Major Histocompatibility Complex Flashcards
Summa CUM laude.
1
Q
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**Enumerate: **Functions of T lymphocytes
A
- Defense against cell-associated microbes
- Inhibition of immune responses
- T cell functions require cell-cell interactions or cytokines that act at short range
2
Q
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Regulatory T cells suppress APCs or other lymphocytes is what function of T-lymphocyte
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Inhibition of immune responses
3
Q
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What function of T-lymphocyte:
Phagocyting and killing infected cells and eliminate reservoirs of infection”
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Defense against cell-associated microbes
4
Q
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Identify: helps phagocytes to kill ingested microbes and help B cells to make potent antibodies
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Helper T cells
5
Q
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kills infected cells and eliminate reservoirs of infection
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Cytotoxic T lymphocytes (CTLs)
6
Q
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Enumerate challenges for T lymphocytes
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- Very few lymphocytes in the body are specific for any one microbe (or antigen)
- Lymphocytes must be able to locate and respond to microbes that enter and reside anywhere in the body
- Lymphocytes must respond to each microbe in ways that are best able to eradicate that microbe
7
Q
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Specificity and diversity of antigen receptors:
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–the immune system recognizes and distinguishes between 106 - 109 antigens; the body contains ~ 1012 lymphocytes; therefore, few lymphocytes (~1,000) can recognize any one antigen and need to find that antigen
8
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Response to extracellular microbes?
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antibodies that promote phagocytosis; destruction in macrophages (need helper T cells)
9
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Response to intracellular microbes?
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killing of infected cells (need CTLs)
10
Q
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Sites of Antigen entry
A
Skin
GIT
Respiratory tract
11
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Sites of Initial Antigen capture
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Lymphatic system
Peripheral blood circulation
12
Q
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Sites of antigen collection and capture
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Lymph node
Spleen
13
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Sites of microbe entry
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skin, GI tract, airways
(organs with continuous
epithelia, populated
with dendritic cells).
Less often – colonized
tissues, blood
14
Q
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Sites of lymphocyte activation:
A
peripheral
lymphoid organs (lymph
nodes, spleen), mucosal
and cutaneous lymphoid
tissues)
15
Q
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Antigens and naïve T cells come together in ???
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lymphoid organs
16
Q
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Why are dendritic cells the most efficient APCs for initiating immune responses?
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- Location
- Receptors for capturing and reacting to microbes:T
- Migration to T cell zones of lymphoid organs
- Maturation during migration
- Practical application
17
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What do T cells see?
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- All functions of T cells are mediated by interactions with other cells
- To ensure cellular communications, T cells see antigens NOT in the circulation but only when displayed by molecules on the surface of other cells
18
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cells displaying the antigen are called
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APCs - Antigen Presenting Cells
19
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Explain:
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During their maturation in the thymus, T cells whose TCRs see MHC molecules are selected to mature, i.e. mature T cells are MHC-restricted
20
Q
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True or False: Mature B cells are MHC-restricted.
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False.
During their maturation in the thymus, T cells whose TCRs see MHC molecules are selected to mature, i.e. **mature T cells are MHC-restricted **
21
Q
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A genetic locus discovered on the basis of transplantation
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Major histocompatibility complex
22
Q
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Human MHC
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HLA (human leukocyte antigens)
23
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Determine how antigens in different cellular compartments are recognized by different classes of T cells (CD4+ and CD8+)
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MHC molecules
24
Q
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Determines which protein antigens are recognized in different individuals
A
MHC
25
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True of False: MHC genes are highly polychromic.
Negative
MHC genes are highly **polymorphic**; the MHC molecules in the population can display many different peptides
26
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What are the antigen receptors of T cells that gives it dual specificities
1. **for peptide antigen** (responsible for specificity of immune response)
2. **for MHC molecules** (responsible for MHC restriction)
27
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WHO first defined by discovering an ab response to circulating WBCs (HLA)
Jean Dausset
28
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MHC is relevant in what clinical situations/conditions
•transfusion reactions, graft rejections, and autoimmune diseases
29
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True or False: MHC is Plays a role in humoral immunity
Negative
MHC plays a role in **both** cellular and humoral immunity
30
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True of False:
MHC is found on all nucleated cells
TRUE
31
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Explain Classes of MHC genes.
