Autoimmunity

Autoimmunity

1. Autoimmunity

   • When the immune system loses sense of self and attacks and destroys healthy body tissue
   • A destructive immune response against self antigens
   • Once started, difficult to stop
   • Severity ranges from minor to lethal
   • Affects 5-7% of the population
   • Can affect any organ or organ system in the body
   • Autoantibodies can be passed from mothers to their babies

2. Autoimmunity vs. hypersensitivity

   • Immunogen in hypersensitivity is an allergen, in autoimmunity it's an autoantigen
   • Hypersensitivity causes a clinical allergy, autoimmunity causes an immune disorder
   • 10% of the population experience hypersensitivity, 5% experience autoimmunity
   • Mortality by hypersensitivity is rare, but in autoimmunity it is high
   • Mechanisms in hypersensitivity include type I, II, III and IV, in autoimmunity type II, III and IV

3. What causes autoimmunity?

   • Failure to maintain self-tolerance
   • Risk factors
     • Genetic susceptibility
       • Presence of susceptible genes
       • Being female
         • Could be due to imbalance in hormone levels
         • Rise in hormones associated with pregnancy may cause abortion of the foetus
         • Endometriosis and preeclampsia are thought to be autoimmune in nature
         • ORE: oestrogen response elements
       • There isn't a single pin-pointable gene
       • Numerous genes involved in susceptibility
     • Environmental triggers
       • Infections
       • Injury
       • Drugs, toxins, UV radiation
       • Stress, poor diet, lack of exercise, lack of sleep, abuse of alcohol and use of tobacco

4. Exceptions to the rule: simple genetic autoimmune illnesses

   • Autoimmune polyglandular syndrome type I (APS-1)
     • Gene: AIRE
       • Knockout causes decreased expression of self antigens in the thymus, resulting in defective selection of self reactive T cells
     • Mechanism: decreased expression of self antigens in the thymus resulting in a defect in negative selection
   • Immunodysregulation polyendocrinopathy enteropathy,X linked (IPEX)
     • Gene: FOXP3
       • Knockout causes decreased function of CD4 CD25 regulatory T cells
     • Decreased generation of regulatory T cells
   • Autoimmune lymphoproliferative syndrome (ALPS)
     • Gene: FAS
       • Knockout causes failure of apoptotic death of self reactive B and T cells
     • Failure of apoptotic death of self reactive T or B cells

5. MHC association

   • Mechanisms underlying the association of MHC alleles with various autoimmune diseases are still not clear
   • Association with MHC class II genes
   • MHC may present a self peptide and activate pathogenic T cells
   • MHC may influence negative selection of developing T cells

6. Genetics of autoimmunity

   • NOD2
     • Polymorphism associated with 25% of Crohn's disease
     • Microbial sensor
   • PTPN22
     • Most common autoimmunity associated gene
     • Phosphatase
   • CD25
     • Associated with MS
     • Role in regulatory T cells

7. Injury

   • Sympathetic opthalamaia
     • Physical trauma in one eye can initiate autoimmune response to both eyes
     • Eye anterior chamber is an immune privileged site
     • Normally autoimmune antigens in this site are not exposed to the immune system
     • Trauma to one eye results in the release of sequestered introcular protein antigens
       • Released intraocular antigens are carried to the lymph node and activate T cells
         • Effector T cells return via bloodstream and attack antigen in both eyes
           • On occasion this causes blindness in both damaged and undamaged eyes

8. Superantigens

   • Several infectious agents contain antigens with the ability to polyclonally activate a subset of CD4+ T cells bearing particular VB TCR families
     • Hypothesis: this may activate auto antibodies
       • This would increase VB in autoimmune lesions
       • Isolated reports in rheumatoid arthritis and diabetes
       • No strong evidence
     • Polyclonal activation
       • Viruses and bacteria can induce non-specific polyclonal B cell activation leading to autoantibodies
       • Gram negative bacteria, cytomegalovirus and EBV are polyclonal activtors
       • SLE patients produce large quantities of IgM polyclonal antibodies
         • Systemic Lupus Erythematosus (SLE) can attack any part of the body resulting in inflammation or tissue damage

9. Local infections

   • Induces inflammation which results in activation of non-professional APC
   • Thyroid cells do not normally express MHC class II
     • IFN-gamma produced during infection or non-specific inflammation induces MHC class II expression on thyroid cells
       • Activated T cells recognise peptides presented by MHC class II and induce autoimmune thyroid disease
   • Hashimoto thyroiditis
     • Follicular cells of the thyroid
   • Type I diabetes
     • beta cells of islets of Langerhans

10. Molecular mimicry

    • Some viruses and bacteria possess antigenic determinants that are identical or similar to normal host cell components
    • The same MHC molecule presents both a pathogen peptide and a self peptide that mimics it
      • Naive T cell is activated by the pathogen peptide present by the MHC molecule
        • Effector Th1 cells responds to the self peptide mimic and activates the macrophage causing inflammation
    • Examples
      • Rheumatic fever
      • Multiple sclerosis
      • Type I diabetes
      • Systemic Lupus erythematosus
      • Post rabies encephalitis
        • Used to develop in individuals that had the rabies vaccine
        • Rabies virus was grown in rabbit cell culture that contained antigens from rabbit brains
        • 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

11. Epitope spreading

    • Once autoimmune diseases begin they tend to be progressive with remissions and exacerbations
    • A mechanism for chronic progression
    • 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
      • Explains how one epitope can mature into full blown autoimmune response
    • Release of sequestered antigen
      • APC with cross reacting Ag (molecular mimicry)
        • Inappropriate MHC expression on non-APCs
          • Activated macrophages from activated T helper cells cause inflammation and local Delayed Type Hypersensitivity (IV) resulting in tissue damage
          • Activated Th cell produces B cells which produce plasma cells by polyclonal activation that produce Abs to self antigens resulting in tissue damage

