HLA and Antigen Processing

Question 1

histocompatability

Answer 1

first discovered in skin graft transplantation

-genes involved in acceptance or rejection

Question 2

HLA

Answer 2

human leukocyte antigens

-same as MHC (which is in mouse)

Question 3

what do T cells recognize?

Answer 3

need to be presented as a peptide

-by HLA

Question 4

HLA genes

Answer 4

tightly linked and highly polymorphic

Question 5

Class III genes of HLA?

Answer 5

code for complement proteins and cytokines

Question 6

what chromosome are HLA genes on?

Answer 6

chromosome 6 (short arm)

Question 7

HLA haplotype

Answer 7

total set of all HLA alleles on both chromosomes
-have one from mom and dad

-expressed co-dominance - more diversity

important in transplantation (want a match)

Question 8

what does the HLA haplotype allow?

Answer 8

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

Question 9

Class I HLA

Answer 9

three separate regions (membrane bound glycoproteins)
HLA-A,
HLA-B,
HLA-C

present antigen to CD8+ T cells***
expressed on all nucleated cells
-not on RBCs

also inhibitory receptors for NK cells***

Question 10

why don’t NK cells kill your RBCs?

Answer 10

???

Question 11

structure of HLA Class I

Answer 11

heterodimer of two proteins

alpha chain encoded by HLA class locus

• alpha 1, 2, and 3
• 3 of the 4 globular domains

beta-2 microglobulin is not HLA encoded
-associates non-covalently with alpha 3 domain of alpha chain

Question 12

peptide binding groove of class I?

Answer 12

area between alpha 1 and alpha 2

• binds peptides 8-10 amino acids
• bc it has closed ends

conformation of groove dictates what can bind

each allele has a different range of peptides it can bind

Question 13

what site of Class I HLA has the greatest polymorphisms?

Answer 13

alpha 1 and 2 domains (peptide binding groove)

Question 14

synthesis of Class I HLA alpha chain?

Answer 14

translated into the ER as glycoprotein

interacts with beta-2 microglobulin in the ER and associates with peptides from cytosolic proteins

Class I HLA/peptide complex transported to cell surface

Question 15

how many different HLAs in an individual?

Answer 15

6 different HLAs

all have slightly different shape and present a different set of peptides

Question 16

Class II HLA genes

Answer 16

encoded by the HLA-D region
-HLA-DP, DQ, DR

membrane bound glycoproteins

present to CD 4+ T cells
-primarily on macrophages, dendritic cells, and B cells

Question 17

Class II HLA structure?

Answer 17

two proteins
-alpha and beta chain

both encoded in the HLA-D region

four globular domain structure

alpha and beta are not covalently linked

Question 18

location of the binding groove in Class II HLA

Answer 18

alpha 1 and beta 2 domains
-binds 13-18 amino acids (has open ends)

beta 2 is highly conserved (where CD4 binds)

Question 19

range of different Class II HLA?

Answer 19

6-8 possible

Question 20

synthesis of HLA class II

Answer 20

alpha and beta are synthesized in the ER
-invariant chain binds to the alpha and beta chain binds to block the groove

in endocytic compartment - invariant chain degrade
-free peptides then bind in groove

**class II bind peptides that have entered cell via endocytosis (from outside of the cell)

then transported to the cell surfaces

Question 21

alpha and beta chain interactions?

Answer 21

any alpha can associate with any beta chain
-adds to the diversity of peptide binding groove

**greater range of peptides that can bind to class II HLA

Question 22

peptide binding to Class II HLA?

Answer 22

pockets in floor of groove that bind side chains of amino acids on antigen peptide

-rest of peptide bows upward
this is what is recognized by T cells

Question 23

-rates of HLA and antigen association?

Answer 23

slow on rate and very slow off rate

-allows peptide-HLA complex to persist for a long time

Question 24

how many peptides can bind HLA cleft?

Answer 24

only one at a time

Question 25

how many peptides can single HLA cleft bind?

