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SFM Exam 1 > Ag Capture And Presentation > Flashcards

Ag Capture And Presentation Flashcards

1
Q

How does the innate immune response initiate the adaptive immune response?

A

By providing two signals

  1. Process and present Ag to T lymphocytes
  2. Generation of surface molecules that functions as co-stimulatory signals with Ag to activate T and B lymphocytes
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2
Q

What occurs when microbes enter the body?

A

They are phagocytosed or pinocytosed by APCs in the tissues

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3
Q

Antigens entering the periphery are filtered by what?

A

Lymph and lymphoid tissues

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4
Q

Antigens in the blood are filtered by what?

A

The spleen

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5
Q

What is Ag processing?

A

Convert proteins to peptides for display (presentation)

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6
Q

What are the three main types of APCs?

A

Dendritic cells, macrophages, B lymphocytes

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7
Q

Which other type of cells can also act as APCs in some cases?

A

Cells that express class II MHC/HLA

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8
Q

Any cell expressing HLA class I can present to which type of cell?

A

CD8+ T lymphocytes

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9
Q

Mature but naive CD8 cells may need help from which cell to become fully activated?

A

CD4 T cell

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10
Q

Which APC is the only one that can activate naive T cells?

A

Mature DCs

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11
Q

What are some characteristics of professional antigen presenting DCs?

A

High constitutive expression of MHC/HLA II and co-stimulatory molecules
Can activate mature, naive T cells
Present processed Ag to recirculating mature, naive lymphocytes in peripheral lymphoid tissue

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12
Q

Where are classical DCs present?

A

In all tissues

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13
Q

Where are plasmacytoid DCs present?

A

Blood and tissues

Promote innate anti-viral state

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14
Q

Activated macrophages can activate which type of cell?

A

Memory T cells

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15
Q

What changes occur when a DC is activated?

A

Lose adhesive markers and up-regulate CCR7 (lymphatic endothelium)
Increase expression of MHC/HLA and CD80 (B7)

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16
Q

When DCs become activated they travel to

A

Regional secondary lymphoid tissue, mature as they migrate and process Ags to T cells once in the lymphoid tissue

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17
Q

Where is class I MHC/HLA found?

A

On all nucleated cells

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18
Q

Where is class II MHC/HLA found?

A

On professional APCs (dendritic cells, macrophages, B lymphocytes and some thymocytes, epithelium, etc)

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19
Q

When was histocompatibility first identified?

A

In transplantation

Determined if transplanted tissues was accepted as self (histocompatibility) or as foreign (histoincompatibility)

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20
Q

Differences in HLA molecules expressed by an individual will influence what?

A

The repertoire of Ags to which T lymphocytes can respond

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21
Q

Can T lymphocytes recognize Ags in free or soluble forms?

A

T cells DO NOT recognize free or soluble Ags

They recognize portions of proteins Ags (peptides) associated with HLA

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22
Q

What does HLA stand for?

A

Human leukocyte Ags

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23
Q

Characteristics of MHC/HLA genes

A

Tightly linked cluster of genes that are highly polymorphic
Unprecedented extent of polymorphism
More than 150 separate alleles have been identified within MHC/HLA
Many alternative versions of each HLA gene

