Lecture 20 Flashcards
What are the problems with trying to have both tolerance and a diverse adaptive immune system?
The B cell receptors can hyper mutate somatically potentially generating a self-reactive response
MHC in peripheral tissues is loaded with self-peptides
There is enormous cross reactivity to self
The bone marrow and thymus remove only the most reactive cells
Our immune system will still need to prevent reactivity to self in the periphery
Why is the problem of tolerance in the presence of a diverse adaptive immune system not as bad as it first appears?
Only a relatively small number of antigens can serve as autoantigens
Each APC can express 10^5 MHC molecules
It takes approximately 10 identical peptides per APC to fully activate a T cell
Potential of 10,000,000 selfpeptides/APC
This results in only a few peptides being present at a high enough level to present a potential autoantigen and because these are likely to be common housekeeping genes they are likely to be present in the thymus
What is central tolerance?
The deletion or rendering anergic of self reactive cells during development
What is peripheral tolerance?
The deletion or rendering anergic of self reactive clones after they have left their site of origin
What are the four main mechanisms of tolerance?
Clonal deletion
Clonal anergy
Ignorance
Regulation/suppression
What are two examples of clonal deletion providing tolerance?
Neonatal tolerance where bone marrow injected into neonatal mice produces profound tolerance to later skin grafts from the donor strain while grafts from other strains is rejected
Viral superantigen deletion of T cells where mice express endogenous viral superantigens from the retrovirus MMTV (mouse mammary tumour virus) these are expressed in the thymus so that any T cell which reacts with thease are deleted through activation this leads to mice having vast holes in their peripheral repertoire due to removal of whole families of TcR through central tolerance
This is actually an good thing as it removes T cells that would normally provide help to virally infected B cells in the gut by wild type virus
How does clonal anergy lead to tolerance?
Self-reacting lymphocytes exist but are resistant to stimulation resulting from a lack of co-stimulation or ineffective antigen presentation
This is due to the fact that without these signals the clone is judged to be self-reactive and dies either through apoptosis or becomes anergic
Anergic cells are not deleted and can on occasion be reactivated to break tolerance
How can reactivation of anergic cells oocur?
this may occur through OX40 a member of the TNF superfamily, this is upregulated on T cells 3-4 days after exposure to MHC bound peptide even if no stimulation occurs it can bind to OX40 ligand on dendritic cells which will reactivate anergic cells to full responsiveness
How does ignorance lead to immunological tolerance?
Antigens are hidden from the immune system or not adequately expressed enough to generate an immune response
This occurs due to a separation of tissue where the antigen presentation occurs from the remainder of the body or due to antigen presenting cells not being able to present the antigen due to it being unable to be stably loaded on the MHC complex or not being present frequently enough to fully activate immune cells
How does suppression/regulation lead to tolerance?
This is due to unique CD4 T cells which express CD25 and the FOXP3 transcription factor these antigen specific T cells can be transferred into a mouse experiencing an immune response leading to dramatic suppression
It is believed these cells rapidly migrate to lymph nodes where the activation is occurring, there they produce IL-10 a suppressor cytokine
These cells are being attempted to be selective stimulated in diseases such as multiple sclerosis, RA and diabetes
What happens when you lack T reg cells?
IPEX syndrome (Immune dysregulation, Polyendocrinopathy. Enteropathy, X-linked) this is a rare syndrome in male children mussing FOXP3 T cells due to a mutation, they usually develop an overwhelming systemic autoimmunity in the first year of life and usually die before they reach 3 years of age
What are the features seen in IPEX syndrome?
Elevated levels of IgE but normal levels of IgA, IgG and IgM
Reduced levels of circulating FOXP3 T cells
Autoantibodies to pancreatic islet antigens, thyroid antigens and small bowel mucosa
Anaemia, thrombocytopenia, neutropenia
Normal B.T neutrophil and complement functions
A bone marrow transplant is the only hope of survival
What is cross priming?
This is an important mechanism that regulates tolerance, CD8 cells do not react with virally infected cells until they have been primed by a “licenced” APC
This APC is first activated by PAMPs which stimulates CD4 T cells which further activates the APC which cross primes the CD8 cell which can then kill virally infected cells in the absence of costimulation
What are the features of B cell tolerance?
Immature B lymphpcytes that express surface IgM but not surface IgD are susceptible to tolerogenesis
Tolerogenesis requiring crosslinking of 2 sIgM molecules
Monovalent antigen can inhibit tolerogeneisis through competition for sIgM
This can be mimicked experimentally with an antimew antibody
There is a certain minimum affinity threshold to cause deletion this prevents weak cross reactivity from destroying the whole B cell repertoire
The B cell must be expoed to the tolerogenic antigen for a minimum threshold time as shorter exposure may allow rescue of the B cell by receptor editing where it finds an alternative Ig light chain and therefore a new antigenic target removing the need for deletion or anergy to occur
What occurs in B cell anergy?
If an antigen is soluble or univalent then the immature B cell is not deleted but emigrates from the bone marrow functionally inactive due to a deliberate signal transduction block
Anergic B cells have surface IgD but not IgM
This has been shown with transgenic mice, all B cells express a receptor for hen egg lysozyme (HEL), if these mice also have this antigen on their cell surfaces in the bone marrow then all B cells are deleted prior to leaving the bone marrow as surface bound HEL will crosslink the B cell receptor causing deletion
However if HEL is made soluble then then HEL specific B cells leave the bone marrow as totally anergic
