Autoimmunity

Autoimmunity

Autoimmunity
1. When the immune system loses sense of self and attacks and destroys healthy body tissue
2. A destructive immune response against self antigens
3. Once started, difficult to stop
4. Severity ranges from minor to lethal
5. Affects 5-7% of the population
6. Can affect any organ or organ system in the body
7. Autoantibodies can be passed from mothers to their babies
Autoimmunity vs. hypersensitivity
1. Immunogen in hypersensitivity is an allergen, in autoimmunity it's an autoantigen
2. Hypersensitivity causes a clinical allergy, autoimmunity causes an immune disorder
3. 10% of the population experience hypersensitivity, 5% experience autoimmunity
4. Mortality by hypersensitivity is rare, but in autoimmunity it is high
5. Mechanisms in hypersensitivity include type I, II, III and IV, in autoimmunity type II, III and IV
What causes autoimmunity?
1. Failure to maintain self-tolerance
2. Risk factors
  1. Genetic susceptibility
    1. Presence of susceptible genes
    2. Being female
      1. Could be due to imbalance in hormone levels
      2. Rise in hormones associated with pregnancy may cause abortion of the foetus
      3. Endometriosis and preeclampsia are thought to be autoimmune in nature
      4. ORE: oestrogen response elements
    3. There isn't a single pin-pointable gene
    4. Numerous genes involved in susceptibility
  2. Environmental triggers
    1. Infections
    2. Injury
    3. Drugs, toxins, UV radiation
    4. Stress, poor diet, lack of exercise, lack of sleep, abuse of alcohol and use of tobacco
Exceptions to the rule: simple genetic autoimmune illnesses
1. Autoimmune polyglandular syndrome type I (APS-1)
  1. Gene: AIRE
    1. Knockout causes decreased expression of self antigens in the thymus, resulting in defective selection of self reactive T cells
  2. Mechanism: decreased expression of self antigens in the thymus resulting in a defect in negative selection
2. Immunodysregulation polyendocrinopathy enteropathy,X linked (IPEX)
  1. Gene: FOXP3
    1. Knockout causes decreased function of CD4 CD25 regulatory T cells
  2. Decreased generation of regulatory T cells
3. Autoimmune lymphoproliferative syndrome (ALPS)
  1. Gene: FAS
    1. Knockout causes failure of apoptotic death of self reactive B and T cells
  2. Failure of apoptotic death of self reactive T or B cells
MHC association
1. Mechanisms underlying the association of MHC alleles with various autoimmune diseases are still not clear
2. Association with MHC class II genes
3. MHC may present a self peptide and activate pathogenic T cells
4. MHC may influence negative selection of developing T cells
Genetics of autoimmunity
1. NOD2
  1. Polymorphism associated with 25% of Crohn's disease
  2. Microbial sensor
2. PTPN22
  1. Most common autoimmunity associated gene
  2. Phosphatase
3. CD25
  1. Associated with MS
  2. Role in regulatory T cells
Injury
1. Sympathetic opthalamaia
  1. Physical trauma in one eye can initiate autoimmune response to both eyes
  2. Eye anterior chamber is an immune privileged site
  3. Normally autoimmune antigens in this site are not exposed to the immune system
  4. Trauma to one eye results in the release of sequestered introcular protein antigens
    1. Released intraocular antigens are carried to the lymph node and activate T cells
      1. Effector T cells return via bloodstream and attack antigen in both eyes
        On occasion this causes blindness in both damaged and undamaged eyes
Superantigens
1. Several infectious agents contain antigens with the ability to polyclonally activate a subset of CD4+ T cells bearing particular VB TCR families
  1. Hypothesis: this may activate auto antibodies
    1. This would increase VB in autoimmune lesions
    2. Isolated reports in rheumatoid arthritis and diabetes
    3. No strong evidence
  2. Polyclonal activation
    1. Viruses and bacteria can induce non-specific polyclonal B cell activation leading to autoantibodies
    2. Gram negative bacteria, cytomegalovirus and EBV are polyclonal activtors
    3. SLE patients produce large quantities of IgM polyclonal antibodies
      1. Systemic Lupus Erythematosus (SLE) can attack any part of the body resulting in inflammation or tissue damage
