Linking: Exceptions and MHC genetics

Question 1

What are the general rules - principle of mhc presentation

Answer 1

Exo= presented on mhc 2
Endo = mhc 1

Question 2

Name 3 exceptions to the rules

Answer 2

Cross presentation
Presentation of cytosolic peptides by mhc class 2 molecules
Allorecognition

Question 3

Describe cross presentation

Answer 3

Exogenous peptides presented on mhc class 1

Question 4

What is the opposite of cross presentation

Answer 4

Presentation of cytosolic peptides by mhc class 2 molecules

Question 5

What is cross presentation

Answer 5

Dendritic cells cross present antigens = take up exogenous antigens and redirect
Exogenous antigens redirected to endogenous pathway and presented on mhc1

Question 6

Which cells can do cross presentation

Answer 6

Dendritic cells = only apcs so far that can cross present

Question 7

Name and describe the 2 exs of cross presentation

Answer 7

Viruses phagocytosed by dendritic cells = exogenous antigens, when virus extra cellular and need c8+ cells
Virally infected cells are phagocytosed and viral peptides - release damps - presented on mhc molecules - class 1

Question 8

Generally describe cross presentation mechanism

Answer 8

Actual redirection mechanism unclear
Dendritic cells need liscene

Question 9

Describe dc licensing

Answer 9

Dc can present foreign antigen to cd4+ helper T cell and get licensed= to redirect exogenous antigen into endogenous pathway from T cells = thinks cd8+ would be better so cd4+ gives liscnece to dendritic cells = to go to endogenous pathway

Question 10

What does license allow

Answer 10

Cytokine and ligand signalling between apc/helper T cell
Allows for their presentation on mhc class 1 = so can prime cd8+ t cell

Question 11

What do we first need before licensing

Answer 11

Need to have activated cd4+ T cell first - then can license and cross present

Question 12

How does presentation of cytosolic peptides by Mhc class 2 occur

Answer 12

Via autophagy= digestion and breakdown of a cell by its own organelles and proteins in lysosomes

Question 13

Describe autohagosome

Answer 13

Specialized double membrane vesicles that contain cytoplasmic content and fuses with lysosomes = can be degraded

Question 14

Describe steps of mechanism - autophagsome

Answer 14

Parts of cytoplasm taken into autopahgosome
Proteins degraded
Links up to exogenous pathway —> mhc2

Question 15

Name EXAMPLE 1 of presentation of cytosolic peptides mhc2

Answer 15

Some pathogens = have adapted to resist intracellualr killing and the macrophages in which they live require stimulation by cytokines in order to kill pathogen (cannot do on own, this situation more common)

Question 16

Describe further how macrophages help with cytosolic presentation of peptides by mhc 2

Answer 16

Will help redirect some of these peptides to be processed via exogenous and presented on mhc 2 = boost macrophages = fight against intracellualr parasite
T helper cell binds macrophage mhc class 2 with peptide

Question 17

What is allorecognition

Answer 17

Tcr - recognize peptide in context of self mhc - mhc class 1

Question 18

Describe h2k mouse exp

Answer 18

H2k mouse was injected with Lymphocytic choriomeningitis virus (LCMV). Days later, spleen cells, including cytotoxic T lymphocytes, from this mouse were incubated with LCMV-infected target cells of the same (H2k) or different haplotype (MHC alleles) (H2b). What do you observe?
= need T cells to be specific to mhc alleles = only h2b lcmv infected target cells = can kill cells, = release 51cr

Question 19

Describe h2k mouse exp = conclusions

Answer 19

Tcrs not only specific to peptides but also specific to mhc

Question 20

Wat are T cell responses

Answer 20

Mhc restricted

Question 21

What does mhc restriction mean

Answer 21

A given T cell is able to recognize a specific peptide only when bound to a specific self mhc molecule

Question 22

Describe ex of mhc restriction

Answer 22

Strain A animal only respond to at presnted by strain A apcs but not by strain B apc

Question 23

When does recognition happen - mhc restriction

Answer 23

Tcr binds mhc AND peptide
If only specific to one or other = no recognition

Question 24

What is allorecognition

Answer 24

Recognition of non self mhc by some T cells in body

Question 25

How many T cells can react to allogenic mhc

Answer 25

1-10% of all T cells in an organism can react to non self (allogenic) mhc molecules (allo-mhc)

Question 26

Describe why allorecognition important

Answer 26

Main mechanism of rejection of transplanted organs between genetically different individuals of same species = why ppl take immunosuppressants If grant mhc a —> mhc b recipient = REJECTED

Question 27

Describe allorecognition generally = images

Answer 27

Tcr= binds both mhc and peptide usually specific to both But sometimes = non self mhc but doesn’t matter, T cells Will activate, proliferate and tru to get all cells with this non self mhc Mhc dominant binding

