Transcript Autoimmunity - Lehigh University

Autoimmunity
“n. of, relating to, or caused by
autoantibodies or lymphocytes that attack
molecules, cells, or tissues of the organism
producing them.”
(from Webster’s Online)
The Study of Autoimmunity
• Molecular Mechanisms of Autoimmunity
• Animal Models for Autoimmune
Dysfunction
• Treatments for Autoimmune Diseases
• Gender Differences in Autoimmunity
• Three Common Autoimmune Diseases
Molecular Mechanisms of Autoimmunity
How is autoimmunity
induced?
What could go wrong
here?
Molecular Mechanisms of Autoimmunity
• Cross-reactivity (Molecular and Viral Mimicry)
Viral and nonviral peptides can mimic self-peptides and
induce autoimmunity
Example: papilloma virus (HPV) and insulin receptor
Cross-Reactivity
Molecular Mechanisms of Autoimmunity
• Release of Sequestered Antigen
Antibodies in blood can attack Myelin Basic Protein if
Blood-Brain barrier is breached.
Molecular Mechanisms of Autoimmunity
• Inappropriate MHC expression
Type I Diabetes: Pancreatic β cells express abnormally
high levels of MHC I and MHC II (?)
MHC II – APC only! This may hypersensitize TH cells to β
cell peptides.
Inappropriate MHC Expression
Normal Pancreas
Fig. 20-3
Pancreas with Insulitis
Molecular Mechanisms of Autoimmunity
• Polyclonal B Cell Activation by Viruses and
Bacteria
If B cells reactive to self-peptides are activated,
autoimmunity can occur.
Example: Epstein-Barr Virus, which is the cause of
infectious mononucleosis.
Putting it all together…the big picture
• Autoimmunity can be caused by immunological, genetic,
viral, drug-induced, and hormonal factors.
• There are 4 immunological mechanisms of
autoimmunity.
• All mechanisms cause abnormal B or T cell activation.
• Centrality of the Ternary Complex
• Most instances of autoimmune diseases occur with
multiple mechanisms, which makes treatment difficult.
Animal Models for
Autoimmune Diseases
Why have them?
• Animal models of autoimmune diseases
contribute valuable insights into the mechanisms
of autoimmunity and to our understanding of
autoimmunity in humans and how we may treat
autoimmune diseases.
Autoimmunity in Animals is
Spontaneous or Induced
• Spontaneous: Autoimmunity develops
spontaneously in some inbred strains of
animals
• Induced: Autoimmunity develops after
being induced by certain experimental
manipulation
Spontaneous Autoimmunity in
Some Animals
• Exhibits important clinical and pathogenic
similarities to certain autoimmune diseases in
humans
• Example: New Zealand Black Mice (NZB) and
F1 hybrids of NZB and New Zealand White Mice
(NZW) spontaneously develop autoimmune
diseases that closely resemble lupus
erythematosus
– Incidence of autoimmunity in hybrids is more common
in females than in males
New Zealand Mice
• NZB spontaneously develops autoimmune hemolytic
anemia between 2-4 months of age
– At this point various antibodies can be detected.
These antibodies include antibodies to erthyocytes,
nuclear proteins, DNA and T lymphocytes
– F1 hybrids develop glomerulonephritis from immunecomplex deposits in the kidneys and die within 18
months
• Glomerulonephritis: nephritis marked by inflammation of the
capillaries of renal glomeruli
– Glomeruli: a tuft of capillaries at the point of origin of each
vertebrate nephron that passes a protein-free filtrate to the
surrounding Bowman’s capsule
Mouse MRL/lpr/lpr (Mouse strain)
• Systemic Lupus Erthematosus develops in the
mouse strain MRL/lpr/lpr
– Mice are homozygous for the lpr gene, which has
been identified as a defective fas gene.
