L20 - Tolerance and Autoimmune Diseases

• Tolerance


  Failure of the immune system to response to an antigen in an aggressive way
• Most self-tolerance


  • Results from the deliberate inactivation of lymphocytes (B & T cells) that recognize and bind the self-antigens
• Central tolerance


  During early maturation of B & T cells recognized & memorized our body antigens
• Peripheral tolerance


  Control or eliminate autoreactive B & T cells
• Anergy


  A state of immune unresponsiveness – T-cells could not get their signals for their activation
• Suppression


  Regulatory cells suppress the activity of T cells stimulated by various self- antigens
• Autoimmune diseases


  Immune system begins to produce antibodies & T-cells directed against the body's own components – an attack on self-antigen / self-cell is called autoimmunity
• Causes of autoimmune diseases

  • An abnormal immune response to normal self-antigen
  • A normal immune response to an abnormal self-antigen
  • An abnormal immune response to an abnormal self-antigen
• Progress of autoimmune disease

  1. Hereditary susceptibility

  2. Triggering vehicle such as a virus

  3. Immune system malfunction
• Antigenic mimicry


  Exogenous antigens bearing a close structural resemblance to normal tissue components
• Features of autoimmune diseases


  • Occurrence of more than one type of autoimmune disorders in an individual
  • Higher incidence among females
  • Usually non-reversible (chronic)
• Predisposing factors for autoimmune diseases

  • Familiar history
  • Certain HLA haplotypes - Rheumatoid Arthritis - HLA DR4
• Mechanisms of Autoimmunization


  • Antigenic alteration
  • Molecular mimicry - Cross reacting foreign Ags
  • Polyclonal B cell activation
  • Breakdown of immunological homeostasis (tolerance)
  • Sequestered Antigens
• Antigenic alteration


  Antigenic alteration of cells or tissues - Altered antigens - Neoantigens
• Causes of antigenic alteration

  • Physical = irradiation, photosensitivity, cold allergy
  • Chemicals = drugs, chemical allergens
  • Biological = infectious agents like EBV
• Molecular Mimicry


  Due to the presence of cross-reacting antigens - presence of identical epitope in some infecting microorganisms & self Antigens
• Molecular Mimicry


  • Streptococcal M proteins and valves and membrane of the heart muscle
• Polyclonal B-cell Activation


  May result in production of autoantibodies by certain stimuli
• Stimuli for polyclonal B-cell activation

  • Chemicals: 2-mercaptoethanol
  • Bacterial products: Purified Protein Derivative (PPD), LPS
  • Enzymes: trypsin
  • Antibiotics: nystatin
  • Micro-organisms: Mycoplasma, EBV, Malaria
• Breakdown of immunological homeostasis (tolerance)


  Cessation of tolerance to self-antigen - Enhanced helper T-cell and decreased suppressor T-cell functions
• Sequestered Antigens


  Certain antigens are present in closed systems (compartments) and are not accessible to the immune apparatus
• Sequestered Antigens


  • Lens protein of the eye
  • Sperm protein
• Classification of Autoimmune Diseases

  • Haemocytolytic autoimmune diseases
  • Localised (or organ-specific) autoimmune diseases
  • Systemic (or non-organ specific) autoimmune diseases
  • Transitory diseases
• Autoimmune haemolytic anaemias (AIHA)

  Antibodies against patient's own RBCs - 2 groups: cold & warm autoantibodies
• Cold auto-antibodies


  IgM class & agglutinate the RBCs at 4°C, not at 37°C
• Warm auto-Antibodies


  IgG class & agglutinate the RBCs at 37°C
• Autoimmune Thrombocytopenia


  Auto-antibodies against platelets: idiopathic thrombocytopenic purpura
• Autoimmune Leucopenia


  Anti-leucocyte antibodies seen in the serum of patients with SLE & RA
• Insulin dependent DM (Type 1)

  Autoimmunity against islets of Langerhans in Pancreas - Damage the insulin producing β cells and causes hyperglycaemia - Major auto antigens are Insulin, islet cells & glutamic acid decarboxylase
• Addison's disease


  Lymphocytic infiltration of the adrenal glands and the presence of circulating antibodies directed against the cells of the zona glomerulosa
• Thyrotoxicosis /Grave's disease (hyperthyroidism)


  Antibodies stimulate the thyroid cellular activity - Causes increased secretion of thyroxine & triiodothyronine - Autoantibodies to the thyrotropin receptor (TRAb)
• Hashimoto's thyroiditis


  Lead to hypothyroidism - More frequently occurs in females (between 30 - 60 years old) - Autoantibodies against thyroid peroxidase & thyroglobulin
• Myasthenia gravis


  Abs against acetylcholine (Ach) receptor on myoneural junctions of striated muscle - prevents binding of acetylcholine to its receptor - impaired muscle contraction - Causes double vision, drooping eyelids, trouble talking, trouble walking
• Pernicious Anaemia


  3 types of antibodies: 1) Against mucosal parietal cells 2) Intrinsic factor blocking antibodies 3) Intrinsic factor + B12 complex antibodies
• Multiple sclerosis


  Autoimmune disease of the central nervous system - The myelin sheaths that surround the nerve axons in the white matter of the brain are progressively destroyed by immunological attack - Causes disruption in nerve transmission and neurological symptoms
• Autoimmune Diseases Of The Eye

  • Phacoanaphylaxis - Autoimmune response to the lens protein following cataract surgery
  • Sympathetic Ophthalmia - in opposite eye following perforating injuries of the eye, involving ciliary body & iris
• Pemphigus vulgaris


  Blistering disease of the skin - Antibodies to desmosomes, results in breakdown of epithelial cells
• Autoimmune orchitis


  Lymphocytic infiltration of testes and circulating Abs to the sperms & germinal cells