Question 28

Name the 2 types of allorecognition

Answer 28

Direct Indirect

Question 29

Describe direct allorecognition

Answer 29

Recipient T cell recognition of donor/transplant mhc molecules expressed on surface of donor cells = try to get rid of donor mhc protein

Question 30

Describe indirect allorecognition

Answer 30

Recognition of processed donor peptides presented onto recipients own apcs via self mhc Donor apc = shed parts of it = necrotic or apoptotic material shed mhc Recipient apc takes up donor cells = include non self mhc —> process and present it to T cells Donor peptide + recipient mhc = presnted on surface mhc = bc peptide non self mhc and not like pathogen = considered indirect allorecognition

Question 31

Define gene

Answer 31

Segment of a chromosome that controls specific characteristics = encodes for protein

Question 32

Define allele

Answer 32

One specific form of a gene

Question 33

Define locus

Answer 33

Loci = Plural Specific chromosomal location of a gene

Question 34

What codes mhc molecules

Answer 34

Hla genes

Question 35

Where mhc molecules found

Answer 35

In a cluster of genes on chromosome 6 in humans

Question 36

Name classses mhc genes

Answer 36

2 main classes = class 1 class2

Question 37

Describe mhc class 1 genes

Answer 37

Hla-a, hla-b, hla-c = All encode for alpha chain (Beta2micro= always the same, also on diff gene)

Question 38

Describe mhc class 2 genes

Answer 38

Hla-dr, Hla-dq, Hla-dm, Hla-doa, Hla-dob Encodes for alpha and beta chain

Question 39

Define polymorphism

Answer 39

Multiple variations (forms) or alleles, exist for each gene

Question 40

Describe polymorphism - allele

Answer 40

2 or more alternative forms of a gene at particular locus

Question 41

How are alleles known

Answer 41

By number after locus = Hla-a1, hla-dr3 etc Many mhc genes have >100 diff alleles

Question 42

Give ex polymorphism

Answer 42

Hla-a= gene Hla-a1 to hla-a2041 = alleles Ex = inherited how-a1 and hla-a6 while someone else = inherited Hla-a2041 and hla-a200 = one from each parent Provides variability in mhc molecules

Question 43

Define haplotype

Answer 43

Particular combo of mhc alleles found on single chromosome Each individual inherits one halpotype from each parent

Question 44

How are mhc alleles expressed

Answer 44

Codominantly = Both maternal and paternal mhc genes expressed in offspring cells Best change of prensting all possible antigen peptides it encounters

Question 45

Why is transplantation difffcult

Answer 45

Bc humans heterozygous at each locus

Question 46

Define polygeny

Answer 46

Each individual has many copies of related genes Multiple genes with same function but slightly diff structures One haplotype form each parent = one of each hla with diff number (polymorphism) from each = 2x3 = 6

Question 47

Describe ex polygeny

Answer 47

Inherit 3 diff mhc-1 alleles from each parent = so 6 alleles expressed in one person = (Hla-a, hla-b and hla-c allele per chromosome) (Same for class 2)

Question 48

What does polygeny result in

Answer 48

High degreee of variance in mhc expression in population

Question 49

What does peptide binding groove have

Answer 49

Allelic variation (the most) Differences clustered at aa locations within groove sites

Question 50

Describe what peptide binding groove allelic variation causes = facilitates

Answer 50

Helps facilitate presentation of diff variety of peptides - diff peptide binding specificities

Question 51

Describe what peptide binding groove allelic variation causes = folding

Answer 51

If areas outside of the binding groove altered too much = can affect structure conformation and folding of mhc molecule

Question 52

What can a given mhc molecule bind

Answer 52

A given mhc molecule can bind numerous diff peptides - depends on type and size, and some peptides clad bind to diff mhc molecules

Question 53

Define polygeny again

Answer 53

Hla-a hla-b hla-c Same for class 2

Question 54

Define polymorphism again

Answer 54

Multiple allelic variants of each of these genes in the population Multiple alleles/forms of them

Question 55

You transplant skin from the b/k progeny mouse into the b/b parent mouse. Will this transplant be successful? Why?

Answer 55

Noooo Will reject k part of it B/k can only give to b/k Bb can give to bb or bk Kk parent can give to b/k or kk only

Question 56

You transplant skin from the b/k progeny mouse into the b/b parent mouse. Will this transplant be successful? Why?= compare to humans

Answer 56

Parent mice =have homologous chromosomes But Humans heterozygous = even more difficult for transplantation of organs

Question 57

Name EXAMPLE 2 of presentation of cytosolic peptides mhc2

Answer 57

Some viruses prevent presentation on mhc1 - if infect host cell - professional apc = chance that virus can inhibit presentation, so apc presents onto mhc2 to try to get help of cd4+ cells