Dr. ihsan edan abdulkareem alsaimary
PROFESSOR IN MEDICAL MICROBIOLOGY AND MOLECULAR IMMUNOLOGY
ihsanalsaimary@gmail.com
mobile : 009647801410838
university of basrah - college of medicine - basrah -IRAQ
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Tolerance & autoimmunity and organ specific autoimmune diseases
1. *TOLERANCE & AUTOIMMUNITY
*ORAN-SPECIFIC AUTOIMMUNE DISEASES
PREPARED BY
Prof. DR.IHSAN EDAN ALSAIMARY
DEPARTMENT OF MICROBIOLOGY
COLLEGE OF MEDICINE – UNIVERSITY OF BASRAH
2. Immunological tolerance
• Definition:
– specific unresponsiveness to an antigen that is
induced by exposure of lymphocytes to that
antigen (tolerogen vs immunogen)
• Significance:
– All individuals are tolerant of their own antigens
(self-tolerance); breakdown of self-tolerance
results in autoimmunity
– Therapeutic potential: Inducing tolerance may
be exploited to prevent graft rejection, treat
autoimmune and allergic diseases, and prevent
immune responses in gene therapy
4. 1. Central Tolerance carried out during fetal
development in the PRIMARY LYMPHOID
ORGANS
I. Thymus for T cells
ii. Bone marrow & fetal liver for B cells
2. Peripheral Tolerance,
operates in the SECONDARY LYMPHOID
ORGNAS, in the periphery after birth
5. The principal fate
of lymphocytes that
recognize self antigens
in the generative organs
is death (deletion), BUT:
Some B cells may change
their specificity (called
“receptor editing”)
Some CD4 T cells may
differentiate into
regulatory (suppressive)
T lymphocytes
Central and peripheral tolerance
From Abbas, Lichtman and Pillai. Cellular and Molecular Immunology 6th ed, 2007
6. Consequences of self antigen recognition in thymus
From: Abbas & Lichtman, Cellular & Molecular Immunology 5th ed 2003
7. Central tolerance
• Lymphocytes that see self antigens
before they are mature are either
eliminated or rendered harmless
•
• Probably continues to occur at some level
throughout life (as new lymphocytes are
produced from bone marrow stem cells)
• Role of the AIRE protein in thymic
expression of some tissue antigens
8. APC TCR
T cell
CD28
Activated
T cells
APC TCR
Functional
unresponsiveness
Normal T cell
response
Anergy
Apoptosis
(activation-induced
cell death)
APC
Deletion
APC
Block in
activation
Suppression
Regulatory
T cell
Peripheral tolerance
Off signals
Activated
T cell
10. T cell anergy
• Multiple mechanisms demonstrated
in different experimental systems
• No clear evidence that natural self
antigens induce T cell anergy
(especially in humans)
• Therapeutic potential: can we
administer antigens in ways that
induce T-cell anergy?
11. “Activation-induced cell death”: death of mature
T cells upon recognition of self antigens
From Abbas and Lichtman. Basic Immunology 2nd ed, 2006
Both pathways cooperate to prevent reactions against self
16. • Thymic development of T cells results in:
1) Production of T cell receptors for antigen
(TCR)
2) Lymphocytes begin to express CD3, CD4,
and CD8
3) Elimination of T cells that are stimulated by
MHC + self Ag- (self-reactive T cells)
4) Mature T cells ready to go to the periphery
are TCR/CD3+, and either CD4 or CD8
positive
20. A failure to control the function of self-reactive
cells which escaped to the periphery, results in
AUTOIMMUE DISEASE
Autoimmunity=any condition where the
immunopathology occurs as a result of an
immune response to self
A breakdown of mechanisms responsible
for tolerance. The auto-reactivity may result in
disease.
21. Effector mechanisms of
autoimmune damage
Specific components:
Antibodies
T cells
Nonspecific components:
Complement
Phagocytes (PMN and macrophages)
NK and other cells
23. 1. Release of Sequestered Auto-antigens:
e.g.
