Exam IV (be brave, there will be tears) Flashcards
(105 cards)
1
Q
Th cells recognize APCs via
A
class II MHC
2
Q
Tc cells recognize targets via
A
Class I MHC
3
Q
NK cells recognize targets via
A
class I MHC
4
Q
Roles of MHC:
A
1) intercellular recognition
2) development of immune responses (due to antigenic properties of peptides presented MHC)
3) discrimination of self vs non-self
-“tissue compatibility”
-depends on antigenic properties of the MHC molecule itself
->
4) Susceptibility to disease
-allelic make-up affects types of peptides presented
5
Q
Does rejection of an organ occur because of certain foreign peptides being presented on an MHC molecule?
A
Organ rejection has nothing to do with the peptides presented on MHC molecules, it’s actually all about the MHC receptors
6
Q
How does TB use MHC molecules to evade the immune system?
A
TB- (several viruses and bacteria use MHCs to access cells)
Binds to specific MHC molecule alleles
-triggers phagocytosis
-blocks endosome maturation
-survives and replicates within the endosome
:0 yikes
7
Q
What do we refer to MHCs as in humans?
A
HLA (human leukocyte antigen)
8
Q
What do we refer to MHCs in mice as?
A
H-2 (histocompatibility 2 complex)
9
Q
What is the H-2 (histocompatibility 2 complex) ?
A
MHCs in mice
10
Q
What is HLA (human leukocyte antigen) ?
A
Human name for MHCs
11
Q
Human HLA complex types
A
See slides for sure, chp 16 MHC slide 11/68
12
Q
HLA class I, look like what (MHCs)
A
3 different alpha chains, use same beta2 microglobulin
13
Q
HLA class II, look like what (MHCs)
A
“little snowmen with tails,” alpha beta together coded
14
Q
MHCs are among the most _____________ genes in humans
A
polymorphic
15
Q
HLA molecules are polygenic, meaning what?
A
multiple genes for each class
16
Q
Does class I or class II generally have more alleles?
(bonus if you remember which humans smelled for)
A
Class I for both bb
17
Q
What chromosome is the human HLA complex located on?
How would you describe this organization?
A
Chromosome 6
Compacted organization, 200+ genes organized
all together as one unit
(it’s on the short arm)
18
Q
MHC family inheritance can be described as a
A
haplotype
19
Q
How is an MHC family typically inherited?
A
The entire set of genes is
typically inherited as a single unit (haplotype)
20
Q
It is rare to find
unrelated individuals
with identical sets of _____________
A
HLA genes
21
Q
Most humans are ________ at each locus
A
heterozygous
22
Q
HLA are usually
inherited as a ______
A
set, see slides unit 15 MHC slides 25-29/68
23
Q
If child needed transplant, is it likely that the parent could donate?
A
Not likely at all
24
Q
If a child needed a transplant, how likely that a sibling could donate?
A
25% child sibling compatible
25
If a parent needed a transplant, could a child possibly donate?
If parent needed transplant, basically zero chance child can donate
26
In relation to HLA inheritance, do A, B, C and D represent genes?
NO, These are
haplotype designations: represent the entire set of alleles
27
Are recombinant haplotypes of HLA possible?
Technically yes, but they're very rare
28
Describe the structure of a class I MHC molecule
3 alpha globulin domains, one beta2 globulin, only one "root" of alpha through a cell membrane
29
Where is the peptide-binding cleft on a class I MHC molecule?
In between alpha 2 and alpha 1 at the top
30
Where are the immunoglobulin domains of a class I MHC?
Bottom two globulins (Alpha 3 and beta 2) closest to the membrane
31
What chromosome is class I MHC encoded on?
Chr. 15
* Used with all three
Class I proteins
(A, B, C)
32
When a Tc binds a class I MHC, where are the TCR and CD8 touching?
