Tolerance

Tolerance

1. Central Tolerance

   • Thymus for T cells
     • Negative selection
       • mTECs
         • AIRE
         • CD103+ DCs
         • Receptor editing and clonal deletion via FasL
         • Diverted to Treg lineage if TCR too self-reactive
     • APECED
       • Mutation in AIRE
         • No presentation of self
       • Autoreactive T cells
       • Widespread autoimmunity
   • BM for B cells
     • BCR tested for strong binding to self
     • Receptor editing
     • Clonal deletion

2. Peripheral Tolerance

   • Regulatory T cells
     • IPEX
       • Mutation in FOXP3
       • Autoimmunity, IBD and allergy
         • Th2 skew
     • IL-10 and TGFb production
       • IL-10 antagonises IL-12
     • High expression of CTLA-4
       • Higher affinity for CD28
     • Already functionally mature
     • Suggested that they can be activated by immature DC
       • Due to low Ag conc. needed for activation
   • Induced by immature APCs
     • Anergy
       • Lack of costimulation
       • Dominance of inhibitory ligands such as CTLA-4 and PD-1
       • Particularly during Type 2 infection
     • Differentiation of T cells into iTregs
     • Exhaustion
       • Chronic viral infections and tumours
       • High expression of inhibitory molecules
       • Especially during Type 1 infection
       • Become antigen dependent
       • IL-7 downregulates PD-1, IL-2 can overcome exhaustion
       • Gene expression altered
     • Deletion
       • FasL-Fas interaction
       • Granzyme/perforin production by Tregs
   • As some autoreactive lymphocytes escape central tolerance
   • Many tissue-specific Ag not expressed in thymus
   • Dependent on self-Ag conc.
   • B cells require T cell help
     • CD40L on activated Th cells induces Fas on B cells (and susceptible to apoptosis) unless they signal through BCR

3. Inducing Tolerance therapeutically

   • Allergen immunotherapy
     • Slowly increasing tolerogenic dose
   • Tolerogenic DCs/Macrophages
     • Peptide-pulsing APC in presence of tolerogenic cytokines (IL-10), NFkB inhibitor (rapamycin) and Vitamin D
   • Tolerogenic Tregs
     • ONE study
       • Kidney transplantation
       • iTregs plastic
   • Anti-CD28 led to cytokine storm resulting in multiple organ failure

4. Break in tolerance= autoimmunity

   • Self Ag plus APC maturation stimulus
     • Infection linked to many autoimmune diseases
   • Autoimmune diseases
     • SLE
       • Linked to mutation in CR1 and CR2 complement Rs
         • Required for lysozyme to induce anergy in anti-lysozyme Ig transgenic B cells
     • Mainly due to autoreactive Ab
     • Crohns linked to mutation in NOD2