Tolerance and immunoregulation

• What are central and peripheral tolerance?

  Central tolerance involves the removal of highly self-reactive clones during lymphocyte development, within the primary lymphoid organs, e.g., bone marrow and thymus.

  Peripheral tolerance describes the multiple mechanisms the limit self reactivity in the periphery.
• What clonal scenarios can arise from TCR gene rearrangement?

  1. T cells fail to make surface expressed TCR- useless
  2. TCR cannot recognise self-MHC molecules- useless
  3. TCR recognises self-MHC and self-antigens too strongly- harmful
  4. TCR recognises self-MHC and does not bind to self-MHC or self-antigens too strongly- useful
• Describe peripheral tolerance in B cells

  Peripheral tolerance is due to lack of T cell help, since TCR cannot recognise self antigen and therefore the B cell isn’t stimulated to become a plasma cells.
• What is clonal anergy?

  This is the mechanism by which T cells are inactivated. It requires one singular signal, which renders the T cell unresponsive and unable to respond to antigen.
• Describe the formation of different classes of Tregs

  Thymic derived Treg: these cells form when a naive T cell recognises a self antigen.

  Peripheral derived Treg: these cells form when the T cell recognises self antigen and non-harmful self antigens in the periphery, in the presence of TGF-beta.
• What are immune privilege sites?

  These are tissues where antigens do no induce immune attack, such as the eyes, brain and uterus. These sites are generally enclosed by a physical barrier, with low MHC I expression, rich in suppressive cytokines (e.g., TGF-beta) and express FasL, which induces T cell apoptosis.