,
competition for receptor
Vitiligo Skin Joints Melanocytes Immunofluorescence
Rheumatoid arthritis Skin, kidney,
joints
IgG IgG-latex agglutination
Systemic lupus
erythematosus
Joints, etc.

DNA, RNA, nucleoproteins RNA-, DNA-latex agglutination,
IF

26. Organ-specific Autoimmune
diseases
Antigens and autoimmunity restricted to specific
organs in the body
Hashimoto’ thyroiditis
Type I diabetes
Multiple sclerosis
Grave’s disease
Myasthenia gravis

27. Systemic Autoimmune Disease
Antigens and autoimmunity are distributed in
many tissues (systemic)
Rheumatoid arthritis
polymyositis
Scleroderma
Systemic lupus erythematosus

28. AUTOIMMUNITY- mechanisms
Antibodies
Effector T cells

29. AUTOIMMUNITY- aetiology
1.Sequestered antigen
Lymphoid cells may not be exposed to some self
antigens during their differentiation,
They may be late-developing antigens or may be
confined to specialized organs (e.g., testes, brain,
eye, etc.).
A release of antigens from these organs
resulting from
accidental traumatic injury or
surgery can
Result in the stimulation of an immune response
and initiation of an autoimmune disease.

30. 1.Escape of auto-reactive clones
The negative selection in the thymus may not be fully
functional to eliminate self reactive cells.
Not all self antigens may be represented in the
thymus
Certain antigens may not be properly processed and
presented.
AUTOIMMUNITY- aetiology

31. 1.Cross reactive antigens
Antigens on certain pathogens may have
determinants which cross react with self antigens
and an immune response against these
determinants may lead to effector cell or
antibodies against tissue antigens.
Post streptococcal nephritis and carditis,
anticardiolipin antibodies during syphilis
Association between Klebsiella and ankylosing
spondylitis.
AUTOIMMUNITY- aetiology

32. Infectious triggers:
stimulation of co-stimulatory signals,
inappropriate MHC II expression, or cytokines
Molecular mimicry (cross-reaction)
Release of sequestered antigens
T cell bypass (pathogen binding to self protein)
Superantigen activity/polyclonal activation
AUTOIMMUNITY- aetiology

33. 2.loss of suppressor cells.
AUTOIMMUNITY- aetiology

34. AUTOIMMUNITY- Diagnosis
Diagnosis:
Clinical
Detection of Ab reactive against soluble antigens
by ELISA.
Detection of Ab against tissues and cells by IF.
In some cases, a biological /biochemical assay
may be used (e.g., Graves diseases, pernicious
anemia).

35. AUTOIMMUNITY- Treatment
Treatment:
Anti-inflammatory e.g.corticosteroid
Immunosuppressive (cyclosporin)
Anti-idiotype antibodies, antigen peptides,
anti-IL2 receptor antibodies, anti-CD4
antibodies, anti-TCR antibodies, etc.