Transcript Autoimmunity 3rd yr

Autoimmunity
• Immune system has evolved to
discriminate between self and
non-self or discriminate
between safe and dangerous
signals
• Ability developed during fetal
life, during the ontogeny of
the immune system
• Termed tolerance, a form of
censorship of the immune system
• Deletion (clonal deletion) or
functional inactivation (clonal
anergy) of developing
lymphocytes that possess
antigenic receptors with high
affinity for self-antigens
Central and Peripheral Tolerance
(Absence of
Co-stimulation)
B Cell Tolerance to Self Antigens
 Developing B lymphocytes recognizing cell-associated self
antigens are effectively deleted.
 Developing B lymphocytes recognizing soluble self antigens
are less efficiently deleted.
B Cell Tolerance to Self Antigens
Sequestered Antigens
Induction of tolerance in selfreactive T cells occurs through the
exposure of immature T cells to
self-antigens in the thymus.
The elimination/silencing of all
self-reactive T cells requires that
all self-antigens be presented
within the thymic environment.
Some self-antigens are sequestered in
specialized tissues and may not be
expressed in the thymus.
These are not seen by the developing
immune system – will not induce selftolerance.
Exposure of T cells to these normally
sequestered/tissue-specific self-antigens
in the periphery results in their activation
Examples of Sequestered Antigens
Myelin basic protein (MBP), associated with MS.
Sperm-associated antigens in some individuals
following vasectomy.
Lens and corneal proteins of the eye following
infection or trauma.
Heart muscle antigens following myocardial
infarction.
Autoimmune Diseases
Self-reactive lymphocytes (the forbidden
clones) should be eliminated from the
immunological repertoire.
Diseases involving an immunological response to
normal tissue – termed autoimmunity or autoimmune
diseases.
Original concept – the receptors of
lymphocytes with specificity for foreign
antigens underwent mutation – results in a
new class of receptors with specificity
for self-antigens.
It is now clear that autoantibodies and self-reactive T
cells are normal components of the immune repertoire.
Autoimmunity with Diseases
Results from:
1- Mistake in selection of B cell and T
cells
2- Broken tolerance
3- Antibody, and T cell activation
against self antigens
The Spectrum of autoimmune Diseases
Organ specific
Systemic
Hashimoto’s thyroiditis
Pernicious anaemia
Insulin dependent diabetes
Myasthenia gravis
Multiple sclerosis
Ulcerative colitis
Rheumatoid arthritis
Systemic lupus erythematous
Pathology of Autoimmune Diseases
Most of the autoimmune diseases attributed to
autoantibodies.
Disease processes and tissue damage are due to
Type II and Type III hypersensitivity reactions.
Other autoimmune diseases have an autoreactive T
cell component.
Disease process and tissue damage due to Type IV
hypersensitivity reactions.
Autoimmune Diseases due to
Type II Hypersensitivity
Autoimmune Diseases
A. Type II (Cytotoxic) Autoimmune Reactions
Involve antibody reactions to cell surface molecules,
without cytotoxic destruction of cells.
– Grave’s Disease:
• Antibodies attach to receptors on thyroid gland and
stimulate production of thyroid hormone.
• Symptoms: Goiter (enlarged thyroid) and bulging
eyes.
– Myasthenia gravis:
• Progressive muscle weakness. Antibodies block
acetylcholine receptors at neuromuscular synapse.
• Today most patients survive when treated with drugs
or immunosuppressants.
B. Type III (Immune Complex) Autoimmune
Reactions
– Systemic Lupus Erythematosus:
• Name derived from red skin rash on face.
• Autoantibodies react against DNA, blood cells,
neurons, and other tissues.
• When cells die, immune complexes form and deposit
under skin, joints, in kidneys, blood vessels, and
central nervous system.
• Inflammation interferes with normal function of these
sites (arthritis, rash, kidney damage).
• Most patients die from kidney damage.
• No cure. Symptoms treated with anti-inflammatory
and immunosuppressive drugs.
Type III (Immune Complex) Autoimmune Reactions
(Continued)
– Rheumatoid Arthritis:
• Cause unknown, but microbial mimicry may be
involved.
• IgM autoantibodies (rheumatoid factors) against IgG
form complexes in joint, leading to inflammation and
cartilage damage.
• Often causes finger and joint deformities.
• No cure. Symptoms treated with anti-inflammatory
(aspirin) and immunosuppressive drugs. Physical
therapy keeps joints movable. Surgical replacement
of joints may be necessary.
Rheumatoid Arthritis
Morning stiffness, joint swelling,
subcutaneous rheumatic nodes,
Auto antibodies.
Associated with HLA-DR4.
Molecular mimicry with bacterial
antigen
T cells found to react with autoantigen
 IgM auto-antibodies
Anti nuclear antibodies
C. Type IV (Cell-Mediated) Autoimmune Reactions
(Continued)
– Insulin-dependent (Type I or Juvenile) Diabetes
Mellitus:
Makes up 10% of diabetes cases. Characterized
by insufficient insulin production due to
immunological destruction of insulin-secreting
cells of the pancreas by T cells. Usually
develops before the age of 15. Treated with
insulin injections.
• Symptoms: Hyperglycemia, abnormal Hunger,
increased thirst, Polyuria, and glycosuria
• Immune component: Antibody against insulin,
and glutamic acid decorboxylase (GADD)
• Cellular infiltrates of CD4+ and CD8 + T cells
• Inflammatory cytokines in lessons.
• Rota virus, Coxsackie virus
Multiple Sclerosis: Demyelinating disease, early sign neuritis
Immune component:
Myelin specific antibodies in cerebral fluid
Antibody dependent cellular cytotoxicity in
tissue damage
CD4 +T cell mediated disease
Th1 cytokines are associated with disease, Th2
cytokines are protective.
Broken tolerance in APC by infection
Epitope spreading
corona virus detected in serum of MS patients.
Proposed Mechanisms of
Autoimmunity