TCR to the peptide binding cleft
CD8 to the beta2 microglobulin
33
Describe the structure of a class II MHC molecule
alpha 1, alpha 2
beta1, beta 2
2 legs rooted in the membrane if you will
34
Where is the peptide-binding cleft on a class II MHC molecule?
between alpha 1 and beta 1
35
Where are the immunoglobulin domains of a class II MHC?
I dont knwo for sure but I think alpha 2 and beta 2 also closest to the membrane???
36
What chromosome is class II MHC encoded on?
idk maybe also 15
37
When a Th binds a class II MHC, where are the TCR and CD4 touching?
The TCR is in the peptide binding cleft, and CD4 is touching the beta 2 microglobulin
38
The peptide-binding cleft is made up (structure wise) of what folds
* Sides: α-helices
* Floor: β-sheet
39
Class I peptide binding cleft-
found between alpha 1 and alpha 2, braced on sides by alpha helices, then bottom beta sheets
40
What order of attachment from a Th cell occurs with a class II MHC?
-CD4 looks at alpha 2 and beta 2 domains to verify is a class II MHC, then TCR comes in to read the peptide
41
What is the difference size wise between peptides bound by class I MHC vs class II MHC?
Class I MHC- 8-10 amino acids
Class II MHC- 13-18 amino acids
42
Gene arrangement Class I:
Alpha chain- (c is cytoplasmic tail)
DNA, also pre-mRNA, same sequence with introns
-after mRNA processing- introns removed
-no recombination going on, normal gene expression
-Transcription processing, translation and then protein assembly
so basically no crazy splicing or anything happening, just intron removal
43
Gene arrangement Class II:
-same, no rearrangement
44
Your limited number of MHC must be able to what?
present an enormous array of different antigenic peptides
45
MHC molecules, they cause scandal why and have have
promiscuous, have general specificity (alleles dictate what peptides you can bind and which you cant bind)
-they bind many different peptides
-bound peptides exhibit common patterns
46
Class I MHC peptides have certain conserved anchor residues, what does this allow for?
bulge, at edges hydrogen bonding with MHC molecule
unit 15 MHC slides 47/68
47
Do class II MHC peptides also present with a bulge?
No, lay flat on the floor (no bulging)
* No conserved anchor residues
* Internal conserved motifs
* Hydrogen-bonding distributed throughout
MHC/Peptide Interactions
48
What is the general genetic relation of all humans vs HLA genes?
Genome-wide, all humans are 99.9% identical in their
genetic makeup
* DNA sequences in HLA region vary by up to 10% from one
individual to another
49
“ability of an animal to mount immune response, as measured buy production of serum of antibodies, is determined by its ______________"
MHC haplotype
50
What are the pros of HLA diversity?
* Potentially millions of different MHC haplotypes in the human population
* Our protection comes from the population as a whole
51
What happens if your MHCs cannot present peptides?
you are fucked.
-without MHCs to present peptides, B cells will never make antibodies
-if we cant present them, we’ll never be protected
52
What are the main two Models of Immune Responsiveness
(Generates holes in our protection:)
-Determinant-selection model
-Holes in the repertoire model (comes more down to t cells)
53
What is the Determinant-selection model?
-your MHC alleles determine which antigens to present
-comes down to which peptides can be presented on MHC molecules
54
What is the Holes in the repertoire model?
(comes more down to t cells)
-T cells with receptors that recognize foreign antigens which closely resemble self-antigens may be eliminated during thymic processing (negative selection)
55
What are two main holes in our protection as explained by the main two Models of Immune Responsiveness?
Generates holes in our protection:
* MHC molecules are binding antigen
* T cells are not there to respond
56
Class I MHC molecules:
bind who, and use what processing pathway?
Bind endogenously-expressed peptides
Cytosolic Processing Pathway
**review slide 56/68 15 MHC to remind how to read alleles vs genes
57
MHC molecules are co-dominantly expressed, what does this mean really?
* One individual can express all polygenes on the same cell
* One individual can express both maternally and paternally inherited alleles on the same cell
* The various combinations all affect the specific
peptides each can present
58
If you see gene products HLA-A, HLA-B, HLA-C, which MHC molecule is being discussed?
class I
59
How many distinctly different Class I molecules
can one individual express on their cells?
