Autoimmunity

• What is self-tolerance?


  This describes the mechanisms that control auto-reactive T and B cell clones to maintain a normal healthy immune system
• What is central tolerance?

  Deletion or editing of lymphocytes that recognise self antigens in early stages lymphoid development.
• What is antigen segregation?

  Physical barriers that separate immune cells from specific antigens that are kept away from lymph so they are not screen against.
• What is peripheral anergy?

  Self reactive T cells become functionally unresponsive due to weak signalling without co-stimulus.
• What are Tregs?


  Tregs are a specialised subpopulation of T cells that act to suppress immune response.
• What is functional deviation?

  Differentiation of Tregs that suppresses inflammatory cytokines.
• What is an autoimmune disease?

  This is a disease caused by autoimmune response, where there is an immune response against one or more self-antigens. This results from the failure to develop self-tolerance, which causes a chronic response.
• Describe how the development of self-tolerance can fail and how this is linked with autoimmunity

  • Mutations in AIRE: involved in promiscuous gene expression in the negative selection of TCRs
  • Mutations in FoxP3: linked with IPEX disease as it is important in the development of Tregs
• Describe the classification of autoimmune diseases

  • Organ specific: effector functions target antigen confined to the affected organ, e.g., MS and type I diabetes
  • Systemic- antigen is widespread and found in most cell types, e.g., Rheumatoid arthritis.
• Describe some of the immunological features of autoimmune diseases

  • Auto-antibodies: found in the serum and can form immune complexes, which are deposited in tissues.
  • Cellular infiltrate: T cells and B cells
  • Autoreactive CD4+ T helper cells
• Describe how auto-antibodies contribute to autoimmune disease mechanisms

  • Damage: complement mediated lysis, opsonisation and Phagocytic removal.
  • Alteration of function: stimulates receptors, which can inhibit or block function
  • Deposition of immune complexes in tissues.
• Describe Graves disease


  Auto-antibody is produced against thyroid-stimulating hormone, which stimulates excessive thyroid hormone production. This also evades normal negative feedback regulation, which results in nervousness, weight loss, tiredness and bulging of the eyes.
• Describe Myasthenia gravis


  This is when auto-antibody is produced, which can bind to acetylcholine receptors and stimulated receptor internalisation and degradation. This reduces action potential stimulation and muscle contraction, resulting in muscle weakness.
• Describe the causes for autoimmune diseases

  Genetic: Autoimmune diseases tend to aggregate in families and concordance is around 50%

  Environment: rapid increase in autoimmune disease incidence over the last 40 years, which cannot be explained by genetics alone.
• Describe the genetic factors that play a part in autoimmunity

  Polymorphisms alters susceptibility to autoimmune diseases, which is where different gene alleles are expressed, leading to altered expression levels and altered protein form. Genes identified as risk factors only account for a small proportion of the risk, but they are multigenic and so can all contribute to susceptibility. Example: MHC allele expression.
• Describe some of the environmental influences on autoimmune disease

  • Vitamin D: active form of Vitamin D suppresses Th17 development
  • Drugs: can bind to self antigens, making them appear as foreign
  • Toxins: pollutants, UV and smoking cause damage and expose areas for autoantibody mediated damage
  • Example: Epstein Barr virus increases the risk of Lupus.
• What are B cell mitogens?

  Substances that stimulate B cell proliferation, such as LPS. This can result in stimulation of auto-reactive B cells.
• Describe chronic autoimmune disease

  This develops via positive feedback from inflammation due to the inability to clear self antigen. This leads to a broadening of the autoimmune response and epitope spreading, as hidden epitopes are revealed.