A, B, C loci = class I
D locus = class II
Class III= in between class I and II, codes for complement, cytokine (TNF)
32
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State the Possible alleles of ALL MHC genes
HLA-A = 580 possible alleles
HLA-B = 921 possible alleles
HLA-C = 312 possible alleles
33
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Crossover rate of MHC genes
***_0.5%_*** crossover rate
34
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Refers to sets inherited from mother or father
Haplotype
35
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True of False: MHC Alleles Are Sex-linked dominantly Expressed
Negative
MHC Alleles Are Co-dominantly Expressed
–Both mother and father alleles are expressed
36
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Counterpart of the MHC in mouse/mice/rats/rodents/shits
H-2
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Centromere= left side, Telomere= right side
Class I MHC locus (A,B,C)-found on telomere
Class II MHC locus [DP, DM, DQ, DR, Proteasome genes (TAP 1,2 )] - found on centromere
Class III MHC locus [Complement proteins (C4, Factor B, C2), Cytokines (lymphotoxin beta, TNF-alpha, LT) - In between
38
Structure of MHC Class I
## Footnote
* Glycoprotein dimer
* Alpha chain = 45 000 MW; folded into three domains (α1, α2, α3)
- α1, α2, α3 consists of 90 aa each
- transmembrane domain consists of 25 hydrophobic aa plus a short stretch of 5 hydrophilic aa and an anchor or 30 aa
•Β2 microglobulin = 12 000 MW: does not penetrate the cell membrane, but is essential for proper folding the alpha chain
**Ag binding cleft :** hold peptides that are between *8-10 amino acids long*
***Alpha3:*** reacts with cytotoxic T cells
39
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Two most important to match for transplantation
**HLA-A** and **HLA-B** expressed at higher levels than HLA-C : two most important to match for transplantation
40
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T or F: Class I is expressed on all nucleated cells
T
41
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Class I is highly expressed on ____ and low or undetected in \_\_\_
•Highest expression on **_lymphocytes**_ and low or undetected on _**liver hepatocytes, neural cells, muscle cell and sperm_**
42
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Designated as E,F,G
Non-classical Class I Antigens
43
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Expressed on trophoblast cells during the first trimester of pregnancy and help ensure tolerance for the fetus by protecting placental tissue from the action of NK cells
**G** non-classical Class I Antigen
44
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Do not function in antigen recognition but play a role in the immune response
Non-classical Class I antigen
45
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Non-classical Class I antigens expressed on the surface of cells
E, F
46
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T or : Class I is more restricted than Class II antigens
F
47
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Found on Ag-presenting cells (monocytes, macrophages, dendritic cells) and B lymphocytes
Class II
48
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Class II gene expressed at the highest level
DR
49
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Major class II genes
DP, DQ, DR
50
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Most polymorphic Class II gene
**DRβ** has 18 possible alleles, therefore most polymorphic
51
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Peptide binding site of Class II
α1 and β1
52
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Class II structure
* Has α chain = 33 000 MW and β chain = 27 000 MW
* Both are anchored to the cell membrane
* Each has 2 domains
53
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Binding site for the CD4.
(Class II Ag)
b2 is the binding site for the CD4.
54
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The a and b chains of the Class II Ag
.
•The a chains are the **HLA DR**
•The b chains are the **HLA DQ and DP**
55
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Products of these genes play a regulatory role in antigen processing
Non-classical Class II
56
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Non-classical Class II genes
DM, DN, DO
57
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Location of polymorphic residues of Class I
a-1 and a-2 domains
58
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Location of polymorphic residues of Class II
a-1 and b-1 domains
59
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Class I MHC nomenclature for mouse
H-2K, H-2K, H-2L
60
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Class II nomenlature for mouse
I-A, I-E
61
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Size of peptide-binding cleft of Class I MHC
Accomodates peptides of 8-11 residues
62
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Size of peptide-binding cleft of Class II MHC
Accomodates peptides of 10-30 residues or more
63
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Binding site for T cell coreceptor of **Class I MHC**
a3 region binds **CD8**
64
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Binding site for T cell coreceptor of **Class II MHC**
B2 binds **CD4**
65
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Polypeptide chains of Class I MHC
a (44-47 kD)
b2-microglobulin (12 kD)
66
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Polypeptide chains of Class II MHC
a (32-34 kD)
B (29-32 kD)
67
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Conversion of native antigen (large globular protein) into peptides capable of binding to MHC molecules
Antigen processing
68
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Where does antigen processing occur?