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24
Q

MHC/HLA location and organization

A 
Chromosome 6 
Divided into three distinct classes: class I, II and III
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25
The total set of MHC/HLA alleles are present on each
Chromosome
26
What is a haplotype?
The set of alleles on each chromosome Encode protein Ag presenting molecules for immune system to discriminate between self and non-self and respond to outside threats
27
Most humans are heterozygous and have two
MHC/HLA haplotypes (one from mon and one from dad) | Both haplotypes expressed simultaneously (co-dominate expression)
28
Each allotype of HLA genes confers the ability to
Bind different peptides for T cells to respond to | Individuals have a nearly unique set of HLA molecules
29
How do HLA polymorphisms impact individual immune responses and disease susceptibility?
Homogeneity of alleles allows pathogen to adapt Heterozygosity of alleles results in more vigorous response Epidemics favor individuals with rare allotypes = frequency dependent selection
30
Class I HLA characteristics
More diverse allotypes Can typically bind 2000-10,000 different peptides per cell Important for discrimination of self/non-self
31
Class II HLA characteristics
Professional APCs Specific to outside threats Displays greater variability in peptides presented
32
Class I genes are encoded by three separated gene regions in the HLA locus including
HLA-A, HLA-B and HLA-C
33
Class I genes
Expressed on all nucleated cells (10-10,000 of each type present on most cells) Discriminates self from non-self Present Ag to CD8 CTLs Inhibit NK cell killing by engagement of CD94/NKG2A receptor
34
Class I MHC/HLA structure
Four extracellular membrane bound domains | Heterodimer of two glycoproteins including an alpha chain and beta-2-microglobulin
35
Characteristics of the alpha chain of class I HLA
``` Encoded by the MHC/HLA class locus Forms three of the four globular domains (alpha1, 2 and 3) Peptide binding within cleft between alpha 1 and 2 ```
36
Characteristics of the beta2-microglobulin in class I HLA
Non-MHC/HLA encoded (chromosome 15) Forms 4th domain Associated non-covalently with the alpha 3 domain of the alpha chain Structural support
37
Describe the class I HLA peptide binding cleft
Area between the alpha 1 and 2 domains (site coded for by the polymorphism unique for each allele) Binds peptides about 8-10 aa in length Closed ends limit size Each allele of class I HLA has a different range of peptides that can bind in the groove Slightly different shape and present a different set of peptides Conformational 3D structure and charge of aa’s of this groove dictates what peptides can bind
38
Describe class I HLA synthesis and assembly
Alpha chains are translated into ER lumen as a glycoprotein with chaperone proteins holding chain structure/domains in place proper to interaction with the beta2-microglobulin
39
Newly synthesized class I alpha chains associate with peptides derived from what?
Cytosolic proteins and with one beta2-microglobulin
40
After assembly and synthesis the class I HLA peptide complex is transported where?
To the cell surface
41
Class II HLA gene
Encoded by the HLA-d region Three sets of genes with alpha and beta chains HLA-DP, DQ and DR Membrane bound glycoproteins
42
Which specific cell type is class II HLA expressed on?
Thymic epithelial cells
43
Class II HLA presents Ags to which type of cell?
CD4 T cells
44
Describe the structure of class II HLA
Composed of two proteins: alpha and beta chain Four globular domain structure (conformation similar to class I) Alpha and beta chains are strongly associated (not covalently linked) Each allele has a different range of peptides that can bind in the peptide groove
45
Describe allele expression of the alpha and beta chains of class II HLA
All alleles of the alpha and beta chain are expressed 6 alpha chains and 6 beta chains (3 from mom and 3 from dad) Any alpha chain allele may associate with any beta chain allele*
46
Describe the class II HLA binding cleft
Formed by the a1 and beta1 globular domains Coding regions for a1 and b1 domains have greatest polymorphism 3D conformation and charge of this groove dictates what peptides bind Binds peptides between 13-18 aa Open ends allow larger peptides to bind Greater range of peptides that can potentially be displayed
47
Describe class II HLA synthesis and assembly
Alpha and beta chain are translated into ER lumen as a glycoprotein with chaperone proteins holding chains in proximity to each other prior to interaction with invariant chain peptide
48
Describe HLA class I and II peptide key binding features
Antigenic peptides and HLA associated is saturatable, low affinity interaction Slow “on rate” Very slow “off rate” which allows peptide HLA complexes to persist long enough to interact with T cells
49
