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micr 386 > module 04 section 01 (the MHC) > Flashcards

module 04 section 01 (the MHC) Flashcards

1
Q

where are the major histocompatibilty complex (MHC) molecules located?

A

on the surface of antigen-presenting cells (APCs)

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2
Q

what is the primary function of MHC molecules?

A

to bind and present antigenic peptide fragments from pathogens, then display the processed peptides on the cell surface for recognition by antigen-specific T-cell receptors (TCRs)

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3
Q

describe the genes that the MHC complex is composed of

A

MHC complex is composed of highly polymorphic genes

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4
Q

define “polymorphic” in terms of the MHC

A

many alternative forms of the MHC gene exist at each locus within the population

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5
Q

each individual possesses a set of MHC molecules with various peptide-binding capabilities, true or false?

A

true

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6
Q

define “MHC restriction”

A

both CD4+ and CD8+ T-cells can only recognize antigens when they’re presented by a self MHC molecule

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7
Q

who discovered MHC restriction

A
  • Zinkernagel and Doherty (1974)

- won the nobel prize for discovering the role of MHC in cell mediated immuntiy

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8
Q

genes encoding the MHC span a large region of approximately ____ bps

A

4 x 10^6

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9
Q

in humans, how many genes does the MHC consist of?

A

over 200

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10
Q

recap: what is the primary function of the MHC and its genes?

A

to process and present antigens to T-cells

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11
Q

do MHC molecules play an integral role in conferring innate or adaptive immunity?

A

adaptive

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12
Q

MHC class II molecules interact with which CD receptor (4 or 8) on the surface of what cell?

A

CD4 on the surface of helper T-cells

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13
Q

recall: what is the function of helper T-cells?

A

they mediate the development of adaptive immuntity by regulating B-cell and cytotoxic T-cell responses

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14
Q

MHC class I molecules interact with which CD receptor (4 or 8) on the surface of which cell?

A

CD8 on the surface of cytotoxic T-cells

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15
Q

recall: what is the function of cytotoxic T-cells?

A

to mediate cell-mediated immunity by destroying infected or malignant host cells

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16
Q

what is the principal target of the recipients immune response when recieving an organ transplant?

A

the MHC molecules expressed on the surface of donor cells

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17
Q

what, in terms of the adaptive immune response, is a key determinant of sucessful transplant?

A

matching recipients with MHC-identical donors

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18
Q

what happens when organs are transplanted btwn MHC antigen-mismatched individuals (in the absense of immunosupressive therapy)?

A

typically rejection

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19
Q

how much of a match (btwn MHC molecules) is required for organ transplantation to be successful?

A

80-90%

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20
Q

what are the strongest risk factors for autoimmune diseases?

A

MHC molecules

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21
Q

define “autoimmune disease”

A

disease caused by an abnormal immune response against self antigens

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22
Q

the development of widescreen genotyping platforms has resulted in:

A

HLA-typing for several common autoimmune diseases

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23
Q

what is HLA-typing?

A

a test done to determine if a patient has antibodies against a potential donor’s HLA (MHC)

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24
Q

list 4 common autoimmune diseases

A

rheumatoid arthritis
psoriasis
multiple sclerosis
inflammatory bowel disease

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25
Q

provide an example of HLA association to disease

A
  • an increased risk of rheumatoid arthritis has been reported in individuals with a specific set of aa sequences in certain MHC genes
  • most significant associations were with 2 aa located in the peptide-binding groove of the MHC molecule
  • this suggests that there’s a functional role for these aa in the binding of rheumatoid arthritis triggering antigens
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26
Q

in addition to polymorphism, the expression of MHC alleles is:

A

codominant

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27
Q

what does it mean to say MHC allele expression is codominant?

A

that the maternal and paternal MHC alleles are inherited and that the products of both alleles are expressed on cells

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28
Q

define “haplotype”

A

the particular combination of MHC alleles found on a single chromosome

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29
Q

how many possible combinations of halotypes can be found in offspring of a mating event?

A

4

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30
Q

can siblings differ in their MHC alleles expressed?

what are the implications of this?

A

yes - can make it hard to find suitable donors for tissue transplants (bc even siblings aren’t suitable matches sometimes)

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31
Q

what does histocompatibility (compatibility of MHC molecules) depend on?

A

the alleles of the MHC gene complex expressed by both the donor and the recipient

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32
Q

what is the MHC gene complex called when expressed in humans? in mice?

A

humans: HLA
mice: H-2

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33
Q

can recipients of an organ transplant accept grafts from donnors who express a haplotype that the recipient does not have? even if the recipient and donor express other identical haplotypes?