• Release of myelin basic protein (MBP) in
infection
• Release of sperm Ag after vasectomy
• Exposure of Eye lens protein after trauma
• Exposure of heart muscle Ag after
myocardial infarction
24. 2. Cross-reactive Auto-antigens: (Molecular
mimicry)
Viruses and bacteria may have antigenic
determinants that are identical or similar to those of
normal host cells
e.g. Rheumatic fever - Streptococci and
heart auto-Ag
25. 3. Inappropriate Expression of Class II MHC:
Auto-antigens+MHC get presented to Th cells by
cells which do not normally express high levels
of MHC. Th cells get activated and may then
activate B, Tc and TDTH cells. e.g.
In IDDM ,b cells from pancreas express high
levels of Class I and Class II MHC molecules
26. 4. Cytokine Imbalance
Increased production of cytokines may result
in excessive T and B cell activation and
subsequent damage e.g.
Increased IL-2 levels in Systemic Lupus
Erythematosus (SLE)
29. Tissues and organs
involved
Organ-specific diseases
Damage is confined to the organ against
which the immune response is mounted
Non-organ-specific diseases
Immune response against antigens which
are not associated with the organ involved
30. ORGAN-SPECIFIC AUTOIMMUNITY:
Autoimmunity limited to a single organ/gland e.g.
thyroid, adrenal, pancreas, stomach.
NON -ORGAN SPECIFIC AUTOIMMUNITY:
Broad range of target Ag involving a number of
organs and tissues e.g. skin, joints, kidney, liver
32. Comparison of organ specific and non-
specific disorders
Non-organ
specific
Organ specific
Widespread
throughout the
body
Essentially localized
to given organ
Antigen
Complexes
deposit
systemically
particularly in
kidneys, joints
and skin
Antigen in a specific
organ is target for
immunological attack
Lesions
34. Disease Diagnostic test
Orga
n Antibody to*
Thyroid
Hashimoto’s
thyroiditis
Immunofluorescence
(IFA), RIA, ELISA
Grave’s disease Thyroid Bioassay on cell lines
Pernicious
anemia
B12 binding to IF
Stomach,
RBC
Thyroglobulin,
thyroid peroxidase
TSH receptor
Examples of autoimmune
diseases
Intrinsic factor (IF)
*In diseases involving tissues, damage is also caused by cytotoxic T cells
35. Disease Diagnostic test
Orga
n Antibody to*
Addison’s
disease
Adrenal IFA
Insulin-dep.
diabetes
Pancreas IFA
Goodpasture’s Kidney, lung IFA
Examples of autoimmune
diseases
Adrenal
Pancreatic
islet β cells
Renal & lung
basement
membrane
*In diseases involving tissues, damage is also caused by cytotoxic T cells
40. Pemphigus and pemphigoid
Immunofluorescent detection of anti-skin
basement membrane antibody in pemphigoid
Immunofluorescent detection of
anti-desmosome antibody in pemphigus
41. Sjogren’s syndrome
Immunofluorescent detection of
Anti-duct mitochondrial antibody
in a patient with Sjogren’s syndrome
Infiltration of lymphoid cells in a lesion
The secretory duct from a patient with
Sjogren’s syndrome
42. Etiology of AI diseases
Sequestered antigen
Escape of auto -reactive clones
Cross reactive antigens
Modification of self antigens
Cross-reactive exogenous antigens
Cytokine dysregulation and inappropriate MHC
expression
Sub-optimal suppressor function
Exact etiology not known
43. Treatment of autoimmune
diseases
Symptomatic correction of metabolic
consequences
Conventional immunosuppressive agents
(see transplantation lecture)
Experimental treatments:
Induction of tolerance by oral administration of
antigen
Immunization with antigen specific receptor
(antiidiotype immunization)
44. AITP AutoImmune Thrombocytopenic Purpura
Autoimmune Thrombocytopenia:
- Organ-specific autoimmune disease against
platelets..
- Primary effector phase of immunopathogenesis:
- IgG Opsonization of platelets for
Fc-receptor mediated
phagocytosis.
- IgG autoantibodies are primarily:
- IgG1 and IgG3 (IgM, IgA)
- Antibody Targets:
- GP IIbIIIa, GPbIX, GPIV....