– The fas/lpr gene product is a cell surface protein in
the TNF family
– When the normal fas protein interacts with its ligand,
signals are sent out leading to apoptic death of the
fas bearing cells: target of CTLs
– Fas is also known to be important for the death of
hyperactive CD4+ cells
– Without fas mature peripheral T cells do not die, and
they continue to proliferate and produce cytokines
that result in enlarged lymph nodes and spleen
Nonobese Diabetic (NOD) Mouse
Model
• Found to develop a form of diabetes that resemble
human insulin dependent mellitus
• As in humans, NOD in mice begins with lymphatic
infiltration into the islets of the pancreas
• There is an association between certain MHC and
development of diabetes in the mice
• Experiments have shown that t cells from diabetic mice
can transfer diabetes to nondiabetic mice
• When bone marrow of a normal mouse is replaced with
NOD bone marrow, diabetes develops
• When bone marrow from NOD mouse is replaced with
healthy bone marrow, diabetes doesn’t develop
Spontaneous Autoimmunity
• A final example….
- Other animals: Obese strain chickens can develop
humoral and cellmediated reactivity thyroglobulin
resembling Hashimoto’s Thyroiditis
Induced Autoimmunity in Animals
• Autoimmune dysfunctions that are similar
to human autoimmune disease can be
induced into animals
Myasthenia Gravis
• 1973: rabbits were immunized with acetylcholine
receptors purified from electric eels. The rabbits then
developed muscular weakness similar to myasthenia
gravis
• Myasthenia gravis: disease characterized by progressive
weakness and exhaustibility of voluntary muscles without
atrophy or sensory disturbance and caused by an
autoimmune attack on acetylcholine receptors at the
neuromuscular junction
• Experimental myasthenia gravis resulted when the
antibodies to the acetylcholine receptors blocked muscle
stimulation by the acetylcholine in the synapse
• From this experiment: the discovery that auto-antibodies
to the acetylcholine receptors were the cause of
myasthenia gravis in humans
CFA: Complete Freund’s Adjuvant
An effective means of potentiating humoral antibody response to
injected immunogens
•CFA is considered to be an
emulsion consisting of equal
volumes of CFA to antigen (1
part CFA or less to 1 part
antigen).
•Improper or unnecessary
use leads to excessive
inflammation, induration,
and/or necrosis in laboratory
animals.
Experimental Autoimmune
Encephalomyelitis (EAE)
• Experimental autoimmune encephalomyelitis (EAE): one of the best
studied models of autoimmune diseases
• Encephalomyelitis: concurrent inflammation of the brain and spinal
cord
• EAE is mediated by T cells and can be induced in many species by
immunization with a myelin basic protein (MBP) or protolipid protein
(PLP) in complete Freund’s adjuvant (20-7)
Within 2-3 weeks animals develop cellular infiltration of the myelin
sheaths of the central nervous system: resulting in demyelination or
paralysis.
• Most animals die, but some have milder symptoms. Some develop
chronic symptoms that resemble multiple sclerosis in humans.
• Animals that recover are resistant to more MBP injections
• EAE model is used to investigate treatment testing for human MS
• Recent mouse experiments suggest that orally administered MBP
may make these antigen-specific peripheral T cell clones selftolerant
• Paved the way for clinical trials in MS patients
Experimental
AutoimmuneThyroiditis (EAT)
• Induced in a number of animals by immunizing
them with thyroglobulin using CFA: humoral and
Tdth cell responses cause inflammation of the
thyroid.
• EAE resembles human hashimoto’s thyroiditis
• Autoimmune Arthritis is induced by immunizing
rats with Mycobacterium tuberculosis in CFA
• Animals develop symptoms similar to human
rheumatoid arthritis
Other Autoimmune Animal Models
Treatment of Autoimmune
Diseases
I.
