Transcript transplantation

Bo Gao, Ph.D.
Email: [email protected]
Tel: 54237379
DEPARTMENT OF IMMUNOLOGY
INSTITUTE FOR IMMUNOBIOLOGY
2010-07-02
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Contents:
Introduction
Organ-Specific Autoimmune Diseases
Systemic Autoimmune Diseases
Mechanisms of Induction
Treatment
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Introduction
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Autoimmunity Origins
Horror
autotoxicus:
Literally, the horror of selftoxicity.
A term coined by the
German immunologist Paul
Ehrlich
(1854-1915)
to
describe the body's innate
aversion to immunological
self-destruction.
Paul Ehrlich , Nobel Prize in 1908 for
demonstrating production of antibody
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Clone selection hypothesis
Self-reactive
lymphocyte were deleted
during development
Frank Burnet 1900--1990
Nobel Prize 1960
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Definition of autoimmune disease
Disease caused by
failure of self-tolerance
and
subsequent
immune
responses
against self antigens
are called autoimmune
diseases.
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5 % to 7% adult affected.
Two third women.
 More than 40 human diseases
autoimmune in origin.
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Organ-Specific Autoimmune Diseases
Insulin-dependent diabetes mellitus
Multiple sclerosis
Myasthenia gravis
Graves’s disease
Hashimoto’ disease
Goodpasture’s syndrome
……
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Systemic Autoimmune Diseases
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Systemic Autoimmune Diseases
Systemic lupus Erythematosus (SLE)
Rheumatoid arthritis (RA)
Sjögren’s syndrome
Scleroderma
Dermatomyositis
Mixed connective tissue disease (MCTD)
…….
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Induction Theories for Autoimmune
Disorders
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1. Ag released from hidden location (by injury
or infection)
Intraocular antigens
Sperm
Post-traumatic uveitis
Orchitis after vasectomy
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2. Molecular mimicry (Cross-reactions)
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Molecular mimicry
 Definition:
Determinants of infectious agent mimic a host
antigen and trigger self-reactive T-cell clones to
attack host tissues.
 Examples:
 Rheumatic fever due to group A streptococcus
 SLE due to Epstein-Barr virus cross reactive with

nuclear Sm antigen
Lyme artrhritis due to Borrelia burgdorferi reactive
with LFA-1 (lymphocyte function antigen-1)
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Rheumatic
fever is a classic
example of
molecular
mimicry
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3. Inappropriate expression of class II MHC
 “Wrong” cells induced to express MHC Class
II
antigen (and act as APCs) – IDDM,
Hashimoto’s
 Additional signals,
such as IFN-gamma IL-1 and TNF
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4.Epitope spreading
Definition:
Initial
response
to
one
self
determinant (one peptide) could expand
to involve additional determinants on
the same molecule as well as additional
self-proteins.
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It explains how a
response to one
cryptic
epitope
can mature into a
full-blown
autoimmune
response .
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5. Polyclonal B cell activation by CMV, EBV,
and some G-negative bacteria
- T-cell-independent
- Large amounts of IgM produced
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6.Role of Infection in Autoimmunity
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7. Gene factors in autoimmunity
Multiple sclerosis – particular alleles of
HLA-DR (DRB1*1501, DRB5*0101)
Systemic lupus – lack of C1q and C4
Genetically determined low expression of
given self-antigen in the thymus
Mutation (usually deletion) of autoimmune
regulator-1 gene (AIRE-1)
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Association
between
HLA and
susceptibilit
y to
autoimmune
disease
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8.Estrogens and Autoimmunity
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9.Other factors favoring autoimmunity
 Lymphocytes abnormalities
 Cytokine Imbalance (↑IL-2 in SLE)
 Disturbances of apoptosis ( Deficiencies in

Fas, complement, CTLA-4)
Toxins, Drugs, Chemicals (including food),
UV, Stress
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THERAPY OF AUTOIMMUNE DISEASES
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Reduce symptoms