A

no

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34
Q

can recipients of an organ transplant accept graphs from donors who express the same haplotype? even if the recipient expresses additional haplotypes which are not expressed in the donor?

A

yes

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35
Q

what are mouse MHC genes encoded by?

A

the H-2 locus

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36
Q

where is the H-2 locus located?

A

chromosome 17

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37
Q

what are the major class I genes in mice?

A

H2-D, H2-L and H2-K

38
Q

what are the major class II gene loci in mice?

A

H2-M, H2-A and H2-E

39
Q

explain the haplotype expressed by inbred mice

A

these mice are homozygous and express the same haplotype twice (e.g. b/b or k/k)

40
Q

define “F1”

A

the first generation of offspring of distictly different parental types

41
Q

explain the haplotype expressed by F1 progeny mice from mating of inbred mouse strains with different MHC haplotypes (H-2(b/b) + H-2(k/k) = ?)

A

these mice are heterozygous and express the MHC proteins of both parents
-i.e. H-2(b/b) + H-2(k/k) –> H-2(b/k)

42
Q

an H-2(b/b) donor can have successful transplantation to:

A

the parental H-2(b/b) and the progeny recipient (H-2(b/k))

43
Q

an H-2(k/k) donor can have successful transplantation to:

A

the parental H-2(k/k) and the progeny recipient (H-2(b/k))

44
Q

an H-2(b/k) donor can have successful transplantation to:

A

only the progeny recipient (H-2(b/k))

45
Q

explain the haplotype expressed by outbred mice

A

these mice are heterozygous and express 2 different haplotypes (e.g. b/d or k/a)

46
Q

explain the haplotype expressed by F1 mice from the mating of outbred mouse strains

A

these mice are heterozygous and express the MHC proteins of both parents

47
Q

describe the histocompatibility for F1 mice (that result from the mating of outbred mouse strains) and their parents

A

these mice are histoINcompatible with both parents, meaning they’ll reject grafts from either parent

48
Q

what are human MHC proteins encoded by?

A

the human leukocyte antigen complex (HLA)

49
Q

where is the HLA located?

A

chromosome 6

50
Q

HLA genes (and their protein products) are divided into how many classes? based on what?

A

3 - based on their tissue distribtuion, structure, and function

51
Q

what are the major MHC class I genes? (3)

A

HLA-A, HLA-B and HLA-C

52
Q

what are the MHC class II genes? (4)

A

HLA-DP, HLA-DM, HLA-DQ and HLA-DR

**LMP and TAP gene encoded molecules are not class II MHC molecules despite the fact that they are located btwn DM and DQ

53
Q 
what do class III genes encode for? 
provide 2 examples
A

various other proteins that function in immunity, e.g:

  • complement proteins (C4, C2, factor B)
  • cytokines (TNF)
54
Q

describe (generally) the structure of MHC class I molecules

A
  • heterodimers expressed on the cell membrane

- consist of α-chain and β2-chain microglobulin

55
Q

is the α-chain of MHC class I molecules highly or slightly polymorphic?

A

highly

56
Q

is the β2 microglobulin gene encoded within the MHC complex?

A

no (separate entity)

57
Q

explain (in detail) the structure of MHC class I molecules

A
  • heterodimers consisting of a 43,000 Da α-chain non-covalently associated wtih a 12,000 Da β2-microglobulin polypeptide chain
  • the β2-m binds to the α3 domain
  • the α-chain is folded into 3 domains (α1, α2, α3)
  • α1 and α2 form the membrane-distal domains
  • α3 and β2-m form the membrane-proximal domains
  • α3 is also attached to the transmembrane segment (coiled), which extends into the cytoplasmic tail
58
Q

describe the binding cleft of class I MHC molecules

what forms it, what does it consist of, what can peptides bind

A
  • α1 and α2 domains fold together to make the binding cleft
  • consists of 2 segmented α helices lying on a sheet of 8 β strands
  • peptides can then bind diff hypervariable aa sequences on the β sheets
59
Q

are MHC class I molecules expressed on all ____ cells

A

nucelated

60
Q

where are MHC class I molecules most highly expressed?

A

hematopoietic cells (blood cells)

61
Q

what do MHC class I complexes expressed on the cell surface bind?

A

peptides derrived from endogenously synthesized proteins in the cell

62
Q

in humans, a heterozygous individual will express which MHC alleles on the membrane of each nucelated cell?

what is the result of this?

