HLA and antigen processing

Question 1

HLA

Answer 1

Human leukocyte antigens

function as antigen presenting structures to t cells b/c T cells do not recognize antigens in free or soluble forms

Differences in HLA molecules expressed by an individual will influence the repertoire of antigens to which T cells can respond

Question 2

HLA gene

Answer 2

highly polymorphic (many different alleles are present in the population)

more than 150 separate alleles

Has class II, class III and class I regions

Question 3

what does class III code for?

Answer 3

cytokines and complement proteins

Question 4

HLA haplotype

Answer 4

the total set of HLA alleles present on each chromosome

encode protein antigens central for immune system to discriminate self and non-self

most humans heterozygous with two haplotypes (one from mom and dad)

Question 5

Co-dominant expression

Answer 5

both parental haplotypes expressed simultaneously (so 6 different alleles)

this generates more diversity by increasing the number of different MHC molecules that can present peptides to T cells

very important in transplant b/c want the best match between recipient and donor for both class I and class II genes

Question 6

MHC class II expressing cell types

Answer 6

Dendritic cells
macrophages
B cells

CD4 T helper cells interact with these cells

Question 7

MHC class I expressing cell types

Answer 7

All nucleated cells

CD8 CTLs can kill any virus-infected cell

Question 8

Gene regions encoding Class I HLA

Answer 8

HLA-A
HLA-B
HLA-C

Question 9

Class I HLA

Answer 9

expressed on all nucleated cells

present antigen to CD8+ cytotoxic T cells

in innate immunity –> functions as the inhibitory receptor for NK cells

Question 10

RBC’s

Answer 10

don’t have nucleus

RBCs do not express the activating ligand for NKs so not expressing the inhibitory ligand (Class I HLA) is irrelevant.

if you can’t start the process you don’t have to worry about inhibiting it

Question 11

where is greatest polymorphism in Class I HLA? what is unique about it

Answer 11

in the peptide binding groove b/w alpha 1 and alpha 2

binds peptides about 8-10 aa in length and cannot bind any bigger b/c it has closed ends

each allele of Class I HLA has a different range of peptides that can bind in the groove so when coexpressing all alleles can bind a greater number of peptides

Question 12

what is unique about the alpha 3 domain of the class I HLA

Answer 12

is not polymorphic, conserved amino acid sequences b/c this is where the TCR coreceptor CD8 binds so it has to be the same for everyone

Question 13

Beta2 microglobulin portion of the Class I HLA

Answer 13

Non HLA encoded

same for everybody!

associates non-covalently with alpha 3 domain (NOT Covalently)

Question 14

Class I HLA structure

Answer 14

alpha chain- 3 of 4 globular domains, HLA encoded

beta domain- non HLA coded

Question 15

Class II HLA

Answer 15

aka D region

Question 16

genes encoding HLA Class II

Answer 16

HLA-DP
HLA-DQ
HLA-DR

Question 17

Class II HLA

Answer 17

Primary on antigen presenting cells (macrophages, dendritic cells and B cell)

presenting antigen to CD4+ Tcell

Question 18

Structure

Answer 18

alpha and beta chains both encoded by HLA-D gene region

alpha and beta genes are strongly associated but NOT covalently linked

peptide binding groove between alpha and beta change is the site of the greatest polymorphism

Question 19

what is unique about the beta 2 region on the Class II HLA

Answer 19

this is highly conserved b/c this is where CD4 binds

Question 20

what is unique about the peptide binding groove in class II HLA

Answer 20

formed at the junction of beta 1 and alpha 1

binds peptides between 13 and 18 aa long

OPEN ENDS allow larger peptides to bind

Question 21

how many class I molecules can be expressed on cells?

Answer 21

Because there are three polymorphic class I genes, called HLA-A, HLA-B, and HLA-C in humans, and each person inherits one set of these genes from each parent, any cell can express six different class I molecules

Question 22

what is unique about the synthesis of class II HLA

Answer 22

synthesized in the ER and interact with a third protein called the invariant chain

helps keep alpha and beta together

also blocks peptide binding groove until reaches endocytic compartment

in the endocytic compartment invariant is degraded, peptide comes in from endocytosis, binds to class II

Question 23

where do peptides that present on MHC class II come from ?

Answer 23

outside world

Question 24

where do peptide that present on MHC class I come from ?

Answer 24

cytosol (inside world)

Question 25

Class II HLA features of diversity/genetic polymorphism

Answer 25

any alpha chain allele may associate with any beta chain allele, which leads to a greater range of peptides that can bind to class II HLA

Question 26

Peptide binding of peptide binding groove

Answer 26

looking for size and shape of Peptide the rest of the peptide that is not bound (the lateral surface or side of the peptide) sticks out of the cleft and this is what is recognized by antigen receptors on T cells

Question 27

how many peptides can an HLA molecule bind at a time?

