Lecture 12 Flashcards

1
Q

what is the MHC complex locus called in mice? what chromosome?

A

H2

chr 17

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2
Q

what is the MHC complex locus called in human? what chromosome?

A

HLA

chr 6

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3
Q

how big the MHC locus?

A

7 million bp

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4
Q

what are 2 genes involved in MHC that are not on the same chromosome as MHC?

A

B2m and Ii

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5
Q

how are the diff MHC classes organized in the locus?

A

in clusters

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6
Q

describe beta chain in HLA-DR

A

2 beta chains in HLA-DR

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7
Q

what is unique about HLA-DM and DO?

A

non-classical class II molecules

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8
Q

since many genes involved in antigen processing are found on the human MHC locus, what is the significance?

A

the genes were co-selected during evolution

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9
Q

what is an example of non-MHC genes that are found in the human MHC locus?

A

complement protein genes

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10
Q

what is encoded in Class I besides HLA-A/B/C?

A

non-classical classIb genes –> HLA-E/F/G

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11
Q

what is a common inducer of MHC locus genes?

A

IFN

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12
Q

example of a gene induced by IFN-gamma and its role?

A

ClassII transactivator (not in MHC locus) induced by IFN-gamma to drive class II transcription

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13
Q

2 ways that MHC genes increase diversity?

A
  1. polymorphism
  2. polygeny
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14
Q

what is polymorphism?

A

many variations of MHC genes (i.e. alleles) at the same locus

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15
Q

what gene in MHC II is most polymorphic?

A

beta chains

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16
Q

what MHC class is the most polymorphic?

A

MHC I

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17
Q

which 2 MHC genes are less polymorphic?

A

HLA-DRalpha and H-2Ealpha

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18
Q

what is a consequence of polymorphism introducing many alleles for MHC I and MHC II?

A

unlikely to be homozygous –> therefore can present many Ag

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19
Q

what is a haplotype?

A

given combo of MHC alleles on 1 chromosome

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20
Q

what is polygeny?

A

many copies of a gene is possible

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21
Q

describe the type of dominant expression of MHC alleles

A

codominant –> all expressed at same time

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22
Q

evolution of MHC

A

MHC co-evolves with pathogens

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23
Q

2 types of polymorphism

A
  1. polymorphism within a population
  2. polymorphism within an individual
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24
Q

what is the name for polymorphism within a population?

A

Negative Frequency Dependent Selection

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25
Q

what is negative frequency dependent selection?

A

puts pressure to maintain rare alleles

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26
Q

why do we want to keep rare alleles?

A

pathogen can mutate to evade allele that is common, but then rare allele gives resistance –> keeps us unpredictable

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27
Q

what is the name for polymorphism within an individual?

A

heterozygous advantage

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28
Q

allelic variations lead to different _______ of MHC

A

allelic variations lead to different isoforms of MHC

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29
Q

how many aa can be different btwn MHC isoforms?

A

up to 20 aa different

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30
Q

what is different btwn MHC isoforms?

A

structure is unaffected, just the peptide binding cleft is affected

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31
Q

what part of the peptide binding cleft is different btwn MHC isoforms?

A

anchor residues

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32
Q

is it possible for Ag processing not to generate peptides that bind our MHC?

A

yes if homozygous –> fewer peptides can be presented (common in inbred animals)

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33
Q

in which instance can it be useful to predict peptide anchor residues?

A

vaccine design –> peptide anchor residues that allow for improved presentation will increase immune response

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34
Q

what is the consequence of MHC isoforms having diff anchor residues?

A

can bind diff peptides

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35
Q

what is required for TCR to be stimulated?

A
  1. matching MHC
  2. matching antigen
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36
Q

what is alloreactivity?

A

primary T cell response against allelic variants of MHC in the species

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37
Q

what occurs in direct allorecognition?

A

non-matching MHC is presented to T cell –> no restriction so will mount T cell response

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38
Q

what occurs in indirect allorecognition?

