Tolerance

Tolerance

1. Central tolerance

   • B cell tolerance
     • Clonal deletion
       • -ve selection
       • Receptor editing
         • RAG genes
           • Light chain recombination
     • BCR = IgM
   • T cell tolerance
     • Thymic education
       • Positive selection
         • MHC interaction
           • Survival signal
           • Best interactions destined to CD8+
       • Negative selection
         • APC interaction
           • Self reactive apoptose
             • Caspases cleave cellular proteins
               • Recruit others
             • TNF - FAS or BCL2
           • Hypothesis
             • Avidity hypothesis
               • Weak MHC = +ve selection
               • Strong = -ve
             • Differential siganl
               • Qualitatively different
         • Limited to thymus antigen

2. Peripheral tolerance

   • Clonal T cell anergy
     • Lack of costimulation
       • Cd28 bind B7
         • Only APCs have B7
     • T cell refractory to activation
       • overcome by IL-2 dose
         • Activation self limited
           • CTLA-4
     • Preventing anergy
       • Ca2+/calcineurin inhibitors
       • Target TCR signalling
   • Oral tolerance
     • Antigens absorbed through mucosa
       • Presented by CD103+ dendritic cells
         • Secrete IL-10 & retinoic acid
           • FOXP3 Tregs
     • Anergy
     • Deletion

3. Antigen segregation

   • Immune privileged sites
     • Break down due to damage
       • Autoimmunity
     • High TGF-beta
       • Treg cells produced
     • Separate lymph drainage