Tolerance Flashcards
Danger hypothesis
The immune system is trained to recognise infectious non-self.
NB Strong immune responses almost always require the antigen to be injected in adjuvant
Adjuvant
E.g Complete Freund’s Adjuvant (CFA)
Cues immune system that infection is taking place. Convert soluble protein into particulate material, which is ingested by APCs e.g macrophages. Many contain bacterial products, which interact with PRRs.
e.g CFA contains ground up mycobacteria
Central tolerance
Occurs during lymphocyte development
T cells
- generated by clonal selection
- negative selection in the thymus: deletion of clones that binds too strongly to MHC + self peptide
- AIRE (TF)- promotes expression of many ‘peripheral’ genes in the thymus
B cells
- B cells that react to abundant antigens on self cells are eliminated as they develop, or remain attached to antigen, in bone marrow (stromal cells) via IgM. Apoptosis or anergy.
Peripheral tolerance
Why necessary? Many antigens are not generally expressed in the thymus or bone marrow (although this is mitigated by AIRE).
- Ignorance
- Split tolerance
- Anergy
- Suppression/ regulation
Peripheral tolerance: ignorance
= when potentially self-reactive T cells are not activated.
Immunologically privileged sites include brain, eye, testis.
Also occurs when antigen is present at too low [ ] to activate T cells.
Peripheral tolerance: split tolerance
As many pathways in the immune system are interdependent, do not all need to be tolerised.
Most commonly: T cell tolerance established but autoreactive B cells still present.
Without T cell help, autoreactive B cells are ‘helpless’.
NB takes 100-1000x more antigen to tolerise B cells than it does T cells.
Reasonably common for self-serum proteins.
Peripheral tolerance: anergy
= state of non-responsiveness.
Can be induced in T cells if receptor is engaged by MHC but second signal is absent (co-stimulatory molecules located on APCs, not all tissue cells)
Anergised cell does not die, but biochemical changes occur so that it no longer responds.
Immature B cells may be also be anergised (less well understood)
- occurs in the bone marrow or just after B cell enters peripheral circulation.
- large amounts of soluble antigen lead to anergy if not cross-linked at the cell surface.
Peripheral tolerance: suppression
Mediated by regulatory T cells (Tregs)
On contacting self antigen presented by MHC class II, Tregs suppress proliferation of naive T cells responding to autoantigen present on the same APC.
- suppressive effects are specific, require cell contact
- IL-4, IL-10, TGFβ implicated.
Tregs
Markers?
Natural vs inducible?
Role in infection?
Regulatory CD4 T cells
- CD25 (IL2 receptor) positive
- express Fox3p transcription factor (may be used as a marker to distinguish from other T cells)
Removal of CD25 cells results in an attack of self tissue and autoimmunity.
Many different types have been proposed, fitting into 2 groups:
Natural- thought to be educated in thymic selection
Inducible- can be generated in peripheral T cells
Hypothesis: Treg functions are down regulated in infection?
NB indicate that the central/peripheral tolerance model is an oversimplification: generated in thymus, peripheral tolerance involves deletion.
Immune dysregulation, Polyendocrinopathy, Entropathy X-linked (IPEX)
Profound systemic autoimmunity
Sufferers lack Fox3p
Factors affecting tolerance:
Timing
Dose of antigen
Amount of costimulation
Location
Medawar’s neonatal tolerance experiment
Involved injecting bone marrow from mice of different strain into another mouse, and then 6 weeks later grafting skin onto recipient mouse from same donor mouse
Cells transferred in first few days tolerise
- Mice A injected at birth with bone marrow from mice B. Skin graft at 6 weeks accepted.
- Bone marrow cells from B establish chimerisation in A. Some differentiate into APCs, migrate to thymus & tolerise developing thymocytes by deletion.
Cells transferred later do not tolerise
- Bone marrow cells injected ~1 week after birth. Skin graft at 6 weeks rejected.
- Number & maturity of peripheral T cells pool of host is sufficient to destroy donor cells before they can engraft.
Tolerance in the placenta
3 mechanisms
Fetus & placenta share childs genotype and not the mothers. Several tolerance mechanisms involved:
- Physical barrier to mother’s T cells
- Lack of MHC class I expression. Trophoblast cells forming outer layer of placenta do not express classical class I molecules - thus not targets for cytotoxic T cells.
- Production of immunosuppressive factors e.g α-fetal protein, and IDO (a tryptophan catalysing enzyme)
Experimental tolerance
2 approaches
Peptide sniffing (inhalation tolerance): if immunogenic, MHC binding peptides are aerosolised and administered via nostril, animals can be rendered tolerant to immunogenic challenge by the same peptide (e.g given subcutaneously by adjuvant)
Co-receptor blockade: using monoclonal antibodies to CD4/8, B7, CD40
Original antigenic sin
A primary response to a pathogen constrains further activation of naive cells during a secondary response.
During a second infection, only those epitopes common to infecting strain and original strain stimulate antibody production. Immune system appears to depend on memory B cells developed during first infection.
Highly mutable pathogens like influenza exploit this. Host does not respond to any new epitopes on re-infecting virus.
