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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
provide an example of HLA association to disease
- 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
26
in addition to polymorphism, the expression of MHC alleles is:
codominant
27
what does it mean to say MHC allele expression is codominant?
that the maternal and paternal MHC alleles are inherited and that the products of both alleles are expressed on cells
28
define "haplotype"
the particular combination of MHC alleles found on a single chromosome
29
how many possible combinations of halotypes can be found in offspring of a mating event?
4
30
can siblings differ in their MHC alleles expressed? what are the implications of this?
yes - can make it hard to find suitable donors for tissue transplants (bc even siblings aren't suitable matches sometimes)
31
what does histocompatibility (compatibility of MHC molecules) depend on?
the alleles of the MHC gene complex expressed by both the donor and the recipient
32
what is the MHC gene complex called when expressed in humans? in mice?
humans: HLA mice: H-2
33
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?
no
34
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?
yes
35
what are mouse MHC genes encoded by?
the H-2 locus
36
where is the H-2 locus located?
chromosome 17
37
what are the major class I genes in mice?
H2-D, H2-L and H2-K
38
what are the major class II gene loci in mice?
H2-M, H2-A and H2-E
39
explain the haplotype expressed by inbred mice
these mice are homozygous and express the same haplotype twice (e.g. b/b or k/k)
40
define "F1"
the first generation of offspring of distictly different parental types
41
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) = ?)
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
an H-2(b/b) donor can have successful transplantation to:
the parental H-2(b/b) and the progeny recipient (H-2(b/k))
43
an H-2(k/k) donor can have successful transplantation to:
the parental H-2(k/k) and the progeny recipient (H-2(b/k))
44
an H-2(b/k) donor can have successful transplantation to:
only the progeny recipient (H-2(b/k))
45
explain the haplotype expressed by outbred mice
these mice are heterozygous and express 2 different haplotypes (e.g. b/d or k/a)
46
explain the haplotype expressed by F1 mice from the mating of outbred mouse strains
these mice are heterozygous and express the MHC proteins of both parents
47
describe the histocompatibility for F1 mice (that result from the mating of outbred mouse strains) and their parents
these mice are histoINcompatible with both parents, meaning they'll reject grafts from either parent
48
what are human MHC proteins encoded by?
the human leukocyte antigen complex (HLA)
49
where is the HLA located?
chromosome 6
50
HLA genes (and their protein products) are divided into how many classes? based on what?
3 - based on their tissue distribtuion, structure, and function
51
what are the major MHC class I genes? (3)
HLA-A, HLA-B and HLA-C
52
what are the MHC class II genes? (4)
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
``` what do class III genes encode for? provide 2 examples ```
various other proteins that function in immunity, e.g: - complement proteins (C4, C2, factor B) - cytokines (TNF)
54
describe (generally) the structure of MHC class I molecules
- heterodimers expressed on the cell membrane | - consist of α-chain and β2-chain microglobulin
55
is the α-chain of MHC class I molecules highly or slightly polymorphic?
highly
56
is the β2 microglobulin gene encoded within the MHC complex?
no (separate entity)
57
explain (in detail) the structure of MHC class I molecules
- 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
describe the binding cleft of class I MHC molecules | what forms it, what does it consist of, what can peptides bind
- 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
are MHC class I molecules expressed on all ____ cells
nucelated
60
where are MHC class I molecules most highly expressed?
hematopoietic cells (blood cells)
61
what do MHC class I complexes expressed on the cell surface bind?
peptides derrived from endogenously synthesized proteins in the cell
62
in humans, a heterozygous individual will express which MHC alleles on the membrane of each nucelated cell? what is the result of this?
- 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
describe (generally) the structure of MHC class II molecules
highly polymoprhic heterodimers expressed on the cell membrane
64
what is the most common MHC class II molecule?
HLA-DQ
65
explain (in detail) the structure of MHC class II molecules
- 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
explain the binding cleft of MHC class II molecules
formed by the non-covalently attached α1 and β1 chains
67
what is the major difference btwn MHC class I and MHC class II binding clefts? what are the implications of this?
MHC class II is open at both ends - allowing for a longer peptide to bind
68
recall: what are the professional antigen presenting cells?
B-cells, macrophages and dendritic cells
69
what are peptides bound to MHC class II molecules derived from?
exogenous proteins that have entered the cell by phagocytosis or endocytosis
70
how many different MHC class II complexes will a heterozygous individual express?
12
71
how many parental MHC class II molecules will a heterozygous individual inherit?
6 - 3 maternal (DPβmam, DQβmam, DRβmam) and 3 paternal (DPβpap, DQβpap, DRβpap)
72
maternal and paternal β and α chains from the same gene (DP, DQ, DR) can: what is the result of this?
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
is HLA-DM expressed on the cell surface?
no
74
where is HLA-DM predominantly found?
in specialized endosomal compartments
75
define "endosomal"
pertaining to a membrane-bound compartment inside a eukaryotic cell
76
why is it that HLA-DM is not expressed on the cell surface like other MHC class II molecules?
bc HLA-DM assists in the binding of peptides to other MHC-II molecules
77
compare MHC class I and MHC class II molecules (5) | domains, binding cleft, expression and binding
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
is α3 of the MHC class I molecules polymorphic?
no
79
polymorphism refers to what at a gene locus?
variability (i.e. more than one allele at one gene locus)
80
polymorphism occurs at a frequency of greater than:
1%
81
can MHC polymorphism extend to a range of antigens that MHC complexes can present? what are the implications of this?
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
is the genetic variation associated with MHC polymorphism random?
no - localized to hypervariable regions
83
what did MHC restriction tell us about lymphocyte recognition of foreign antigens?
must recognize both the foreign antigen and certain self-molecules in order to kill the virus infected cells
84
where is allelic variability clustered to?
positions that line the peptide binding cleft
85
where, on MHC class I molecules, is allelic variability clustered to?
the α1 and α2 domains
86
where, on MHC class II molecules, is allelic variability clustered to?
amino-terminal β1 domains
87
what are the 3 characteristics of MHC molecules that allow for antigen presentation?
irreversible, antigen-dependent, self presentation
88
describe "irreversible" as a property of MHC molecules
MHC peptide binding is essentially irreversible, allowing for long-term display of these complexes on the cell surface
89
describe "antigen-dependent" as a property of MHC molecules
loss of peptide from the binding cleft of the MHC molecule halts MHC presentation at the cell surface
90
describe "self-presentation" as a property of MHC molecules
self peptides can be presented on MHC molecules and is the mechanism for grafting

micr 386 (31 decks)

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