Answer 27

one

Question 28

antigenic peptides and HLA association

Answer 28

slow on rate and very slow off rate saturatable and low affinity interaction

Question 29

how many peptides can an HLA bind?

Answer 29

same molecule of HLA can bind multiple epitopes but NOT at the same time

Question 30

HLA restriction

Answer 30

The ability of T cells to recognize antigens when associated with the organism's own HLA haplotype, providing a dual recognition system critical to T-cell function. CD4 --> recognize Ag bound to Class II CD8--> recognize Ag bound to Class I

Question 31

Class I HLA synthesis

Answer 31

alpha chain translated into ER as glycoprotein in the ER alpha chains interact with B2 chains class I associates with peptides derived from cytosolic (internal) proteins HLA/peptide complex transported to the cell surface

Question 32

APC's

Answer 32

Antigen presenting cells Convert proteins to peptides for display Three main types: Macrophages Dendritic Cells B cells Thymic epithelial cells can also express Class II HLA during T cell maturation

Question 33

Dendritic cells

Answer 33

most effective at presenting antigen pinocytose Ag and process it for presentation home to T cell rich areas in lymph nodes and spleen produce co-stimulatory molecules activate naive CD4 and CD8 t cells

Question 34

Macrophages

Answer 34

Pinocytose or phagocytose | very good at activating memory T cells

Question 35

B cells

Answer 35

bind soluble Ag via IgM and IgD ingest by pinocytosis bind Ag with high affinity b/c highly specific, thus effective when Ag levels are low not effective at presenting Ag to naive T cells very effective at presenting to memory T cells

Question 36

Capture of antigens

Answer 36

Microbes enter body Phagocytosed or pinocytosed by APC's lose adhesive markers and up regulate CCR7 increase expression of HLA (Both I and II) and B7

Question 37

HLA-DM

Answer 37

acts as a peptide exchanger, facilitating the removal of CLIP and addition of peptides into class II HLA

Question 38

Ii (invariant)

Answer 38

``` occupies the peptide binding cleft of HLA class II promotes folding, assembly, trafficking ``` is degraded to CLIP by lysosomal enzymes

Question 39

TAP

Answer 39

transports peptides from cytosol to interior of ER functions in the pathway of Class I MHC antigen processing

Question 40

Tapasin

Answer 40

B2 microglobulin is bonded to TAP by this tapasin protein makes sure there is a class I molecule ready to receive a peptide

Question 41

Outcomes of Antigen presentation

Answer 41

Dendritic cells--> naive T cell activation -differentiation into Effector T cells Macrophages--> effector T cell activation (cell-mediated immunity) activation of macrophages B cell--> effector T cell activation B cell activation and antibody production (humoral immunity)

Question 42

Cross presentation

Answer 42

Dendritic cells ingest virally infected cells and display Ag to CTL (via class I) and Ths (via class II)

Question 43

what two effector mechanisms are best able to eliminate microbes that are internalized from the extracellular environment?

Answer 43

T helper cells help B lymphocytes produce antibodies T helper cells help phagocytes to destroy ingested microbes these are both done with the use of cytokines!! neither of these mechanisms (which are of the class II/CD4 + pathway) are helpful in elminating viruses and other pathogesn that survive in the cytoplasm

Question 44

what is the mechanism that is most effective for eliminating cytoplasmic microbes?

Answer 44

Class I–associated peptides are recognized by CD8 + T lymphocytes, which differentiate into CTLs. The CTLs kill the infected cells and eradicate the infection, all nucleated cells can be infected with some virus so they all must have class I MHC molecules in order to kill that virus/infection

Question 45

Ankylosing spondoylitis

Answer 45

Inflammation of spine individuals (88 percent) express HLA B27 possible that HLA-B27 doesn't present a critical antigenic peptide

Question 46

Rheumatic fever

Answer 46

generation of antibodies react against streptococci as well as heart tissue pt's who have the HLA-DR4 allele

Question 47

Sjogren's syndrome

Answer 47

associated with HLA-DR3 | Defect in salivation and lacrimination

Question 48

Insulin dependent diabetes

Answer 48

associated with HLA-DQw8

Question 49

Psoriasis

Answer 49

Associated with HLA-B3

Question 50

Processing defects?

Answer 50

leads to cancers neuroblastoma renal carcinoma--> class I antigen processing

Question 51

non-responder

Answer 51

if you do not have the genetics that allow a certain peptide to be bound in the peptide binding groove....the T cells can never respond to the antigen b/c they can never see it and nothing can be done about this

Question 52

every immune response is poly-clonal why?

Answer 52

because you are seeing different parts of the antigen as it is being processed so have many different antigen peptides presented for one antigen/infection/virus