6
HLA-A^m HLA-A^p
HLA-B^m HLA-B^p
HLA-C^m HLA-C^p
slide 59/68 MHC 15
60
How many distinctly different Class II molecules can one individual express on their cells?
DP-αMβM, DP-αPβP, DP-αMβP, DP-αPβM
DQ-αMbM, DQ-αPBP, DQ-αMBP, DQ-αPbM
DR-αMbM, DR-αPBP, DR-αMBP, DR-αPbM
basically you could have an alpha chain from one parent and a beta chain from another
Twelve
**see slide 60/68 MHC 15
61
What does HLA stand for?
human leukocyte antigen
62
Target cell vs antigen-presenting cell
Can an antigen be a target cell?
-antigen itself can be target cell if infected/altered
63
What antigens are involved with the Cytosolic Processing Pathway?
Which class of MHC molecule involved?
* Endogenous antigens
* Class I
64
Describe the Endogenous antigens involved with the Cytosolic Processing Pathway
* Misfolded proteins
* Unfolding/misfolding exposes
hydrophobic patches
* Attracted to the 20S proteasome
65
Why is it helpful that the lifespan of cellular proteins is regulated?
* Key metabolic enzymes have rapid turnover
* Allows for a fine-tuned response to environmental changes
* Structural proteins have longer life
66
How are aged proteins are targeted for
proteolysis? (marked if you will)
* Tagged with ubiquitin
67
26S proteasome (20S proteosome, 19S regulatory component)
(same as 20S just has regulatory component on each end)
68
Assuming that the average gene is 1000 bp
(coding sequence), how long is the average
polypeptide chain?
330 amino acids
each 3 bp make one amino acid (1000/3)
69
How long are the peptides produced by the proteasome?
(cytosolic processing pathway, class I MHC)
8-10 amino acids
70
How many ideal peptides could be produced
from the average protein?
(cytosolic processing pathway, class I MHC)
33-41 peptides
71
What other feature(s) may be taken into
account when cutting a polypeptide chain into
peptides?
(cytosolic processing pathway, class I MHC)
Anchor residues
72
Does the proteasome cut solely by size?
(cytosolic processing pathway, class I MHC)
No!
73
Proteasome cleaves peptides that
follow basic and/or
hydrophobic residues
74
Loading onto MHC-
Who are the guys funneling the peptides into the MHC cup?
(bonus for where this happens)
o Transporter Associated with Antigen Presentation (TAP1 and TAP2)
Kind of like nozzle/funnel putting peptides into the MHC cup (happens in lumen or rough ER)
75
Who holds the class I MHC alpha chain in proper conformation before beta arrives?
(hint it sounds sorta sick)
calnexin chaperone
76
After formation the Class I MHC/peptide complex proceeds to the cell surface via what?
Golgi apparatus
77
Which MHC involves the Endocytic Pathway?
Where do these peptides come from?
Class II bb, exogenous peptides being presented
78
Cytosolic processing pathway- all this happens where?
happens in cytosol (cytosol is liquids, cytoplasm is liquid and organelles outside nucleus) floating around in the liquid, prepares peptides (endogenous) for class I MHC
79
3 main players assisting in the cytosolic processing pathway-
Calreticulin: Stabilizes the MHC molecule and prepares it for peptide binding.
Tapasin: Facilitates the transfer and editing of peptides to ensure proper peptide-MHC binding.
Erp57: Maintains the structural integrity of the MHC molecule during the loading process.
80
o Calreticulin
Role: Chaperone protein.
Binds to the alpha chain of the Class I MHC molecule in the endoplasmic reticulum (ER) to stabilize its folding.
Prevents premature peptide binding, ensuring the MHC molecule remains in a state ready to bind high-affinity peptides.
81
o Tapasin
Role: Bridging protein.
