28 - Self/Non-Self Discrimination Flashcards
Central tolerance
Removing autoreactive lymphocytes during development of these cells (in thymus, bone marrow)
Mechanisms used to induce tolerance 1 2 3 4
– To delete (eliminate the problem) - Central tolerance
– To anergize (switch off the problem) - Peripheral
– To ignore (ignore the trigger) - Peripheral
– To regulate (contain the problem) -Peripheral
Central mechanisms of B cell tolerance
Deletion, anergry
Peripheral B cell tolerance
Ignorance, anergy, death
- Lack of co-ordinated T cell help
Is B cell or T cell tolerance more effective?
T cell
Effect of B cell encountering soluble self protein in the periphery
Anergy
Effect of B cell activation without T cell costimulation
Differentiate to short-lived IgM+ plasma cell
Form of tolerance -> without cognate CD4+ help, autoreactive B cell can only do so much damage
T cell development in the thymus
Early T-lineage precursor
Pro T-cell (rearrange beta chain, express with surrogate light chain)
Double negative thymocyte
Double positive thymocytes (rearrangement of alpha chain)
Positive selection (can bind self-MHC)
Commit to either CD4 or CD8, depending on either recognising MHCI or II
T cell positive selsction
Only thymocytes that express TCRs capable
of recognising self-MHC are selected to survive
T cell negative selection
Thymocytes expressing TCRs that bind too strongly to a self antigen presented on MHC will undergo apoptosis
Transcription factor responsible for ectopic presentation of self antigens in the thymic medulla
AIRE (autoimmune regulator of expression).
Involved in T cell maturation (negative selection).
Expresses tissue-specific antigens (EG insulin)
Cells that express AIRE transcription factor
Thymic epithelial cells.
If a TCR can detect these antigens, they undergo apoptosis.
Either detect these on the surface of thymic epithelial cells, or thymic epithelial cells die, are phagocytosed by DCs, which then present self-antigens.
Mechanism of T cell anergy
Without DC costimulation, T cells become antergic
Role of immunosuppressive T cells
Treg release TGFb, IL-10, which are immunosuppressive
nTregs
Natural Tregs.
Develop in the thymus to be nTregs
iTregs
Induced Tregs
Naive CD4+ T cells activated in the presence of TGFb become iTregs.
– Secrete immunosuppressive cytokines - IL-10 and TGFb
– Express CTLA4 and inhibit co-stimulation
– Release molecules that create a ‘suppressive’ environment
CTLA4
Present on the surface of B cells.
Binds to CD80/CD86 with a higher affinity than CD28.
Negatively regulates activated T cells by inhibiting co-stimulation.
Two broad classifications of autoimmune disease
Organ-specific
Systemic
Disease that arises when AIRE is defective
APECED
Multi-system autoimmunity
Loss of central tolerance
Disease from defect in Foxp3 gene
IPEX.
Loss of Tregs and peripheral tolerance mechanism.
Transcription factor for Treg differentiation
Foxp3
Two examples of T-cell-mediated autoimmunity
Type I diabetes.
MS
MS aetiology
CD4 T cells specific for myelin antigens promote an
inflammatory response and degrade the myelin
sheaths covering nerve axons
Th1 and Th17 responses are detrimental
Th2 responses associated with remission
Dysregulation of Tregs has been associated with MS
How can self antigens be recognised?
Recognition of self antigen in the presence of inflammation (death of self cells, release of internal antigens)
Example of molecular mimicry autoimmunity
Streptococcal infection response directed against Strep M protein.
Persisting anti-M protein lymphocytes can autoreact with antigens of cardiac valves.
