WK 4- MHC COMPLEX, ANTIGEN PROCESSING AND PRESENTATION Flashcards

1
Q

What is MHC also called

A

HLA

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2
Q

What is the MHC

A

MHC is a cluster of genes which form a molecule on the surface of cells- aids in presenting peptides from pathogens. MHC determines if transplanted tissue is compatible between donor and host.

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3
Q

Where is MHC1 found

A

MHC1 is found on all nucleated cells, including plasma cells

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4
Q

Where is MHC2 found

A

Found on subsets of haematopoietic cells- APC (dendritic, macrophage and NK cells)

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5
Q

What genes encode for MHC1

A

Alpha chain is encoded by HLA-A, HLA-B, HLA-C

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6
Q

What genes encode for MHC2

A

Alpha and beta chains are encoded by HLA-DR, HLA-DP, HLA-DQ

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7
Q

What MHC complex presents peptides from intracellular pathogens

A

MHC1 expresses peptides from pathogens that reside within the cell-> MHC1 presents the peptides to CD8 cytotoxic cells

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8
Q

What MHC complex presents peptides from exogenous peptides

A

MHC2 expresses peptides from pathogens that were exogenous and then engulfed and broken down-> presents them to CD4T cells

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9
Q

What is MHC restriction

A

MHC restriction is the requirement that APC cells express MHC molecules that the T cell recognizes and matches, in order for T cell to respond to the antigen presented by that APC. (T cells will only recognize antigens presented by their own specific MHC molecules- allows for T cell specificity)

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10
Q

What does polygeny mean

A

MHC molecules display polygeny as they have multiple genes encoding for the same structure/function

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11
Q

What does polymorphic mean

A

Refers to a minor difference between genes-> caused by inheriting multiple alleles for each gene because you inherit combinations from each parent, and both are expressed

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12
Q

What is a haplotype

A

A set of genetic determinants located on a single chromosome and inherited as a block- the HLA genes from each parent are inherited as a haplotype

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13
Q

True or false, HLA genes are expressed co-dominantly

A

True- each inherited gene is expressed-> polygeny and polymorphism contribute to diversity

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14
Q

What is an altered cell

A

Altered cells are those which are infected with a virus or cancer-> MHC1 allows for these cells to be identified and killed by cytotoxic CD8T cells

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15
Q

What is antigen processing

A

Generation of peptides from intact antigens-> must occur in order for MHC to present signals to T cells (T cells only recognise peptides)

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16
Q

What is antigen presentation

A

Display of peptide on cell surface by MHC molecules

17
Q

What is a super antigen

A

Super antigens are produced by bacteria and viruses and don’t require processing into peptides and aren’t presented by MHC-> they bind directly to the portion between the MHC and TCR and activates the T cell directly, causing toxic shock

18
Q

Why is toxic shock so severe

A

Super antigens activate around 20% of the T cell population at once, causes an over exaggerated immune response leading to an overproduction of cytokines into the body-> causes life threatening tissue damage and systemic effects

19
Q

Why don’t super antigens create memory cells

A

No memory cells can be created because super antigens don’t need to be processed by MHC so therefore don’t initiate the adaptive immune response

20
Q

What is immunological tolerance

A

Defined as the state of specific immunological unresponsiveness of the lymphoid tissue to an antigen (tolerogen) that would normally cause an immune response

21
Q

What is self-tolerance

A

Inability to mount an immune response to self-antigens or endogenous antigens (important in preventing auto-immune)

22
Q

What causes self-tolerance

A

Self-tolerance is due to the deletion of self-reactive T cells and B cells-> these cells are tested in the primary lymphoid tissue for self-reactivity

23
Q

What is central tolerance

A

Is clonal deletion that deletes self-reactive lymphocyte clones

24
Q

What is peripheral tolerance

A

Mechanisms acting on lymphocytes after they have left primary lymphoid organs-> if the self-reactive lymphocytes escaped the BM/Thymus they are captured and destroyed by anergy, suppressor cells and clonal deletion

25
Q

What is acquired tolerance

A

Tolerance arising as a result of administration of an exogenous antigen-> this is how immunisations work

26
Q

What is the structure of MHC1- what forms the peptide binding cleft

A

Consists of 2 polypeptide chains and an alpha heavy change encoded by HLA-A/B/C, and a non-covalently bound B2 microglobulin
Alpha 1 and Alpha 2 pair together to form the peptide binding cleft

27
Q

What is the structure of MHC2- what forms the peptide binding cleft

A

Consists of two non-covalently bound polypeptide chains, each has 2 domains (alpha 1/2, beta 1/2)- beta 1 and alpha 1 form the peptide binding cleft

28
Q

What is the process of presentation by MHC1 molecules

A
  1. Virus adheres to membrane and enters cell
  2. Once inside the cell it will enter the nucleus and begin to replicate→ will then move to cytosol where it is synthesized (translation and transcription) into proteins
  3. The proteins then encounter proteasomes in the cytosol→ proteasome cleaves the protein into small peptides
  4. The peptides are transported to the ER via the TAP1/2 (transporters associated with antigen processing)
  5. MHC is in its inactive form in the ER and has several molecules capping it→ MHC1 is originally bound to calnexin→ when released from calnexin it binds to a complex of proteins (calreticulin, ERp57) and TAP via tapasin→ the proteasome (that degrades the viral protein) also degrades the cytostolic proteins and DRIPs (defective ribosomal products) and causes the TAP to deliver the peptides to the ER→ the peptide will then bind to the MHC1 molecule and be released from TAP and into the cell membrane
  6. At the cell membrane the MHC1:peptide complex is presented and will trigger CD8 cells that will release cytotoxic granules and cause the virus infected cell to undergo apoptosis
29
Q

What is the process of presentation by MHC2 molecules

A

Process of presentation:

  1. Virus/protein is taken up form extracellular space into by an endosome or phagosome via phagocytosis
  2. In early endosomes the pH is neutral and the proteases are inactive→ acidification of vesicles will activate the proteases that degrade the antigen into peptides
  3. Initially, the MHC2 has an invariant chain→ this invariant chain is cleaved in an acidified endosome leaving a short peptide ‘CLIP’ still bound to the MHC (removal of capping molecules only occurs when there is a peptide containing vesicle fusing with an MHC molecule)
  4. When HLA-DM binds to the MHC2 molecule is will release CLIP and allow binding
  5. . Vesicles full of peptides produced from the virus will fuse with vesicles containing MHC class 2 molecules in the ER and the peptides will bind to the peptide binding site
  6. The MHC2 molecule will then travel to the cell surface and trigger CD4 cells→ the functions CD4 depend on the subtype produced
30
Q

What is the invariant chain

A

Present in MHC2 presentation- blocks the binding site to prevent binding of peptides or misfolded proteins in the ER

31
Q

What is required to bind to the MHC2 in order for CLIP to be released

A

HLA-DM

32
Q

What is a the difference in antigen processing between MHC2 and MHC1

A

MHC1 uses a proteosome in order to digest the pathogens proteins to peptides
MHC2 uses the acidic granules in a lysosome to break down proteins from a peptide