Local infections
1. Induces inflammation which results in activation of non-professional APC
2. Thyroid cells do not normally express MHC class II
  1. IFN-gamma produced during infection or non-specific inflammation induces MHC class II expression on thyroid cells
    1. Activated T cells recognise peptides presented by MHC class II and induce autoimmune thyroid disease
3. Hashimoto thyroiditis
  1. Follicular cells of the thyroid
4. Type I diabetes
  1. beta cells of islets of Langerhans
Molecular mimicry
1. Some viruses and bacteria possess antigenic determinants that are identical or similar to normal host cell components
2. The same MHC molecule presents both a pathogen peptide and a self peptide that mimics it
  1. Naive T cell is activated by the pathogen peptide present by the MHC molecule
    1. Effector Th1 cells responds to the self peptide mimic and activates the macrophage causing inflammation
3. Examples
  1. Rheumatic fever
  2. Multiple sclerosis
  3. Type I diabetes
  4. Systemic Lupus erythematosus
  5. Post rabies encephalitis
    1. Used to develop in individuals that had the rabies vaccine
    2. Rabies virus was grown in rabbit cell culture that contained antigens from rabbit brains
    3. In vaccinated people these antigens would induce formation of antibodies and activated T cells which would cross react with the recipient's own brain cells causing encephalitis
Epitope spreading
1. Once autoimmune diseases begin they tend to be progressive with remissions and exacerbations
2. A mechanism for chronic progression
3. In a persistent microbial infection and tissue damage, initial response to one self epitope expands to involve additional epitopes on the same molecule as well as additional self proteins
  1. Explains how one epitope can mature into full blown autoimmune response
4. Release of sequestered antigen
  1. APC with cross reacting Ag (molecular mimicry)
    1. Inappropriate MHC expression on non-APCs
      1. Activated macrophages from activated T helper cells cause inflammation and local Delayed Type Hypersensitivity (IV) resulting in tissue damage
      2. Activated Th cell produces B cells which produce plasma cells by polyclonal activation that produce Abs to self antigens resulting in tissue damage
Autoimmunity classification
1. Organ specific autoimmune diseases
  1. Type I diabetes
  2. Goodpasture's syndrome
    1. Autoantibodies specific for antigens in the basement membranes of the kidney and the alveoli of the lungs
    2. Leads to complement activation and direct cellular damage as well inflammatory response mediated by the build up of complement split products
    3. Tissue damage leads to kidney damage and pulmonary haemorrhage
    4. Smoking can be the trigger because it damages alveoli and exposes collagen
  3. Multiple sclerosis
  4. Grave's disease
  5. Hashimoto's thryoiditis
2. Systemic autoimmune diseases
  1. Rheumatoid arthritis
  2. Scleroderma
  3. Systemic lupus erythematosus
Autoimmune diseases of the endocrine glands
1. Insulin dependent diabetes mellitus
  1. Type 1
  2. T cells attack and destroy insulin producing cells (beta cells) located in the islets of Langerhans
  3. The pancreas does not produce or properly use insulin and consequently increased levels of blood glucose
  4. Islets of Langerhans contain several cell types secreting distinct hormones, each cell expresses different tissue specific proteins
    1. In IDDM an effector T cell recognises peptides from the beta cell specific protein and kills the beta cell
      1. Glucagon and somatostatin are still produced by the alpha and delta cells but no insulin can be made
  5. Treated with daily insulin injections
  6. Factors involves in the destruction of beta cells
    1. Activated CTLs migrate to the islets and begin to attack the beta cells
    2. Cytokine production released during response: IFN-y, TNF-a and IL-1
    3. Coxasckie virus group B- direct destruction of the beta cells by the virus as a result of molecular mimicry
2. Chronic thyroiditis: Hasimoto's disease
  1. Production of autoantibodies and sensitised to Th1 cells specific for thyroid antigens