Answer 25

many (but only bind one at a time)

Question 26

H-Y HLA

Answer 26

antigen encoded on Y chromosome | -associated with acute rejection of male grafts in female recipients

Question 27

HLA restriction

Answer 27

ability of T cells to recognize antigen when associated with own HLA -dual recognition critical to T cell funcion leads to CD4 only binding Class II and CD8 only binding Class I

Question 28

APC

Answer 28

antigen-processing cells | -convert proteins to peptides for presentation

Question 29

three types of APCs?

Answer 29

macrophages, dendritic cells, and B cells **other cells can express class II HLA and can act as APCs in some cases (thymic epithelial cells)

Question 30

most efficient APC?

Answer 30

dendritic cells

Question 31

activity of dendritic cell?

Answer 31

pinocytose antigen and process it for presentation -draw in their dendrites and home to the T cell rich areas in nodes and spleen activate naive CD4+ and CD8+ T cells

Question 32

macrophage activity?

Answer 32

phagocytose or pinocytose antigen not as effective as dendritic cells **activate memory T cells (not naive as well)

Question 33

B cell activity?

Answer 33

bind soluble antigen via surface Ig -ingest by pinocytosis bind antigen with high affinity thus effective when antigen low levels **very effective at presenting to memory T cells

Question 34

antigen capture

Answer 34

microbes enter body and are phagocytosed or pinocytosed by APCs lose adhesive markers and upregulate CCR7 and increase HLA and B7 expresion

Question 35

what do lymph node and spleen filter?

Answer 35

lymph node - antigens from periphery | spleen - antigens in blood

Question 36

two procesing pathways of the APC?

Answer 36

``` intracellular - class I extracellular - class II ```

Question 37

Class II HLA pathway

Answer 37

exogenous protein ingested and degraded alpha and beta and invariant chain in ER -transported through golgi in late endosome - peptide loaded to the HLA class II

Question 38

fate of the invariant chain?

Answer 38

degraded and leaves CLIP protein behind - HLA-DM acts as peptide exchanger - removes CLIP and adds peptide to groove unbound HLA are not displayed

Question 39

CLIP

Answer 39

fragment left over after the invariant chain is degraded in the Class II binding groove

Question 40

Class I HLA Pathway

Answer 40

for cytosolic antigens -proteasome - degrades proteins protein transported to the ER (via TAP - uses ATP) - ER forms Class I alpha chain - beta-2 microglobulin associated with TAP via tapasin in the ER - alpha chain associates with beta-2

Question 41

TAP

Answer 41

transports cytosolic antigen peptides to the ER to form the class I HLA

Question 42

tapasin

Answer 42

binds the beta-2 microglobulin to TAP while HLA class I is forming

Question 43

outcome of dendritic cell antigen presentation?

Answer 43

naive T cell activation

Question 44

outcome of macrophage antigen presentation?

Answer 44

effector (memory) T cell activation -class II -activation of macrophage (cell-mediated)

Question 45

outcome of B cell antigen presentation?

Answer 45

effector (memory) T cell activation -class II -antibody production of B cells (humoral)

Question 46

cross-presentation

Answer 46

dendritic cells can ingest virally infected cells and display antigen class I and class II

Question 47

what is the major factor limiting transplantation?

Answer 47

HLA

Question 48

large number of autoimmune disease due to what?

Answer 48

HLA mutations

Question 49

ankylosing spondylitis

Answer 49

inflammation of spine over 88% express HLA-B27 allele -each allele has a limited number of peptides it can present possible HLA-B27 doesn't present critical peptide

Question 50

rheumatic fever

Answer 50

can lead to antibodies agains cardiac tissue HLA-DR4 allele involved

Question 51

Sjogrens syndrome

Answer 51

associated with HLA-DR3 | -defects in salvation and lacrimation

Question 52

Insulin-dependent diabetes mellitus

Answer 52

associated with HLA-DQw8

Question 53

psoriasis

Answer 53

associated with HLA-B3

Question 54

every immune response is polyclonal

Answer 54

see different part of antigen every time you respond to it ex/ hepatitis -display different pieces of the virus immune response is not one and done**