A

matching MHC presents non-matching MHC as its peptide to T cell –> presented by correct MHC and will induce T cell response

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39
Q

what are MHC congenic mice?

A

genetically identical except at MHC locus

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40
Q

what do MHC congenic mice allow for? (2)

A
  1. to compare biological effect of diff alleles in the same genetic background
  2. compare effect of given allele in diff genetic backgrounds
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41
Q

assay to determine alloreactivity?

A

mixed lymphocyte reaction (MLR)

42
Q

describe MLR

A

irradiated/mitomycin-C treated donor cells containing T cells and APC
+
recipient CD4 T cells

if proliferation of CD4 T cells –> there was allogenic reaction allowing TCR to be activated

43
Q

what are super antigens?

A

antigens that bind independently to MHC and TCR –> don’t need to be processed and don’t bind peptide binding cleft

44
Q

describe specificity of T cell response by super antigens

A

not peptide-specific response –> does not prime Ag specific T cells

45
Q

describe T cell response by super antigens?

A

drives massive cytokine production by CD4 T cells

46
Q

how do super antigens work?

A

stable MHC presenting a peptide and non-matching TCR are brought together by the super antigen

47
Q

2 reasons why MHC-encoded class 1B genes are not like other MHC-encoded genes?

A
  1. not polymorphic
  2. don’t all interact with T cells
48
Q

what are MHC-encoded class 1B genes involved in?

A

involved in innate immunity –> interact with NK cells

49
Q

characteristics of ligands of non-MHC encoded class 1B genes?

A

some don’t have ligands, ligands can be non-peptidic

50
Q

example of non-MHC encoded class 1B gene

A

CD1

51
Q

CD1 vs MHC-encoded gene

A

genetically identical except for the MHC locus

52
Q

role of CD1

A

presents non-linear LIPID ligands to T cells

53
Q

CD1-restricted T cells vs other T cells

A

CD1-restricted T cells don’t express CD4 or CD8

54
Q

What is CD1 recognized by?

A

invariant NK T cells

55
Q

why is the CD1 recognition process considered to be btwn innate and adaptive immunity?

A

innate –> presents diff lipids from many organisms

adaptive –> NK T cell has fully rearranged TCR

56
Q

3 main APCs

A
  1. DCs
  2. macrophages
  3. B cells
57
Q

ANTIGEN UPTAKE

  1. DCs
  2. macrophages
  3. B cells
A

1/2. DCs/macrophages –> macropinocytosis and phagocytosis

  1. antigen-specific BCR
58
Q

MHC EXPRESSION

  1. DCs
  2. macrophages
  3. B cells
A
  1. DCs –> MHC low on tissue-resident DCs, high on lymphoid DCs
  2. macrophages –> MHC inducible by bacteria and cytokines
  3. B cells –> MHC is constitutive but increases when activated
59
Q

CO-STIMULATION

  1. DCs
  2. macrophages
  3. B cells
A
  1. DCs –> inducible, high on lymphoid DCs

2/3. macrophages/B cells –> inducible

60
Q

LOCATION

  1. DCs
  2. macrophages
  3. B cells
A
  1. DCs –> ubiquitous thru body
  2. Macrophages –> lymphoid tissue, connective tissue, body cavities
  3. B cells –> lymphoid tissue, peripheral blood
61
Q

main role of APC for DCs

A

T cell priming and expansion

62
Q

main role of APC for macrophages and B cells

A

to get recognized by CD4+ T cell to get activated

63
Q

describe movement of DCs and what allows them to be motile

A

inflammation allows them to deliver Ag to lymphoid tissue from site of infection

64
Q

immature DCs vs mature DCs

A

immature –> highly phagocytic

mature –> high MHC II expression

65
Q

how do APCs get activated? (3)

A
  1. receptors (PRR, BCR)
  2. tissue damage
  3. inflammatory cytokines
66
Q

why are DCs, macrophages, and B cells the only cells that can activate naive T cells?