Occurs in **cellular compartments** where MHC molecules are synthesized and assembled
–Determines how antigen in different cellular compartments generates peptides that are displayed by class I or class II MHC molecules
69
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stimulates T helper cell in the case of bacterial infections
Class II
70
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bind exogenous protein and present it to CD4 T cells
Class II
71
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watchdogs of viral, tumor & certain parasitic Ags that are synthesized w/in the cell (endogenous Ags)
Class I
72
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present peptides that have been synthesized within the cell to CD8 T cells
Class I
73
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Class I MHC pathway
Protein antigen in cytosol (cytoplasm)
74
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Class II MHC pathway
Protein antigen in vesicles
75
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must be transported from ER to an endosomal compartment before they can bind peptides
Class II
76
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bind peptides while still in the ER
## Footnote
binding stabilize association of α with β2 microglobulin
Class I
77
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Both Class I and II molecules are synthesized in the ___ and for a time anchored in the \_\_\_\_
Both Class I and II molecules are synthesized in the **RER**, and for a time anchored in the **ER**
78
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88 kd molecule, membrane bound in the ER, keeps the α chain partially folded while it awaits binding to β2 microglobulin, once β2 microglobulin binds it is released , and other **chaperone molecules (calreticulin, tapason, and ERp57)** are associated w/complex and help to stabilize it for the peptide binding
Calnexin
79
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Pathways of antigen processing
1. Antigen uptake
2. Antigen processing
3. MHC biosynthesis
4. Peptide-MHC association
80
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Explain: The class I MHC pathway of processing of endogenous cytosolic protein antigens
1. Production of proteins in the cytosol
2. Proteolytic degradation of proteins
3. Transport of peptides from cytosol to the ER
4. Assembly of peptide-class I complexes in the ER
5. Surface expression of peptide-class I complexes
81
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Defective ribosomal products, peptides that fail to correctly fold and hence defective, about 20-70percent of all proteins synthesized by the cell, must be digested by the proteases (by proteasome)
DRiPs
82
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Peptides derived from proteins found in the cytosol that are then degraded by the multiproteolytic \_\_\_\_\_\_\_\_\_complex into peptides. (Class I pathway)
Proteasome
83
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Brings the TAP transporters into close proximity to the newly formed MHC molecules and mediates interaction with them so that the peptides can be loaded to MHC class I
Tapasin
84
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are cooperatively folded into the newly synthesized MHC-I molecule.
**transporter associated with antigen processing (TAP**)
85
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The first step in the activation of a CD8+ cellular program
The MHC-I molecule allows the APC bearing a particular MHC–peptide complex to **engage an appropriate alpha beta T cell receptor **
86
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The activation of a CD8+ cellular program that might lead to \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_.
**cytolysis of the APC as a target** and/or to the **secretion of lymphokines by the T cell. **
87
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The class II MHC pathway of processing of internalized vesicular protein antigens
1. Uptake of extracellular proteins into vesicular compartments of APC
2. Processing of internalized proteins in endosomal/lysosomal vesicles
3. Biosynthesis and transport of Class II MHC molecules to endosomes
4. Association of processed peptides with with Class II MHC molecules in vesicles
5. Expression of peptide-MHC molecule on cell surface
88
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31 kd protein that is made in excess to make sure all Class I molecules have Ii, prevents interaction of Class II binding site to the endogenous proteins of ER, helps to bring α and β chains together in the ER lumen and then moving them thru the golgi apparatus to the endocytic vesicles where digested Ag is found
Invariant chain
89
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serves as a chaperone to direct the ab heterodimer to an endosomal, acidic protein–processing location.
invariant chain (Ii)
90
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Help to mediate the reaction by removing the CLIP fragment
HLA-DM
91
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Class II invariant chain peptide, attached to the peptide-binding cleft
CLIP
92
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inside-out pathway
MHC-I
93
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outside-in pathway
MHC-II
94
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How does class I-associated antigen presentation
## Footnote
influence the nature of the host T cell response/Activation of a CD4+ cellular program might lead to
**Macrophage activation**: destruction of phagocytosed antigen
**B cell antibody secretion**: antibody binding to antigen
95
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How class II-associated antigen presentation
influence the nature of the host T cell response
Killing of antigen-expressing taget cell
96
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Association of Human MHC Alleles and Risk for Diseases
Disease Associated HLA Allele Relative Risk\*\*
Ankylosing Spondylitis\* B27 90
Hereditary Hemochromatosis A3/B14 90
Insulin Dependent Diabetes\* DR4/DR3 20
Multiple Sclerosis\* DR2 5
Myasthenia Gravis\* DR3 10
Rheumatoid Arthritis\* DR4 10
Systemic Lupus Erythromatosis\* DR3 5
\* Autoimmune Disease \*\*Percent of Patients with Allele Divided by Percent of Non-Affected Persons with this Allele
•
Narcolepsy DR2 130
97
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