Only one peptide binds to a moleule of
HLA at any one time (both classes)
50
Same molecule of HLA has the capacity to bind to
Multiple peptides but not at the same time (both classes)
51
Describe peptide binding
There are pockets in the floors of the peptide binding clefts The side chains of aa on the Ag peptides fit into these pockets and anchor the peptides in the cleft The rest of the peptide contains some residues that bow upwards and are recognized by the Ag receptors on T cells
52
Describe HLA restriction
The ability of T cells to recognize Ags when associated with the individuals own HLA haplotype, providing a dual recognition system critical to T cell function T cells are restricted to a specific HLA
53
Ex of HLA restriction
``` CD4 T cells recognize class II (CD4 binds to beta2) CD8 T cells recognize class I (CD8 binds to alpha3) ```
54
The Ag processing pathways are a function of
Chemical nature of the fragment, density of protein, specific HLA and its binding site, self vs non self, and where it came from
55
Each Ag processing pathway stimulates the T cell population most effective against a
``` Specific class of Ags Intracellular pathogens and self: class I Extracellular pathogens: class II ```
56
The exogenous pathway of Ag presentation will result in the activation of which T cell?
CD4
57
The endogenous pathway of Ag presentation will result in the activation of which type of T cell?
CD8 T cell
58
Describe the class I HLA Ag presentation pathway
``` Responds to cytosolic (intracellular) Ags Damaged proteins are tagged by ubiquitin and then degraded by the proteasome (found in the cytoplasm) TAP and tapasin (bound to TAP) then transport the peptides from the cytosol to the interior of the ER Peptide is trimmed and loaded into a class I molecule to be presented (in the ER) ```
59
Class II HLA Ag presentation pathway
Exogenous proteins are ingested and degraded Alpha and beta invariant chains (Ii) are synthesized in the ER Transported through the golgi Site of peptide loading of MHC molecules occurs in late endosomes
60
Functions of class II associated invariant chains and HLA-DM in the class II HLA Ag presentation pathway
Ii occupies the peptide-binding cleft, promotes folding, assembly, trafficking and place holder Ii is degraded to CLIP by lysosomal enzymes HLA-DM acts as a peptide exchanger facilitating the removal of CLIP and the addition of peptides to class II HLA Unbound HLA molecules are not displayed
61
Describe cross presentation
DCs ingest virally infected or transformed cells and display Ags to CTLs Can also display to T helper cells (cross presentation)
62
What are the outcomes of Ag presentation?
Even in the absence of infection, protein degradation and peptide transport occur continuously MHC/HLAs carry peptides derived from normal self proteins but normally these do not provide immune responses
63
List some T cell dependent effector functions that are a result of Ag presentation
``` Macrophage activation (killing of phagocytosd microbe) - class II B cell Ab secretion (Ab binding to Ag) - class II Killing of Ag expressing target cell - class I ```
64
What is a major factor limiting the success of transplantation?
The immune response of the recipient to the donor tissue Differences in HLA expression between individuals can lead to donor tissue being recognized as non-self by the T cells of the recipient and attacked as foreign
65
Broadly describe HLA associated diseases
A large number of autoimmune diseases and susceptibility to infectious agents are associated with particular HLA alleles Most HLA associated diseases have unknown etiologies that contribute to the immunologic abnormalities
66
What is bare lymphocyte syndrome?
Caused by defects leading to a deficiency in HLA class I or II expression on cells
67
Bare lymphocyte syndrome associated with deficiency in HLA class I results in what?
Decreased CTL responses | Poor response to viruses and chronic respiratory infections
68
Describe the results of bare lymphocyte syndrome associated with a deficiency in class II HLA
Reduced Th cell count due to failed thymic selection Reduced Ag presentation to mature CD4 T cells Decreased humoral and cell mediated responses Pts have severe recurrent infections
69
Broadly describe processing defects
Multiple defects of the Ag processing machinery components in human neuroblastoma Class I Ag processing defects are seen in renal carcinoma and TAP is down regulated
70
Newly synthesized class II alpha and beta chains associate with peptides derived from
Endosomal vesicles and the class II HLA/peptide complex is then transported to the cell surface
71
Where are the polymorphic residues of class I MHC located?
Alpha 1 and 2 domains
72
Where are the polymorphic residues of class II MHC located?
Alpha 1 and beta 1 domains

SFM Exam 1 (8 decks)

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