A

they have the necessary costimulatory molecules

67
Q

DCs are the main drivers of….

A

DCs are the main drivers of clonal expansion and T cell differentiation

68
Q

where are DCs located in the lymph nodes?

A

throughout the cortex, in T cell zones

69
Q

what antigens can DCs present?

A

basically any type

70
Q

where are macrophages located in the lymph nodes?

A

throughout lymph nodes (in marginal sinus) close to afferent and efferent lymphatics

71
Q

main role of DCs

A

prime T cells

72
Q

what type of antigens do macrophages present?

A

bacterial Ag

73
Q

what type of T cells do macrophages interact with?

A

primed T cells

74
Q

where are B cells found in the lymph nodes?

A

in the follicles

75
Q

what type of antigen do B cells present?

A

soluble Ag

76
Q

what type of T cells do B cells interact with?

A

B cells interact with primed T cells via BCR

77
Q

B cells and toxins

A

B cells can also neutralize toxins

78
Q

2 types of DCs

A
  1. conventional DC
  2. plasmacytoid DC
79
Q

where are conventional DCs found?

A

under surface epithelia and solid organs with IMMATURE phenotype

80
Q

when mature, what do conventional DCs express?

A

MHC II and co-stim molecules to activate naive T cells

81
Q

where are plasmacytoid DCs found?

A

in blood and lymphoid tissue

82
Q

what do plasmacytoid DCs secrete?

A

type 1 IFN

83
Q

role of plasmacytoid DCs

A

poor at priming T cells bc has fewer co-stim molecules but has TLRs for sensing VIRAL infection

84
Q

5 ways that conventional DCs process/present Ag

A
  1. receptor-mediated phagocytosis
  2. macropinocytosis
  3. viral infection
  4. cross-presentation after phagocytic/macropinocytic uptake
  5. transfer from incoming DC to resident DC
85
Q

RECEPTOR-MEDIATED PHAGOCYTOSIS

  1. pathogen type
  2. MHC type
  3. T cell type
A
  1. extracellular bacteria
  2. MHC II
  3. CD4 T cells
86
Q

macropinocytosis

  1. pathogen type
  2. MHC type
  3. T cell type
A
  1. extracellular bacteria, soluble antigens, virus particles
  2. MHC II
  3. CD4 T cells
87
Q

VIRAL INFECTION

  1. pathogen type
  2. MHC type
  3. T cell type
A
  1. viruses
  2. MHC I
  3. CD8 T cells
88
Q

CROSS-PRESENTATION AFTER PHAGOCYTIC/MACROPINOCYTIC UPTAKE

  1. pathogen type
  2. MHC type
  3. T cell type
A
  1. viruses
  2. MHC I
  3. CD8 T cells
89
Q

TRANSFER FROM INCOMING DC TO RESIDENT DC

  1. pathogen type
  2. MHC type
  3. T cell type
A
  1. Viruses
  2. MHC I
  3. CD8 T cells
90
Q

What are langerhans cells?

A

immature conventional DC in the skin

91
Q

role of langerhans cells

A

highly phagocytic –> transfer skin Ag to mature DC in lymph node

92
Q

what allows langerhans cells to migrate?

A

Ag capture

93
Q

what activates DCs in tissue?

A

TLR signaling

94
Q

what happens once DCs have been activated by TLR signaling?

A

LICENSING: chemokine receptor (CCR7) expression is increased

95
Q

what happens once the DC has been licensed?

A

MIGRATION: CCR7 binds CCL21 ligand binding on lymphoid tissue for migration AND maturation

96
Q

what happens once the DC matures?

A

morphology changes so they become less efficient at phagocytosis and increase MHC and co-stim molecules

97
Q

what co-stim molecules are increased in mature DCs?

A

B7.1 and B7.2

98
Q

what is reduced in mature DCs?

A

MARCH1

99
Q

why is MARCH1 reduced in mature DCs?

A

to allow for increased MHC I stability for better Ag interaction

100
Q
A