lecture 12 Flashcards
- immunological tolerance -- central tolerance -- peripheral tolerance - when tolerance fails -- autoimmune diseases -- allergy
1
Q
What is immunological tolerance?
A
- key feature of the adaptive immune system
- self/non-self discrimination
- occurs in both T cells and B cells
- specific unresponsiveness to an antigen following prior exposure to that antigen
- self antigen
- non-self antigen
2
Q
Who discovered acquired immunological tolerance? How?
A
- Sir Frank Macfarlane Burnet and Sir Peter Medawar
- nobel prize in physiology or medicine in 1960
- showed that the neonatal period is fundamental in the development of tolerance and that it can be produced
- in mice - introduced strain B graft into adult strain A mice –> rejected
- introduced strain B graft into strain A mice that had been injected with spleen cells from strain B during the neonatal period –> accepted
3
Q
Why is tolerance important?
A
- specificity of the adaptive immune system critical
- results from the processes that drive both T cell and B cell diversity during lymphocyte development
- 10^11 different antibody (B cells) and TCR specificities
- self-reactivity can occur and result in host damage
- immune system is in balance between immunity and tolerance
4
Q
What are key factors determining whether an immune response (or tolerance) occurs?
A
- [Ag]
- avidity
- costimuli
- timing and duration
5
Q
What are T cell tolerance mechanisms?
A
Central tolerance
- occurs in the thymus
- positive/negative selection of immature T cells
Peripheral tolerance
- occurs in peripheral tissues
- ‘regulatory’ responses involving mature T cells
- anergy - cell is there but receives no costimulation
- inducing apoptosis
6
Q
What is something B cells can do in the development of central tolerance?
A
- change receptors: receptor editing
7
Q
What happens in T cell selection in the thymus?
A
- occurs as the T cell matures
- dependent on affinity of TCR binding to self antigen
- in the initial phase positive selection
- T cells are selected for based on their recognition of antigen both self and non-self, in the context of MHC and the TCR
- cells where the affinity for the antigen is very low, they undergo apoptosis by neglect - signalling too low, considered to be an unwanted immune response so they die
- if the affinity is too high they are negatively selected
- it is only a small fraction of maturing T cells, that have intermediate affinity for antigen in the context of MHC, that survive
- these cells enter the periphery
8
Q
How is peripheral tolerance generated?
A
- self reactive T cells that enter the circulation are regulated by peripheral tolerance
- mechanisms include:
- clonal anergy (lack of costimulation)
- ignorance (do not encounter their antigen) (e.g. proteins in the eye are immune privileged)
- suppression by cytokines (e.g. TGF-beta)
- specific regulation (Treg induction)
- negative regulation (engagement of CTLA4)
9
Q
How do B cells generate tolerance?
A
- occurs in the bone marrow
- needs T cell tolerance to be intact
- self-reactive B cells can be:
- deleted when high affinity for antigen
- made anergic when antigen is soluble and at high concentration
- ignorance when lack of T cell help or low antigen concentration
10
Q
What happens when tolerance fails?
A
- autoimmune disease can occur when mechanisms of immunological tolerance break down
- “Horror autotoxicus” (Ehrlich)
- can be caused by:
- acquisition of T cell help
- molecular mimicry
- failure of regulatory networks
11
Q
What is autoimmunity?
A
- immune response against self-antigen
- involve both self-reactive T and B cells
- presence of autoreactive lymphocytes does not necessarily result in autoimmunity
- naturally occurring autoantibodies (thought to be involved in mopping up debris etc)
12
Q
What is the pathogenesis of autoimmunity?
A
- multifactorial
- genetic susceptibility
- environmental influence e.g. infection, smoking, drugs
- lead to the presence of an autoantigen
- combined lead to autoimmunedisease
13
Q
What is molecular mimicry?
A
- similar/identical epitopes between microbe and host
- could be linear or conformational
- important when host antigen has important biological function
- e.g. streptococcal protein and bacterial endocarditis
14
Q
What is the Treg function in autoimmunity?
A
- major mechanism in the development of autoimmunity
- contact and contactless
- IL-10 and TGF-beta important cytokines in suppressing a response
- also inhibition via cell-cell contact through TCR
- key feature is to render cells non-responsive
- if that fails either genetically or through some environmental factor you can get loss of regulation and those self-reactive T cells in the periphery that might normally be kept in check can be left and expand and become pathogenic
15
Q
What are Milgrom and Witebsky’s criteria for autoimmune diseases?
A
- lymphocytic infiltration of the target organ
- presence of circulating autoantibodies and/or cellular immunity against the target organ
- identification of the specific antigen(s)
- production of humoral and/or cellular autoimmune response in animals sensitised by autologous antigen
- close association with other autoimmune disorders
