Mechanisms of Auto-Immunity & Hypersensitivity I

• What is autoimmune disease?

  Loss of immunological tolerance to self, associated with pathology

  
  

  Disease may involve self-reactive T cells and/or self-reactive B cells
• What cannot be cleared in autoimmune disease?

  Self antigen
• What factors predispose to autoimmune disease?

  Background: incidence, gender bias

  
  

  B or T lymphocytes that can react with self antigens

  
  

  Genetics

  
• What can autoimmune disease be categorised into?

  - Organ specific

  
  

  - Systemic

  
• Is there gender bias in autoimmune disease?

  Yes, females tend to be more susceptible due to :

  
  

  - Incomplete X chromosome inactivation

  
  

  - Hormones

  
• Where does the potential for self-reactive B- & T-cells come from?

  -Generation of cell surface antigen receptors for B cells (sIgM, sIgD), Th and Tc cells is a random process

  
  

  -so the mechanisms that drive diversity also produce large numbers of auto-reactive lymphocytes
• Where does the negative selection of B- and T-cells occur?

  B-cells: bone marrow

  T-cells: thymus medulla
• How is central tolerance achieved?

  By negative selection of auto reactive cells
• What is positive selection?

  Where cells that recognise the body's own tissues are allowed to mature.

  
  

  Cells that cannot recognise self-antigens are eliminated
• What is negative selection?

  - After positive selection

  
  

  - Cells that strongly react to self-antigens are eliminated.

  
  

  - This prevents the immune system from attacking it's own tissues.
• Why would it actually be disadvantageous if all cells with autoimmune potential were removed from lymphocyte repertoire?

  Because it would provide a space for pathogens to mimic human structures & evade immune response

  
  

  By maintaining some auto-reactive lymphocytes together with tight control of immune responses, the immune system has reached a balance between auto-reactivity & resistance to infection
• What 2 transcription factors in the medulla promote promiscuous expression of proteins?

  Aire - helps developing developing T cells to recognise self-antigens. Regulates the expression of self-antigens in the thymus to prevent auto-immune disease

  
  

  Fez2f
• What happens to the some auto-reactive T cells that are not deleted in the thymus?

  They develop into Treg cells & migrate to the periphery

  
  

  Their function is to suppress the activity of potentially pathogenic, auto-reactive T cells
• How do Treg cells suppress the activity of potentially pathogenic, auto-reactive T cells?

  1. Removal of 2 costimulatory activating receptors CD80, CD86 via Treg CTLA-4

  
  

  2. Cytokine interleukin-2 required for activation, function and Maintence. High affinity IL-2 receptor depletes II-2. ??

  
  

  3. Treg Fas ligand (death receptor) binds to Th Fas - apoptosis

  
  

  4. Treg secretes inhibitory cytokines (IL-10, TGFB)

  
• What do genome-wide association studies (GWAS) show about genetic predisposition?

  It shows association with MHC/HLA types e.g.

  
  

  Ankylosing spondylitis: 90% patients HLA-B27 (~5% of those with HLA-B27)

  
  

  Rheumatoid arthritis: HLA-DRB1 (80% patients)

  
  

  Psoriasis: HLA-Cw6 (60%)
• What are the main points to take away from this lecture?