response to infection and tolerance Flashcards
lecture 9
general progression of immune response as infection developes
invests progressively more resources.
viral = burst of cytokines to activate NK cells to control spread whilst the adaptive response unfolds. CD8 after a few days and then the produciton of specific antibody
what is immunological tolerance
the way the immune system avoids reacting to innocuous substances to prevent unnecessary tissue damage and resource waste.
tolerance - genetic or acquired
“tolerance is acquired, not hard wired.”
trained to recognise infectious non-self
whats the danger hypothesis
the idea that the immune system descriminates harmful from harmless through the presence or absence of a danger signal.
- response to a protein is dependent on context, hence why immunisation with proteins usually requires the addition of an adjuvant - a mixture that acts to activate this danger signal via PRRs.
what is complete freund’s adjuvant
contains ground up mycobacteria
2 types of tolerance
1 - central - during lymphocyte development
2 - peripheral - occurs after theyve left the primary lymphoid organs
central tolerance of T cells
via affinity, positive and negative selection in the thymus
central tolerance of B cells
shouldnt be needed as they require T cell help anyway but not a perfect system so B cells that react to antigens on self stromal cells in the bone marrow undergo apoptosis
why do we need peripheral tolerance
as not all the possible antigens are present in the thymus or bone marrow.
- this can be circumvented a bit if a TF called AIRE is expressed which turns on many peripheral genes in the thymus sot that developing T cells are exposed.
4 of the proposed mechanisms of peripheral tolerance
1 - ignorance
2 - split tolerance
3 - anergy
4 - suppression
describe peripheral ignorance
the potentially autoreactive T cells arent activated possibly because the antigen is in immunologically privileged sites eg brain, eye, testis
describe peripheral split tolerance
as many pathways in the immune response are interdependent they dont all need to be tolerised. common - T cell tolerance is established but autoreactive B cells are still present but cant be activated.
- takes 100-1000 times as much antigen to tolerise B cells
decribe anergy
a state of non-responsiveness.
- induced in T cells if the TCR is engaged by MHC but the 2nd signal is absent
- biochemical changes so that it no longer responds, believed to happen in immature B cells too
describe suppression
some autoreactive T cells prevented from reacting by T regs.
- T regs are CD25 + (IL2 receptor +ve)
- removal of the CD25+ cells results in self tissue attack and autoimmunity.
- some appear natural (educated in thymic selection) and others inducable
how are T regs distinguished
by the fact they express the Fox3p TF.
how do Tregs work
contact self antigen presented by MHC2 and tehn suppress the proliferation of naive T cells that respond to the same autoantigens being presented by the same APC.
- this is a specific effect which requires cell contact. non inflammatory cytokines may contribute eg IL4
what happens if FoxP3 is lost
IPEX syndrome
immune dyeregulation, polyendocrinopathy, entropathy X-linked
what are the variables affecting tolerance
timing
dose of antigen
costimulation
location
medawar’s neonatal tolerance experiment
inject bone marrow of mouse B into mouse A at birth. the result was that it didnt reject future transplants from B. experiment didnt work if the injection was delayed by a week or so.
probably due to chimerism in A.
some of the transplanted cells diferentiate into APCs then migrate to the thymus to tolerise.
- if the bone marrow is delayed then there are sufficient mature peripheral T cells to destroy the donor stem cells before they engraft
3 tolerance factors in pregnancy to prevent foetus rejection
1 - physical barrier to the mothers T cells.
2 - lack of MHC 1 on trophoblast cells that fomr the outer layer of the placenta so are not targets for CD8
3 - production of immunosuppressive factors such as alpha-fetal protein and IDO
2 methods of experimental tolerance
1 - peptide sniffing (inhalation tolerance)
2 - co-receptor blockade
describe peptide sniffing
immunogenic, MHC binding peptides are aerosolised and inhaled by mice. the result is tolerance to immunological challenge by the peptide when injected with adjuvant. similar effects with oral antigens
describe co-receptor blockade
MAB for any of them. CD4/8, B7, CD40.
where a particular response i dependent on the blocked coreceptor it can lead to tolerance.
mechanisms of immune evasion by microbes
1 - fungal spores - highly immunogenic but coated in inert hydrophobin
2 - varying the surface antigens - strep pneumoniae = antigenically different serotypes. trypanosomes - frequent gene rearrangements of surface antigens. flu virus = antigenic drift and shift
whats original antigenic sin
primary response to an antigen constrains the further activation of naiive cells in a secondary repsonse.
- in the second infection , only the epitopes common to the original train stimulate antibody production as the immune system appears to depend on the memory cells.
- this strategy makes sense as the memory B cells are rapidly mobilised but highly mutable pathogens exploit this as the host doesnt respond to the new epitopes.
superantigens?
staphylococci make them
- they activate large numbers of T cells by bridging the MHC 2 and TCR, and hence mask any specific response.
4 examples of how a virus blocks MHC 1 presentation
1 - EBV protein resists proteosomal degredation
2 - CMV US6 - blocks TAP
3 - CMV US2,3,11 block or degrade MHC 1
4 - Kaposis virus K3/5 removes class 1 from the cell surface
immune response and cancer
immune respnse is imp in dealing with cancer, particularly with tumours associated with viruses eg Kaposi’s in immunosuppressed AIDS patients.
- many tumours make altered proteins that cna be presented by MHC1.
- many tumours that progress appear to lose MHC1 expression by mutation or chromosome fragmentation.