Links the Class I MHC molecule to the TAP (Transporter Associated with Antigen Processing) complex.
Facilitates the transfer of peptides from TAP to the peptide-binding groove of the MHC molecule.
82
o Erp57
Role: Thiol oxidoreductase.
Assists in the correct folding of the Class I MHC molecule and ensures the integrity of disulfide bonds in the MHC heavy chain.
Works in conjunction with calreticulin and tapasin as part of the peptide-loading complex.
83
What two things must happen to exogenous antigens in order to be presented on class II MHC?
(exogenous processing pathway)
1) Internalization (Receptor-mediated endocytosis)
2) Processing (endosome fuses with lysosome after engulfment) (pH drops, hydrolytic enzymes activated, bac is chopped up)
84
What is the Endocytic processing pathway?
how exogenous proteins are processed and presented (by class II MHC)
85
CLIP: Class II-
associated
invariant chain
peptide
Holds the place of where exogenous peptide will do, holding indiana jones rock
16 antigen presentation, slide 23/32
(after placeheld by HLA DM)
86
Who prevents crossover of exogenous and endogenous peptides being processing pre MHC?
Invariant chain (Ii, CD74)
It stays on top in place of exogenous DNA until the golgi then is digested and replaced with CLIP I
87
What is the main takeaway from the Classic Experiment: Jules Bordet (1890) did with the inoculated sheep?
Complement cannot kill bacs alone, antibodies cant alone, but together they can kill bacteria. Antibodies heat resistant, proteins not
88
What things does the complement system aid in?
Cell lysis, phagocytosis, inflammatory response,
also plays important role in B-cell activation, greatly enhances activation signal
89
Components of the complement system-
(Eg C) inactive
-proteolytic cleavage
Cb and Ca
90
What is the complement component rule and evil exception to the rule?
Rule: Large fragment = “b”
Small fragment = “a”
**Evil Exception to the rule: C2
Large fragment = “a”
Small fragment = “b”
91
Activation of a complement employs 3 possible pathways. What are they?
1) Classical pathway
2) Alternative pathway
3) Lectin pathway
God help you remember the mechanism for each of them 😫
92
In the Complement Activation: Classic Pathway, what must happen to the C1 heads?
Heads must simultaneously bind to at least two antibody C-binding sites for activation
(note it is also antibody mediated)
93
In the Complement Activation: Classic Pathway, ~how much of which antibodies are required for activation?
Activation requires:
~1000 IgG
1 IgM
94
Alternative Pathway:
What initiates the pathway?
initiated by spontaneous breakdown of C3
95
In all these pathways what's the general jist?
Someone splits, then a bunch assemble to form the C3 convertase, who then joins the party to form the C5 convertase which will then split C5, C5b then contributes with the MAC
96
What does C3b do?
bind to cell membranes, but we can protect nucleated cells Inactivated by sialic acid
97
What inactivates C3b and stops it from lysing healthy nucleated cells?
sialic acid
98
Classical: ab-dependent
Alternative: innate
beyond this, what're the main differences between the two pathways component and product wise?
Different components
Same end-result
99
Lectin Pathway- part of what immune system, initiated by what
(innate immune system, no antibodies required) initiated by presence of bacterial sugars
100
Lectin Pathway-
lotta mannose on bacs, what does body do
-mannose binding lectin (MLB)
-MASP 1 and MASP 2 bind MLB
Manose binding lectin binds
MASP 1 and MASP 2 bind MLB (act like C3 convertase)
101
What happens after MASP 1 and MASP 2 bind MLB
-then able to break down C2 and C4, forming C2a and C4b, which combine to form C3 convertase
102
Lectin Pathway: initiated by
bacterial sugars, no antibodies required
103
How does the lectin pathway relate to the classical and alternative?
Different activation route
Lectin: Innate
Same components as Classical
Same end-result
104
Out of the 3 complement pathways (classical, alternative, lectin) do any share components?
Classical + lectin have same components
All have same end result of the MAC
105
