Download Tolerance - BHS116.3 Physiology III

Aims
• Review mechanisms of T cell tolerance.
• Describe the factors involved in the breakdown of
tolerance.
• Define autoimmunity.
• Describe autoimmune diseases, concentrating on
the role of immunity in their pathogenesis.
• Readings: Robbins, Chapter 5
Tolerance
• Tolerance is the process by which the body
ensures that immune responses are directed
against foreign or altered self antigens and not
normal self.
• It is defined as “the state of specific
unresponsiveness of an individual to a
particular antigenic epitope”.
• Regulation of antigen-specific receptors.
Only B and T lymphocytes
Tolerance
• Lymphocytes generate receptors (Ig or
TCR) for antigen randomly via somatic
mutations.
• Therefore, receptors for antigen that bind
self are also generated.
• 90-99% of all thymocytes do not survive
positive and negative selection (tolerance)
in the thymus.
T Lymphocyte Development
Robbins & Cotran’s Pathologic Basis of Disease 6-27
Central T Lymphocyte Tolerance
Robbins & Cotran’s Pathologic Basis of Disease 6-27
Central T Cell Tolerance
• Tolerance learned during ontogeny is called “central
tolerance”
• Involves Immature “double positive” T cells.
• Strong recognition to self antigens results in apoptosis.
• Remember antigens present in the thymus are almost
always self antigens.
Robbins & Cotran’s Pathologic Basis of Disease 6-27
Peripheral T Lymphocyte Tolerance
Robbins & Cotran’s Pathologic Basis of Disease 6-27
Peripheral T Cell Tolerance
• Anergy
IL-2R
X
IL-2
Functional inactivation
of T cells.
Occurs when the
Primary signal
(MHC/peptide-TCR
binding) happens
without secondary signal
(example B7-CD28
binding).
• Secondary signal needed
to stablize IL-2 mRNA
Adapted from Robbins & Cotran’s Pathologic Basis of Disease 6-27
Peripheral T Cell Tolerance
• Activation-induced cell
death
Activated T lymphocytes
will die by apoptosis if
repeatedly stimulated with
antigen.
Induces expression of Fas
and Fas ligand resulting in
apoptosis.
Expression of pro-apoptotic
proteins resulting in
apoptosis.
Adapted from Robbins & Cotran’s Pathologic Basis of Disease 6-27
Peripheral T Cell Tolerance
• Regulatory T cells
CD4+, CD25+ T Cells
Suppress or inhibit the
activation of other T cells.
Most likely due to the
production of inhibitory
cytokines.
Adapted from Robbins & Cotran’s Pathologic Basis of Disease 6-27
How is Tolerance Broken?
• Exposure of antigens in an immunologically privileged
site.
Traumatic Injury
Inflammation of CNS, eyes, or testes.
Results in the unmasking of previously hidden antigens.
• Sympathetic ophthalmia
Perforating ocular injury results in the unmasking of uveal or
retinal antigens.
Results in a delayed hypersensitivity reaction in the
contralateral eye.
Treated with steroid anti-inflammatory medications and by
removing the damaged eye.
How is Tolerance Broken?
• Cellular injury and release of intracellular
components not normally exposed to the
immune system.
• Older cells may express “distinct” antigens from
younger cells.
How is Tolerance Broken?
• Molecular mimicry
Ankylosing spondylitis – Antibodies against antigens from
Klebsiella cross-react with antigens in the spine resulting in
a chronic inflammation, fibrosis and ossification of the
articulations of the spine.
• >90% of patients with this disease are HLA-B27 positive.
How is Tolerance Broken?
• Molecular mimicry
Rheumatic fever – Antibodies against antigens from
Streptococcus cross-react with heart valve antigens resulting
in myocarditis.
How is Tolerance Broken?
• Molecular mimicry
Guillian-Barre Syndrome – Antibodies against LPS from
Campylobacter cross-react with gangliosides of the motor
neurons resulting in paralysis and polyneuritis.
How is Tolerance Broken?
• Heat shock proteins
Up-regulated by stressed cells.
Conserved from prokaryotes to eukaryotes.
g/d TCR+ T cells recognize these proteins.