Current Therapies
- aimed at reducing symptoms by
providing non-specific suppression of the
immune system
II. Experimental Therapeutic Approaches
- try to induce specific immunity
I. Current Therapies
• Immunosuppressive drugs
- corticosteroids, azathioprine
- slows the proliferation of lymphocytes
• Cyclosporin A
- blocks signal transduction mediated by the TCR
(inhibits only antigen-activated T cells while sparing
non-activated ones)
• Thymectomy
- removal of thymus from patients with myasthenia
gravis
• Plasmapheresis
- removes antigen-antibody complexes for a shortterm reduction in symptoms
II. Experimental Therapeutic
Approaches
• T-cell Vaccination
- autoimmune T-cell clones elicit regulator T-cells
that are specific for the TCR on the autoimmune Tcells
- results in suppression of the autoimmune cells
• Peptide Blockade of MHC molecules
- a synthetic peptide is used to bind in place of the
regular peptide on the MHC
- induces a state of clonal anergy in the autoimmune
T-cells
(Experimental Therapies continued)
• Monoclonal-Antibody Treatment
- monoclonal antibody against the IL-2 receptor
blocks activated TH-cells
- blockage of preferred TCRs with monoclonal
antibodies
- monoclonal antibody against an MHC molecule
that is associated with autoimmunity while sparing
the others
• Oral antigens
- tend to induce tolerance
- still in early clinical trials
Sex-based Differences in
Autoimmunity
• Differences can be traced to sex hormones
- hormones circulate throughout the body and alter
immune response by influencing gene expression
- (in general) estrogen can trigger autoimmunity and
testosterone can protect against it
• Difference in immune response
- ♀ produce a higher titer of antibodies and mount
more vigorous immune responses than ♂
- ♀ have a slightly higher cortisol secretion than ♂
- ♀ have higher levels or CD4+ T-cells and serum
IgM
Sex-based Differences
• Estrogen
- causes autoimmunity (generally)
- stimulates prolactin secretion (helps regulate
immune response)
- stimulates the gene for CRH (corticotropinreleasing hormone) that promotes cortisol secretion
- causes more TH1-dominated immune responses
(promotes inflammation)
• Testosterone
- can cause autoimmunity or protect against it
Sex-based Differences
• Pregnancy
- during this, ♀ mount more of a TH2-like response
- the change in hormones creates an antiinflammatory environment (high cortisol levels)
- diseases enhanced by TH2-like responses are
exaggerated and diseases that involve
inflammatory responses are suppressed
- fetal cells can persist in the mother’s blood or the
mother’s cells may appear in the fetus
(microchimerism)
- can result in autoimmunity if the fetal cells
mount an immune response in the mother’s
body (or vice versa)
Rheumatoid Arthritis (RA)
•
•
•
•
Cause (s) and Demographics
Molecular Mechanism
Mechanism of Tissue Damage
Treatment Options
Cause and Demographics
• Cause is unknown!
• Affects 1-2% of worldwide population
• Patients are 75% Women, between 40-60
years of age
Molecular Basis
• Rheumatoid Factor (Rf): Antibodies to IgG
• HLA-DR4 Antibody (MHC II!)
Mechanism of Tissue Damage
Treatment Options
•
•
•
•
NSAIDs
Cox-2 Inhibitors
Methotrexate
Herbal Remedies
– Glucosamine
– Chondroitin
Grave’s Disease
•Production of thyroid hormones is
regulated by thyroid-stimulating
hormones (TSH)
•The binding of TSH to a receptor on
thyroid cells activates adenylate
cyclase and stimulates the synthesis
of two thyroid hormones: thyroxine
and triiodothyronine
•A person with Grave’s Disease
makes auto-antibodies to the
receptor for TSH. The binding of
these auto-antibodies to the receptor
mimics the normal action of TSH,
without the regulation, leading to
overstimulation of the thyroid
•The auto-antibodies are called longacting thyroid stimulating hormones
Grave’s Disease
•Beta-blockers such as
propranolol are often used to
treat symptoms of rapid heart
rate, sweating, and anxiety until
the hyperthyroidism is
controlled.
•Hyperthyroidism is treated with
antithyroid medications,
radioactive iodine or surgery.
•Both radiation and surgery
result in the need for lifelong
use of replacement thyroid
hormones, because these
treatments destroy or remove
the gland.
Autoimmune Anemias
• Pernicious Anemia
What is it?
- deficiency in vitamin B12
What causes it?
- auto-antibodies to intrinsic factor
What happens?
- B12 remains in the stomach and is excreted
Treatment
- treated with injections of B12
• Hemolytic Anemia
- results from monoclonal antibodies to normal
RBC constituents
- antibodies coat the erythrocytes, causing clumping,
lysis, and premature clearance by the spleen
- can be induced by an “offending” agent (parasite,
drug, or toxin) that adheres to the RBC
- Drug-induced Hemolytic Anemia- drug binds
to RBC’s and causes them to become
antigenic
- antibodies that develop from the drug
recognize these cells and they are
lysed