Immunosuppression
Corticosteroids, azathioprine,
cyclophosamide


Removal of thymus
Plasmapheresis
Short-term relief
(Grave’s disease, RA, SLE)
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Reduce inflammation
 TNF-alpha blockers (RA, Crohn’s dis.,
psoriasis)
e.g., Enbrel, Remicade, Humira
 IL-1 receptor antagonist (RA)
 Ab’s against IL6R and IL-15R
 Statins, shown to lower CRP (RA, MS)
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Block MHC with similar peptide or antibody
 Anti-CD4
 Blockage of IL-12
activity
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T cell vaccines
(against activated Ag-specific T cells)
Monoclonal antibodies against a variety of
target antigens
Oral induction of tolerance (MS)
So far, efforts have been more successful
in mice than humans
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Insulin-dependent diabetes mellitus (IDDM)
Disease in which the body does not produce
enough insulin.
It is a “ T cell” Disease.
T cells attack and destroy pancreatic beta
cells.
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Insulin-dependent diabetes mellitus (IDDM)
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Insulin-dependent diabetes mellitus (IDDM)
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Multiple Sclerosis
Myelin sheath of
nerves targeted
CNS attacked by
inflammatory lesions
Starts in 20-40 yr.
old people
Characterized by
weakness, paralysis
and ocular symptoms
MS patients can have autoantibodies and/or self reactive T
cells which are responsible for the demyelination
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Myasthenia Gravis
Disease marked by progressive weakness
and loss of muscle control
Classified as a “B cell” Disease
Autoantibodies against nicotinic
acetylcholine receptors
Eventually destroys it
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Myasthenia Gravis
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Graves’s disease
Autoantibody mimics TSH, leads to constant
thyroid stimulation
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Hashimoto’s thyroiditis
 Th1 cells and autoantibodies specific
for thyroid Ag’s  infiltration of thyroid
by L, M, and PC’s  hypothyroidism
 Chronic inflammation and enlargement
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Normal thyroid gland
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Hashimoto’s thyroiditis
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Hashimoto’s thyroiditis
(From Robbins Basic Pathology ,2003）
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Goodpasture’s syndrome

Antibodies to membrane antigens
in kidney and alveoli in lungs

Specificity – part of type IV collagen

Complement activation, cell damage,
inflammation
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The anti-basement membrane antibody in Goodpasture’s syndrome
forms an even layer on the glomerular basement membrane.
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Systemic Lupus Erythematosus (SLE)
 Typical patient: young
woman with butterfly rash
 Symptoms unpredictable
(relapsing/remitting)
 Multisystem (skin, kidneys,
joints, heart)
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Systemic Lupus Erythematosus (SLE)
Etiology
• Autoantibodies!
• Antinuclear Ab present in all patients with
SLE... but found in other autoimmune
diseases too
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Systemic Lupus Erythematosus (SLE)
What’s so bad about having these
autoantibodies?
 They cause tissue injury!
Form immune complexes
Cause destruction, phagocytosis of cells
 Multisystem effects:
Kidney (renal failure)
Skin (“butterfly rash”)
CNS (focal neurologic deficits)
Joints (arthritis)
Heart (pericarditis, endocarditis)
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Systemic Lupus Erythematosus (SLE)
prognosis
 Variable! Some have few symptoms, rare patients
die within months.
 Most patients: relapses/remissions over many
years.
 Acute flare-ups controlled with steroids
 80% 10-year survival
 Most common cause of death: renal failure
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Systemic Lupus Erythematosus (SLE)
Lupus nephritis. There are two focal necrotizing lesions at 11 and
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2 o’clock. (H&E stain.) (Dr. Helmut Rennke)
Slide 7.24
Systemic Lupus Erythematosus (SLE)
Lupus nephritis, diffuse proliferative type. Note the marked increase in
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throughout the glomerulus. (H&E stain.) (Dr. Helmut Rennke)
Slide cellularity
7.25
Immunofluorescence micrograph stained with fluorescent anti-IgG
from a patient with diffuse proliferative lupus nephritis. One
complete glomerulus and part of another one are seen. Note the
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mesangial and capillary wall deposits of IgG.
Slide 7.26
Lupus nephritis showing a glomerulus with several “wire loop”
lesions representing extensive subendothelial deposits of immune
complexes. (Periodic acid-Schiff [PAS] stain.)
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Slide 7.28
Systemic lupus erythematosus involving the skin. A, An H&Estained section shows liquefactive degeneration of the basal layer of
the epidermis and edema at the dermoepidermal junction. B, An
immunofluorescence micrograph stained for IgG reveals deposits of
immunoglobulin along the dermoepidermal junction.
Slide 7.29
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Rheumatoid Arthritis
 Symmetric, mostly small-joint arthritis
 Systemic symptoms (skin, heart,
vessels, lungs)
 Rheumatoid factor
 Cytokines (especially TNF) cause
damage
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Rheumatoid Arthritis
Etiology
 Circulating IgM antibody
 Directed against patient’s OWN IgG!
 Forms IgM-IgG immune complexes,
which deposit in joints and cause
badness
 Present in 80% of patients
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Rheumatoid Arthritis
Etiology
 T cells release cytokines:
activate macrophages
(causing destruction)
cause B cells to make
antibodies against joint
Most important of these
cytokines: TNF
 Cytokines cause inflammation
and tissue damage
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Rheumatoid Arthritis
Joint disease
Mainly small joints
(hands), but also knees,
elbows, shoulders
 Symmetric; characteristic hand features
 Chronic synovitis with pannus formation:
synovial cell proliferation
inflammation
granulation tissue
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Rheumatoid Arthritis
Systemic disease
 Weakness, malaise, fever
 Vasculitis
 Pleuritis, pericarditis
 Lung fibrosis
 Eye changes
 Rheumatoid nodules on forearms
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Rheumatoid Arthritis
prognosis
 Variable!
 A few patients stabilize
 Most patients have chronic course
with progressive joint destruction and
disability
 Lifespan shortened by 10-15 years
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