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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
Q

The total set of MHC/HLA alleles are present on each

A

Chromosome

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26
Q

What is a haplotype?

A

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

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27
Q

Most humans are heterozygous and have two

A

MHC/HLA haplotypes (one from mon and one from dad)

Both haplotypes expressed simultaneously (co-dominate expression)

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28
Q

Each allotype of HLA genes confers the ability to

A

Bind different peptides for T cells to respond to

Individuals have a nearly unique set of HLA molecules

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29
Q

How do HLA polymorphisms impact individual immune responses and disease susceptibility?

A

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
Q

Class I HLA characteristics

A

More diverse allotypes
Can typically bind 2000-10,000 different peptides per cell
Important for discrimination of self/non-self

31
Q

Class II HLA characteristics

A

Professional APCs
Specific to outside threats
Displays greater variability in peptides presented

32
Q

Class I genes are encoded by three separated gene regions in the HLA locus including

A

HLA-A, HLA-B and HLA-C

33
Q

Class I genes

A

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
Q

Class I MHC/HLA structure

A

Four extracellular membrane bound domains

Heterodimer of two glycoproteins including an alpha chain and beta-2-microglobulin

35
Q

Characteristics of the alpha chain of class I HLA

A 
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
Q

Characteristics of the beta2-microglobulin in class I HLA

A

Non-MHC/HLA encoded (chromosome 15)
Forms 4th domain
Associated non-covalently with the alpha 3 domain of the alpha chain
Structural support

37
Q

Describe the class I HLA peptide binding cleft

A

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
Q

Describe class I HLA synthesis and assembly

A

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
Q

Newly synthesized class I alpha chains associate with peptides derived from what?

A

Cytosolic proteins and with one beta2-microglobulin

40
Q

After assembly and synthesis the class I HLA peptide complex is transported where?

A

To the cell surface

41
Q

Class II HLA gene

A

Encoded by the HLA-d region
Three sets of genes with alpha and beta chains
HLA-DP, DQ and DR
Membrane bound glycoproteins

42
Q

Which specific cell type is class II HLA expressed on?

A

Thymic epithelial cells

43
Q

Class II HLA presents Ags to which type of cell?

A

CD4 T cells

44
Q

Describe the structure of class II HLA

A

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
Q

Describe allele expression of the alpha and beta chains of class II HLA

A

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
Q

Describe the class II HLA binding cleft

A

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
Q

Describe class II HLA synthesis and assembly

A

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
Q

Describe HLA class I and II peptide key binding features

A

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
Q

Only one peptide binds to a moleule of

A

HLA at any one time (both classes)

50
Q

Same molecule of HLA has the capacity to bind to

A

Multiple peptides but not at the same time (both classes)

51
Q

Describe peptide binding

A

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
Q

Describe HLA restriction

A

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
Q

Ex of HLA restriction

A 
CD4 T cells recognize class II (CD4 binds to beta2)
CD8 T cells recognize class I (CD8 binds to alpha3)
54
Q

The Ag processing pathways are a function of

A

Chemical nature of the fragment, density of protein, specific HLA and its binding site, self vs non self, and where it came from

55
Q

Each Ag processing pathway stimulates the T cell population most effective against a

A 
Specific class of Ags 
Intracellular pathogens and self: class I 
Extracellular pathogens: class II
56
Q

The exogenous pathway of Ag presentation will result in the activation of which T cell?

A

CD4

57
Q

The endogenous pathway of Ag presentation will result in the activation of which type of T cell?

A

CD8 T cell

58
Q

Describe the class I HLA Ag presentation pathway

A 
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
Q

Class II HLA Ag presentation pathway

A

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
Q

Functions of class II associated invariant chains and HLA-DM in the class II HLA Ag presentation pathway

A

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
Q

Describe cross presentation

A

DCs ingest virally infected or transformed cells and display Ags to CTLs
Can also display to T helper cells (cross presentation)

62
Q

What are the outcomes of Ag presentation?

A

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
Q

List some T cell dependent effector functions that are a result of Ag presentation

A 
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
Q

What is a major factor limiting the success of transplantation?

A

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
Q

Broadly describe HLA associated diseases

A

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
Q

What is bare lymphocyte syndrome?

A

Caused by defects leading to a deficiency in HLA class I or II expression on cells

67
Q

Bare lymphocyte syndrome associated with deficiency in HLA class I results in what?

A

Decreased CTL responses

Poor response to viruses and chronic respiratory infections

68
Q

Describe the results of bare lymphocyte syndrome associated with a deficiency in class II HLA

A

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
Q

Broadly describe processing defects

A

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
Q

Newly synthesized class II alpha and beta chains associate with peptides derived from

A

Endosomal vesicles and the class II HLA/peptide complex is then transported to the cell surface

71
Q

Where are the polymorphic residues of class I MHC located?

A

Alpha 1 and 2 domains

72
Q

Where are the polymorphic residues of class II MHC located?

A

Alpha 1 and beta 1 domains

SFM Exam 1 (8 decks)

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