Autoimmunity

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Autoimmunity

• n. of, relating to, or caused by autoantibodies
  or lymphocytes that attack molecules, cells, or
  tissues of the organism producing them.
• (from Websters Online)

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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

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Molecular Mechanisms of Autoimmunity
How is autoimmunity induced?
What could go wrong here?
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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

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Cross-Reactivity
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Molecular Mechanisms of Autoimmunity

• Release of Sequestered Antigen
• Antibodies in blood can attack Myelin Basic
  Protein if Blood-Brain barrier is breached.

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Molecular Mechanisms of Autoimmunity

• Inappropriate MHC expression
• Type I Diabetes Pancreatic ß cells express
  abnormally high levels of MHC I and MHC II (?)
• MHC II APC only! This may hypersensitize TH
  cells to ß cell peptides.

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Inappropriate MHC Expression

• Normal Pancreas Pancreas with Insulitis
• Fig. 20-3

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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.

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Putting it all togetherthe 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.

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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.

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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

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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

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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
  immune-complex 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 Bowmans
  capsule

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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

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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 doesnt develop

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Spontaneous Autoimmunity

• A final example.
• - Other animals Obese strain chickens can
  develop humoral and cellmediated reactivity
  thyroglobulin resembling Hashimotos Thyroiditis

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Induced Autoimmunity in Animals

• Autoimmune dysfunctions that are similar to human
  autoimmune disease can be induced into animals

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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

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CFA Complete Freunds 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.

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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 Freunds 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 self-tolerant
• Paved the way for clinical trials in MS patients

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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 hashimotos thyroiditis
• Autoimmune Arthritis is induced by immunizing
  rats with Mycobacterium tuberculosis in CFA
• Animals develop symptoms similar to human
  rheumatoid arthritis

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Other Autoimmune Animal Models
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Treatment of Autoimmune Diseases

• Current Therapies
• - aimed at reducing symptoms by
  providing non-specific suppression of the
  immune system
• II. Experimental Therapeutic Approaches - try to
  induce specific immunity

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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
  short- term reduction in symptoms

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II. Experimental Therapeutic Approaches

• T-cell Vaccination
• - autoimmune T-cell clones elicit regulator
  T-cells that are specific for the TCR on the
  autoimmune T- cells
• - 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

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(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

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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

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Sex-based Differences

• Estrogen
• - causes autoimmunity (generally)
• - stimulates prolactin secretion (helps
  regulate immune response)
• - stimulates the gene for CRH (corticotropin-
  releasing hormone) that promotes cortisol
  secretion
• - causes more TH1-dominated immune responses
• (promotes inflammation)
• Testosterone
• - can cause autoimmunity or protect against it

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Sex-based Differences

• Pregnancy
• - during this, ? mount more of a TH2-like
  response
• - the change in hormones creates an anti-
  inflammatory 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 mothers blood
  or the mothers cells may appear in the fetus
  (microchimerism)
• - can result in autoimmunity if the fetal
  cells mount an immune response in the
  mothers body (or vice versa)

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Rheumatoid Arthritis (RA)

• Cause (s) and Demographics
• Molecular Mechanism
• Mechanism of Tissue Damage
• Treatment Options

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Cause and Demographics

• Cause is unknown!
• Affects 1-2 of worldwide population
• Patients are 75 Women, between 40-60 years of age

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Molecular Basis

• Rheumatoid Factor (Rf) Antibodies to IgG
• HLA-DR4 Antibody (MHC II!)

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Mechanism of Tissue Damage
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Treatment Options

• NSAIDs
• Cox-2 Inhibitors
• Methotrexate
• Herbal Remedies
• Glucosamine
• Chondroitin

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Graves 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 Graves 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 long-acting
  thyroid stimulating hormones

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Graves 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.

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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

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• 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 RBCs and causes them to become
  antigenic
• - antibodies that develop from the drug
  recognize these cells and they are lysed