Immune tolerance Flashcards
Define immune intolerance
State of unresponsiveness of the immune system to substances or tissue that have the capacity to elicit an immune response
What are the types of immune tolerance
Self tolerance - prevents damage to ‘self’:
- central tolerance
- peripheral tolerance
Neonatal (repro) tolerance - needed for foetal and placental survival:
- peripheral tolerance
Oral tolerance - food is tolerated:
- peripheral tolerance in GALT
Describe mechanisms of central tolerance
Positive selection - survival of functional lymphocytes
Negative selection - deletion of self-reactive lymphocytes
Describe mechanisms of peripheral tolerance
Apoptosis of B and T cells
Anergy of B and T cells
Inactivation of T regulatory cells
Receptor revision
Receptor dilution
What tissues are involved in central tolerance?
Generative (central) lymphoid organs:
- bone marrow (B cells)
- thymus (T cells)
- Bursa of Fabricius (B cells in birds only)
What tissues are involved in peripheral tolerance?
Peripheral lymphoid tissue:
- GALT
- lymph nodes
- spleen
- MALT
Describe central tolerance: T cells
In thymus
Positive selection in thymic cortex:
- T cells which recognise body’s own MHC I (CD8+) or II (CD4+) are retained
- Double positive (CD4+CD8+) are retained
Negative selection in thymic medulla:
- removes cells that target self antigens to protect against autoimmunity => self tolerance
- Single positive (CD4+CD8- or CD4-CD8+) and double negative (CD4-CD8-) T cells removed
How does central T cell tolerance change with age?
thymus gets small
Less naive T cells in blood with age
Describe peripheral T cell tolerance
Self reactive T cells that escape into periphery are deleted or angerised (failure => hypersensitivity)
Apoptosis
Anergy
Suppression via Tregs (secretion of IL-10 and TGFB)
what are the signals required for the activation of naive T cells?
Interaction of antigen with MHC molecules on surface of APC
Interactions of costimulatory molecules on T cells with APCs
Describe central B cell tolerance
In bone marrow or bursa of fabricius (birds)
Positive and negative selection at same time
Positive selection:
- functional IgM which doesn’t bind antigen is retained
- lack of functional IgM => developmental arrest allowing receptor rearrangement (3 days or apoptosed)
Negative selection:
- Cells in bone marrow present self-antigens
- autoreactive B cells are downregulated and arrested in development to allow receptor rearrangement for 3 days before apoptosis
Why is central B cell tolerance not fully effective?
Not all self-antigens are accessible in native form to B cells in bone marrow
Some polyreactive B cells pass through
Describe peripheral B cells tolerance
Further education in peripheral lymphoid tissue where B-cells co-express IgM and IgD
Enforced by:
- anergy
- clonal deletion
- receptor revision
- receptor dilution (additional light chains decreases immunoreactivity of IgM)
Describe oral tolerance
Peripheral tolerance
Can be antigen specific or inhibit lymphocytes in vicinity
Failure => hypersensitivity (food allergy, inflammatory bowel disease)
Describe the routes of antigen sampling in the gut
Dendritic cell route:
- dendritic cells extend processes through epithelium into lumen to sample antigens
M-cell route:
- M cells over Peyer’s patches sample antigens and deliver them to subepithelial dendritic cells
Epithelial cell route:
- soluble antigens cross through transcellular or paracellular routes to encounter T cells or macrophages in lamina propria