12. Autoimmunity classification

    • Organ specific autoimmune diseases
      • Type I diabetes
      • Goodpasture's syndrome
        • Autoantibodies specific for antigens in the basement membranes of the kidney and the alveoli of the lungs
        • Leads to complement activation and direct cellular damage as well inflammatory response mediated by the build up of complement split products
        • Tissue damage leads to kidney damage and pulmonary haemorrhage
        • Smoking can be the trigger because it damages alveoli and exposes collagen
      • Multiple sclerosis
      • Grave's disease
      • Hashimoto's thryoiditis
    • Systemic autoimmune diseases
      • Rheumatoid arthritis
      • Scleroderma
      • Systemic lupus erythematosus

13. Autoimmune diseases of the endocrine glands

    • Insulin dependent diabetes mellitus
      • Type 1
      • T cells attack and destroy insulin producing cells (beta cells) located in the islets of Langerhans
      • The pancreas does not produce or properly use insulin and consequently increased levels of blood glucose
      • Islets of Langerhans contain several cell types secreting distinct hormones, each cell expresses different tissue specific proteins
        • In IDDM an effector T cell recognises peptides from the beta cell specific protein and kills the beta cell
          • Glucagon and somatostatin are still produced by the alpha and delta cells but no insulin can be made
      • Treated with daily insulin injections
      • Factors involves in the destruction of beta cells
        • Activated CTLs migrate to the islets and begin to attack the beta cells
        • Cytokine production released during response: IFN-y, TNF-a and IL-1
        • Coxasckie virus group B- direct destruction of the beta cells by the virus as a result of molecular mimicry
    • Chronic thyroiditis: Hasimoto's disease
      • Production of autoantibodies and sensitised to Th1 cells specific for thyroid antigens
      • Intense infiltration of the thyroid gland by lymphocytes, macrophages and plasma cells
      • Binding of autoantibodies against thyroid tissue proteins interferes with the iodine uptake and leads to decreased production of thyroid hormones
      • Treatment: oral administration of thyroid hormone
    • Hyperthyroidism: Graves' disease
      • Autoantibodies produced against the thyroid gland
      • Long acting thyroid stimulating antibody causes unregulated overproduction of thyroid hormones
      • Symptoms
        • Heat intolerance
        • Nervousness
        • Irritability
        • Warm, most skin
        • Thyroid enlargement
      • Treatment
        • Thyroidectomy
        • Destruction of thyroid by radioactive 131I
      • Autoantibodies can be passed from mothers to their babies
        • Mother with Graves disease makes anti-TSHR antibodies
          • 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

14. Myasthenia Gravis

    • Blocks normal binding of acetylcholine and mediates complement mediated degradation of receptors
      • Binding autoantibodies to the acetylcholine receptors on the motor end plates of muscles
      • Progressive weakening of the skeletal muscles and loss of muscle control
    • Symptoms
      • Drooping eyelids
      • Inability to retract the corners of the mouth

15. Systemic autoimmune diseases

    • Defects in immune regulation
    • Response is directed towards a broad range of target antigens and involves a number of organs
    • Tissue damage is widespread by...
      • Cell mediated immune responses
      • Direct cellular damage caused by autoantibodies
      • Accumulation of immune complexes
    • Celiac disease
      • Wheat flour gluten peptide specific CD4 T cells
      • Gluten is degraded in the gut lumen to give a resistant fragment
        • Gluten fragment enters the gut tissue and is deaminated by transglutaminase
          • Naive CD4 T cells respond to deaminated peptides presented by MHC II
            • Inflammatory effector T cells cause villous atrophy
    • Systemic Lupus Erythematosus (SLE)
      • Appears in women age 20-40
      • More prevalent in females
      • Symptoms
        • Low grade fever
        • Ulcers
        • Aching muscles
        • Arthritis
        • Fatigue
        • Loss of appetite
        • Butterfly rash on face
        • Poor circulation
      • Antinuclear antibodies directed against DNA, nucleoprotein, histones and nucleolar RNA
        • IgG against a wide variety of cellular constituents (defect in maintenance of B cell self tolerance
          • 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
      • Damage occurs by...
        • Formation of immune complexes
          • Type III hypersensitivity
        • Antibody mediated injury to blood cells
          • Type II hypersensitivity
      • Gene: C1q
        • Knockout causes defective clearance of immune complexes and apoptotic cells
    • Rheumatoid arthritis
      • Mostly affects women age 40-60
      • Major symptom: chronic inflammation of joints
      • B cells in joints produce IgM autoantibodies called rheumatoid factors
        • This binds to Fc region of normal circulating IgG, forming IgM-IgG complexes that are deposited in the joints and activate the complement cascade
          • Type III hypersensitivity reaction which leads to chronic inflammation of the joints
    • Multiple sclerosis
      • Autoimmune neurological disease
      • Symptoms may be mild such as numbess in the limbs or severe such as paralysis and loss of vision
      • Most people are diagnosed between the ages of 20 and 40
      • Autoreactive Th1 cells in the cerebrospinal fluid induce expression of chemokines and cytokines that recruit inflammatory cells
        • Inflammatory lesions along the myelin sheath of nerve fibres
          • Treated with immunosuppressive drugs
      • Possible environmental influence and genetic infleunce
      • Cause unknown, possibly a virus