response to infection and tolerance

Question 1

general progression of immune response as infection developes

Answer 1

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

Question 2

what is immunological tolerance

Answer 2

the way the immune system avoids reacting to innocuous substances to prevent unnecessary tissue damage and resource waste.

Question 3

tolerance - genetic or acquired

Answer 3

“tolerance is acquired, not hard wired.”

trained to recognise infectious non-self

Question 4

whats the danger hypothesis

Answer 4

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.

Question 5

what is complete freund’s adjuvant

Answer 5

contains ground up mycobacteria

Question 6

2 types of tolerance

Answer 6

1 - central - during lymphocyte development

2 - peripheral - occurs after theyve left the primary lymphoid organs

Question 7

central tolerance of T cells

Answer 7

via affinity, positive and negative selection in the thymus

Question 8

central tolerance of B cells

Answer 8

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

Question 9

why do we need peripheral tolerance

Answer 9

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.

Question 10

4 of the proposed mechanisms of peripheral tolerance

Answer 10

1 - ignorance
2 - split tolerance
3 - anergy
4 - suppression

Question 11

describe peripheral ignorance

Answer 11

the potentially autoreactive T cells arent activated possibly because the antigen is in immunologically privileged sites eg brain, eye, testis

Question 12

describe peripheral split tolerance

Answer 12

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

Question 13

decribe anergy

Answer 13

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

Question 14

describe suppression

Answer 14

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

Question 15

how are T regs distinguished

Answer 15

by the fact they express the Fox3p TF.

Question 16

how do Tregs work

Answer 16

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

Question 17

what happens if FoxP3 is lost

Answer 17

IPEX syndrome

immune dyeregulation, polyendocrinopathy, entropathy X-linked

Question 18

what are the variables affecting tolerance

Answer 18

timing
dose of antigen
costimulation
location

Question 19

medawar’s neonatal tolerance experiment

Answer 19

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

Question 20

3 tolerance factors in pregnancy to prevent foetus rejection

Answer 20

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

Question 21

2 methods of experimental tolerance

Answer 21

1 - peptide sniffing (inhalation tolerance)

2 - co-receptor blockade

Question 22

describe peptide sniffing

Answer 22

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

Question 23

describe co-receptor blockade

Answer 23

MAB for any of them. CD4/8, B7, CD40.

where a particular response i dependent on the blocked coreceptor it can lead to tolerance.

Question 24

mechanisms of immune evasion by microbes

Answer 24

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

Question 25

whats original antigenic sin

Answer 25

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.

Question 26

superantigens?

Answer 26

staphylococci make them

- they activate large numbers of T cells by bridging the MHC 2 and TCR, and hence mask any specific response.

Question 27

4 examples of how a virus blocks MHC 1 presentation

Answer 27

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

Question 28

immune response and cancer

Answer 28

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.