A
  • the A, B, and C alleles from each parent
  • this results in 6 different MHC class I molecules
  • this diversity allows each cell to display a large number of peptides
63
Q

describe (generally) the structure of MHC class II molecules

A

highly polymoprhic heterodimers expressed on the cell membrane

64
Q

what is the most common MHC class II molecule?

A

HLA-DQ

65
Q

explain (in detail) the structure of MHC class II molecules

A
  • heterodimers consisting of a 34,000 DA α-chain associated with a 29,000 Da β chain
  • each chain folds into 2 domains (2 α and 2 β domains) that collectively compact to form a 4 domain structure
  • α1 and β1 form the membrane distal domains
  • α2 and β2 form the membrane-proximal domains
  • the α2 and β2 domains are connected to transmembrane segments (coiled), which extend into the cytoplasmic tail
66
Q

explain the binding cleft of MHC class II molecules

A

formed by the non-covalently attached α1 and β1 chains

67
Q

what is the major difference btwn MHC class I and MHC class II binding clefts?

what are the implications of this?

A

MHC class II is open at both ends - allowing for a longer peptide to bind

68
Q

recall: what are the professional antigen presenting cells?

A

B-cells, macrophages and dendritic cells

69
Q

what are peptides bound to MHC class II molecules derived from?

A

exogenous proteins that have entered the cell by phagocytosis or endocytosis

70
Q

how many different MHC class II complexes will a heterozygous individual express?

A

12

71
Q

how many parental MHC class II molecules will a heterozygous individual inherit?

A

6 - 3 maternal (DPβmam, DQβmam, DRβmam) and 3 paternal (DPβpap, DQβpap, DRβpap)

72
Q

maternal and paternal β and α chains from the same gene (DP, DQ, DR) can:

what is the result of this?

A

pair with each other - resulting in a total of 4 different class II molecules that can be produced for each gene (4x3 for each gene = 12)

e.g. DPβmam, DPβpap, DPβpam and DPβmap

73
Q

is HLA-DM expressed on the cell surface?

A

no

74
Q

where is HLA-DM predominantly found?

A

in specialized endosomal compartments

75
Q

define “endosomal”

A

pertaining to a membrane-bound compartment inside a eukaryotic cell

76
Q

why is it that HLA-DM is not expressed on the cell surface like other MHC class II molecules?

A

bc HLA-DM assists in the binding of peptides to other MHC-II molecules

77
Q

compare MHC class I and MHC class II molecules (5)

domains, binding cleft, expression and binding

A

MHC class I:

  • separate β2 microglobulin not encoded with MHC
  • α chain folds into 3 domains
  • α1 and α2 form the binding cleft
  • expressed on all nucleated cells
  • bind endogenous peptides

MHC class II:

  • no separate β2 microglobulin domain
  • α and β chains fold into 2 domains
  • α1 and β1 form the binding cleft which can accomodate larger peptides
  • only expressed on APCs
  • bind exogenous proteins
78
Q

is α3 of the MHC class I molecules polymorphic?

A

no

79
Q

polymorphism refers to what at a gene locus?

A

variability (i.e. more than one allele at one gene locus)

80
Q

polymorphism occurs at a frequency of greater than:

A

1%

81
Q

can MHC polymorphism extend to a range of antigens that MHC complexes can present?

what are the implications of this?

A

yes - affects which antigens T-cells can bind through MHC restriction
(characteristic of T-cells that permits them to recognize antigens only after its processed and displayed with an MHC molecule)

82
Q

is the genetic variation associated with MHC polymorphism random?

A

no - localized to hypervariable regions

83
Q

what did MHC restriction tell us about lymphocyte recognition of foreign antigens?

A

must recognize both the foreign antigen and certain self-molecules in order to kill the virus infected cells

84
Q

where is allelic variability clustered to?

A

positions that line the peptide binding cleft

85
Q

where, on MHC class I molecules, is allelic variability clustered to?

A

the α1 and α2 domains

86
Q

where, on MHC class II molecules, is allelic variability clustered to?

A

amino-terminal β1 domains

87
Q

what are the 3 characteristics of MHC molecules that allow for antigen presentation?

A

irreversible, antigen-dependent, self presentation

88
Q

describe “irreversible” as a property of MHC molecules

A

MHC peptide binding is essentially irreversible, allowing for long-term display of these complexes on the cell surface

89
Q

describe “antigen-dependent” as a property of MHC molecules

A

loss of peptide from the binding cleft of the MHC molecule halts MHC presentation at the cell surface

90
Q

describe “self-presentation” as a property of MHC molecules

A

self peptides can be presented on MHC molecules and is the mechanism for grafting

micr 386 (31 decks)

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