Other Factors in Autoimmunity
• Genetic factors
Strong associations between HLA alleles and
autoimmune diseases.
Disease
HLA allele
Relative risk
Rheumatoid arthritis
DR4
4
DR3
Insulin-dependent diabetes
DR4
mellitus
DR3/DR4 heterozygote
5
5-6
25
Ankylosing spondylitis
B27
90-100
Multiple sclerosis
DR2
4
Systemic lupus
erythematosus
DR2/DR3
5
Other Factors in Autoimmunity
• Hormones and gender
Autoimmune diseases are more common in women.
• Immune system dysregulation
Loss of regulatory function during immune
suppression.
• Regulatory cytokines
IL-10 and IL-4 inhibit Type 1 (Th1) immune responses.
Transforming growth factor beta (TGF-) suppresses T
cell proliferation.
Autoimmune Diseases
• Classify according to:
Systemic or organ-specific.
Antibody-mediated, T cell-mediated, or both.
HLA association
Mechanism (Cell and Coombs classification if
established)
Myasthenia Gravis
• “Grave muscle weakness”
• Antibody-mediated
neuromuscular disease.
• Associated with specific
alleles of HLA-DR3.
• An example of an organ
specific autoimmune disease.
Myasthenia Gravis
• Type II hypersensitivity
reaction.
• Antibodies are produced
against acetylcholine
receptors at the
neuromuscular junctions
causing a blockage of
neuromuscular impulses.
 Steric hindrance
 Destruction by complement
 Increase receptor turnover
• Can be passively transferred.
 In mice via sera transfer.
 In humans from mother to
neonate.
Systemic Lupus Erythematosus (SLE)
• Systemic autoimmune disease
• Involves the production of antibodies against dsDNA and
other nuclear components (ANA).
• Resulting in antibody-mediated manifestations in the:
 Blood vessels
• Vasculitis
 Skin
• Butterfly rash
• Photosensitivity
 Heart
• Pericarditis
 Kidneys
• Nephritis
 Joints
• Arthritis
 Lymphnodes
• lymphadenopathy
Systemic Lupus Erythematosus (SLE)
• ANA form soluble immune complexes with their
antigens and get deposited in tissues resulting in
inflammation.
Activate complement
Attract PMNs
• Type III hypersensitivity
reaction.
Robbins & Cotran’s Pathologic Basis of Disease 6-33 & 6-36
Systemic Lupus Erythematosus (SLE)
• 10Xs more frequent in
females.
• Genetic association with
HLA-DR3, and DR2.
• Linked to individuals
with complement
deficiencies.
 80% of individuals who
lack C1, C4, or C2 will
get SLE.
 Resulting in a lack of C3b
and poor removal of
immune complexes.
Robbins’ Basic Pathology 5-21
Ocular Symptoms
• ~20% of patients with SLE have ocular
manifestations.
• Dry eye (keratoconjunctivitis sicca)
due to damage to lacrimal gland.
Due to secondary Sjogren’s syndrome.
• Retinopathy
Cotton wool spots
Scleroderma (Systemic Sclerosis)
• Literally means “hard skin”.
• A progressive systemic autoimmune disease of the
connective tissue leading to fibrosis, arthritis and
arteritis.
• Affects many organ systems including:
Skin
Vascular system
GI
Lungs
Kidney
Robbins & Cotran’s Pathologic Basis of Disease 6-41
Scleroderma (Systemic Sclerosis)
• Abnormal immune response and vascular damage.
• Autoantibodies against nuclear antigens are present.
Topoisomerase-1
RNA polymerase-1
Centromere antigens
Robbins & Cotran’s Pathologic Basis of Disease 6-39
Next Time
• Describe autoimmune diseases, concentrating on
the role of immunity in their pathogenesis.
• Readings: Robbins, Chapter 5
Objectives
1. Compare and Contrast Central & Peripheral T
cell tolerance.
2. Describe how T cell tolerance is broken.
3. Describe systemic lupus Erythematosus.
1. Pathophysiology, systemic and ocular symptoms
4. Describe scleroderma.