Lecture 7- Mechanism of Tolerance Flashcards
What is immunological tolerance?
-lack of immunological reactivity is induced and maintained to self, harmless antigens (food) and commensal microbiota
How do T Cells recognise antigens?
TCR/CDR - and have CD4 or CD8
What does CD4 and CD8 recognise antigens via?
CD8- MHC class I CD4- MHC class II
How does B cells produce antibodies?
- B Cell receptor (BCR) recognises non-self antigen
- produce antibodies (immunoglobulins)
How do T cell initiate an immune resposne?
- T cells do not recognise the native antigens
- Antigen must be presented
- APC process the protein and present into MHC
- T Cell recognise peptide with their TCR
what does the immunological equilibrium rely on?
-Balancing lymphocyte activation and control
How does the immune system learn to discriminate between self and non-self?
-Normal immune system does not exhibit self reactivity
Describe the pathway taken by B cells to come to B memory cells and plasma cells?
1) Antigen independent phase in bone marrow: progenitor B cell—>Ig-gene rearrangement selection —>Mature B cell
2) Antigen dependent phase (activation and proliferation)- peripheral lymphoid organ
- Naive B cell—>-Ag selection–>cell death
- Naive B cell—>+Ag —-> memory cells
-Naive B cells+Th cells —>affinity maturation and class switching —> plasma cell- secreted AB
describe the process of formation of CD4 and CD8 T cells
1) Thymocytes from bone marrow—->rearrangement of TCR genes—-> immature thymocytes
- death by apoptosis of the cells that do not interact with MHC molecules
2) Positive selection of cells whose receptor bind MHC molecules
3) Negative selection and death of cells with high affinity receptors for self MHC or self MHC+self antigen
4) formation of mature CD4+ Th cell
- CD8+Tc cell
where do the lymphoid progenitor migrate to develop into mature T cells?
from BONE MARROW to THYMUS
When does the Thymus develop and when does it increase in size?
fully develops before birth and increases in size during puberty
when does the thymus shrink?
atrophies with age and the degeneration is complete by 30
Why is a mechanism for repertoire selection and self tolerance needed?
- Generation of TcR repertoire involves random mechanisms to allow diversity
- The specificty of TcR in the immature repertoire us also random and will include cells with receptors that are:
1. Harmful - self antigen recognition- (Negative select)
2. Useless (Neglect)
3. Useful- foreign antigen recognition (positive select)
Which T cells mature and form the peripheral T cell pool?
T cells that bear antigen receptor with appropriate affinity for the peptide presented in self MHC complex
Where is the positive selection and negative selection of T cells occur?
Positive- Cortex
Negative- medulla
what is positive selection?
-Retention of the thympcytes expressing TcR that are RESTRICTED in their recognition of of antigen by self MHC
Which thymocytes survive?
thymocytes able to recognise self MHC expressed on the surface of the epithelial cell
What is negative selection?
Removal of thymocytes that express TcR that recognise self antigen presented by self MHC
Which APC cells at the cortico-medullary junction express MHC I and MHCII and self peptides?
Dendritic and macrophages
What happens if the Double positive T cell shows modest binding to MHC molecules?
T Cell Lives
What happens if the Double positive T cell shows STRONG binding to MHC molecules?
Possible autoimmunity- T cell dies via apoptosis- Known as negative selection
what is the name of the gene that helps to prevent autoimmunity?
Autoimmune regulator- (AIRE)
What does the mutation in this gene cause?
- Autoimmune poleyendocrinopathy
- ectodermal dysplasia
How is the tolerance established to antigens that cannot be expressed in the thymus?
T-cell bearing TcR reactive with proteins expressed in the thymus are deleted
- some self proteins are not expressed in the thymus
- Tolerance needs to be induced and maintained outside the thymus
Name the 4 mechanisms of peripheral tolerance?
1) Ignorance-lypmpocytes fail to recognise/respond
2) Clonal anergy: binding of antigen makes lymphocyte unresponsive
3) Suppression: interaction with suppressor cytokines to inhibit lymphocyte responsiveness
4) Clonal exhaustion: continued stimulation by persistent antigen may wear out the responsive cells
What is split tolerance?
- Auto reactive B cell ca not be activated if no help is availabe
- If help is provided via injecting an auto-ag coupled with an immunogenic feorign carrier- B cells will mount an immune response
Describe ignorance as a method for peripheral tolerance?
- Self reactive T cell sometimes ignore ag
- Antigen antatomically sequestered from the immune system- T cells can not reach the cells bearing the ag
- immunologically privileged sites- (eyes, testes, uterus/placenta)
What is the result if having immune privilege site?
-Allow foreign graft survival
What is the result of the trauma in one eye?
Physical trauma in ONE eye can initiate autoimmune response to BOTH eyes
-Blindness BOTH eyes-sympathetic opthalmia
Explain the mechanism of clonal anergy?
- Presentation without co-stimulation (lack of CTLA-4)
- Antigen recognised without co-stimulation
- Antigen recognition with CTLA-4:B7 interaction
- Re stimulation with APC expressing co-stimulators - CAUSES T -CELL ANERGY
What are the inhibitory signals on T Cells and what prevents these?
- CTLA-4 provides inhibitory signal
- Anti CTLA-4 antibody blocks CTLA-4 and prevents inhibitory signals
What are the therapeutic application of anti-CTLA-4 antibody?
-Blocking CTLA-4 promotes tumour regression (tumour immunotherapy)
What induces the expression of CTLA-4 on naiive T cells?
Activation via APC
What is the role of the CTLA-4 in this?
-termination of response
what is the role of T-regulatory response?
- T-reg mediated suppression of response
- T-reg suppress the activation T effector
What is the consequence of absence of T regulatory cells?
-Aggressive auto-immunity
what is the role od CD25 in preventing auto-immunity?
- expressed on T reg cell
- consumes IL2 and limmits the expansion of Teff
- Depletion of CD25 T cells leads to auto-immunity
What is the role of FOXP3 gene in preventing auto-immunity?
- Critical for T-reg development
- Mutation in FOXP3 leads to IPEX (Immunodysregulation, Polyendocrinopathy and Enteropathy, X-linked syndrome)
How can the role of T reg be used in therapy?
- strenthen/re-establish self tolerance in autoimmune disease
- induce tolerance to non-self antigens in organ transplantation, GVHD and allergy
- Induce tumour immunity in cancer patients- get rid of tumour
Explain activation induced cell death (AICD)?
- repeated stimulation of T lymphocytes by persistent antigens results in death by apoptosis of the activated cell
Can the same antigen tolerogenic or immunogenic and what factors determine which it becomes?
Yes- same antigen can be tolerogeinc of immunogenic depending on how, where and when it is encountered
How the antigen is presented to the lymphocytes?
- Concentration
- Timing
- Persistence
- Tissue distribution
- Nature of the cell presenting the antigen
Name three antigen properties?
- Molecular weight
- Dosage
- Routes of administration
Explain how the antigen properties determine whether it is immunogenic or tolerogenic?
Molecular weight-Smaller, soluble, not aggregated molecules favour tolerance
-Large, aggregated and complex molecules favour immunogenicity
-Dosage:
very small or very large favour tolerance
inermediate favours immunogenicity
-Routes of administration:
-oral, intratracheal, orbital exposure can activate T cells
What prevents the food proteins from being recognised as immunogenic?
-Interaction of food proteins with gut associated lymphoid tissue in the intestinal transit is essential for oral tolerance
Explain what hypo-sensitisation immunotherapy is?
- using small amount of allergen (food/pollen) to induce antigen specific tolerance
- Continued administration of the allergen- development and maintenance of tolerance