  2. Intense infiltration of the thyroid gland by lymphocytes, macrophages and plasma cells
  3. Binding of autoantibodies against thyroid tissue proteins interferes with the iodine uptake and leads to decreased production of thyroid hormones
  4. Treatment: oral administration of thyroid hormone
3. Hyperthyroidism: Graves' disease
  1. Autoantibodies produced against the thyroid gland
  2. Long acting thyroid stimulating antibody causes unregulated overproduction of thyroid hormones
  3. Symptoms
    1. Heat intolerance
    2. Nervousness
    3. Irritability
    4. Warm, most skin
    5. Thyroid enlargement
  4. Treatment
    1. Thyroidectomy
    2. Destruction of thyroid by radioactive 131I
  5. Autoantibodies can be passed from mothers to their babies
    1. Mother with Graves disease makes anti-TSHR antibodies
      1. During pregnancy antibodies cross the placenta into the foetus
        Newborn infant also suffers from Graves' disease
        Plasmapheresis removes maternal anti-TSHR antibodies and cures the infant's disease
Myasthenia Gravis
1. Blocks normal binding of acetylcholine and mediates complement mediated degradation of receptors
  1. Binding autoantibodies to the acetylcholine receptors on the motor end plates of muscles
  2. Progressive weakening of the skeletal muscles and loss of muscle control
2. Symptoms
  1. Drooping eyelids
  2. Inability to retract the corners of the mouth
Systemic autoimmune diseases
1. Defects in immune regulation
2. Response is directed towards a broad range of target antigens and involves a number of organs
3. Tissue damage is widespread by...
  1. Cell mediated immune responses
  2. Direct cellular damage caused by autoantibodies
  3. Accumulation of immune complexes
4. Celiac disease
  1. Wheat flour gluten peptide specific CD4 T cells
  2. Gluten is degraded in the gut lumen to give a resistant fragment
    1. Gluten fragment enters the gut tissue and is deaminated by transglutaminase
      1. Naive CD4 T cells respond to deaminated peptides presented by MHC II
        Inflammatory effector T cells cause villous atrophy
5. Systemic Lupus Erythematosus (SLE)
  1. Appears in women age 20-40
  2. More prevalent in females
  3. Symptoms
    1. Low grade fever
    2. Ulcers
    3. Aching muscles
    4. Arthritis
    5. Fatigue
    6. Loss of appetite
    7. Butterfly rash on face
    8. Poor circulation
  4. Antinuclear antibodies directed against DNA, nucleoprotein, histones and nucleolar RNA
    1. IgG against a wide variety of cellular constituents (defect in maintenance of B cell self tolerance
      1. Binding of antibodies to cell surface antigens causes inflammatory responses leading to cell and tissue destructon
        Immune complexes, deposited in blood vessels, kidney, joints and other tissues cause tissue inflammation and destruction
  5. Damage occurs by...
    1. Formation of immune complexes
      1. Type III hypersensitivity
    2. Antibody mediated injury to blood cells
      1. Type II hypersensitivity
  6. Gene: C1q
    1. Knockout causes defective clearance of immune complexes and apoptotic cells
6. Rheumatoid arthritis
  1. Mostly affects women age 40-60
  2. Major symptom: chronic inflammation of joints
  3. B cells in joints produce IgM autoantibodies called rheumatoid factors
    1. This binds to Fc region of normal circulating IgG, forming IgM-IgG complexes that are deposited in the joints and activate the complement cascade
      1. Type III hypersensitivity reaction which leads to chronic inflammation of the joints
7. Multiple sclerosis
  1. Autoimmune neurological disease
  2. Symptoms may be mild such as numbess in the limbs or severe such as paralysis and loss of vision
  3. Most people are diagnosed between the ages of 20 and 40
  4. Autoreactive Th1 cells in the cerebrospinal fluid induce expression of chemokines and cytokines that recruit inflammatory cells
    1. Inflammatory lesions along the myelin sheath of nerve fibres
      1. Treated with immunosuppressive drugs
  5. Possible environmental influence and genetic infleunce
  6. Cause unknown, possibly a virus

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	Created by sophie_connor over 11 years ago