Week 6 Immuno- Diversity Plfsom Jr

Front 1

E. MHC

Back 1

Major Histocompatibility Complex (MHC) molecules: MHC molecules function in the presentation of antigens to cells of the immune system.

Front 2

F. class I MHC

Back 2

Proteins expressed in the cytoplasm (endogenous proteins) are broken up into peptides, picked up by MHC class I molecules, carried to the cell surface and displayed.

Front 3

class II MHC

Back 3

Extracellular proteins (exogenous proteins) are endocytosed, broken up into peptides, picked up by MHC class II molecules, carried to the cell surface and displayed.

Front 4

H. allele

Back 4

genes

Front 5

I. polymorphism

Back 5

This phenomenon of having multiple stable forms of a gene (referred to as alleles) in the population is known as genetic polymorphism.

Front 6

J. HLA

Back 6

Unfortunately, these different MHC molecules act as foreign antigens and cause graft rejection between genetically unmatched individuals. This is why the human MHC is often referred to as human leukocyte antigen (HLA). HLA is an older term that comes from transplantation studies in the 1930 and 1940s. Before their function in the immune system was understood, MHC molecules were recognized as antigens expressed on leukocytes that were associated with tissue graft rejection

Front 7

K. co-dominantly expressed

Back 7

each individual expresses all of the class I and class II MHC molecules that they inherit (i.e., the haplotype or set of genes they inherit from their father and the haplotype or set of genes they inherit from their mother).

Front 8

L. haplotype

Back 8

set of genes they inherit from their father and the haplotype or set of genes they inherit from their mother

Front 9

Μ. β2m

Back 9

The class I MHC molecule is expressed on the cell surface in noncovalent association with a small molecule called β2-microglobulin (β2m). β2m does not bind peptide, does not vary in sequence between individuals (it is nonpolymorphic) and is encoded on a different chromosome from the MHC genes.

Front 10

N. somatic recombination

Back 10

V(D)J recombination. This site-specific recombination reaction generates a diverse repertoire of T cell receptor (TCR) andimmunoglobulin (Ig) 

Front 11

O. RAG-1 and RAG-2

Back 11

 RAG-1 and RAG-2 are proteins (enzymes) at the ends of VDJ genes that separate, shuffle, and rejoin the VDJ genes

Front 12

P. P-nucleotides

Back 12

These additions create palindromes in the DNA; therefore, the nucleotides that are added are called palindromic (P)-nucleotides.

Front 13

Q. TdT

Back 13

Before joining occurs these DNA ends are also vulnerable to nucleotide removal by cellular exonucleases, and to further nucleotide addition by an enzyme called terminal deoxynucleotidyl transferase (TdT). Since TdT does not require a DNA template, the nucleotides that it adds are called nontemplated (N)-nucleotides.

Front 14

R. N-nucleotides

Front 15

S. combinatorial diversity, junctional diversity

Back 15

The combinatorial diversity that comes from the V, D and J gene segments, and the junctional diversity imprecise cutting and nucleotide additions/subtractions, all contribute to the variability of the antigen-binding region of antibody molecules.

Front 16

U. CDR1and CDR2

Back 16

While the V region gene sequence is the major diversification factor for CDR 1 and CDR2

Front 17

V. CDR3

Back 17

CDR3 is subject to a high degree of both combinatorial and junctional diversity.. CDR3 shows the greatest variability as it is encoded by a recombination of the VJ in the case of a light chain region and (VDJ in the case of heavy chain) regions.

Front 18

W. nonproductive rearrangement

Back 18

One consequence of somatic recombination is that frame shifts may occur creating stop codons so that the RNA transcribed from the recombined DNA cannot be translated into a functional protein. In this case the recombination is called a nonproductive rearrangement.

Front 19

X. allelic exclusion

Back 19

Since there are two copies of each chromosome, each B cell first attempts to rearrange one of copy (one allele). If that rearrangement is successful (productive), it stops. This process is called allelic exclusion and is true for both the heavy and light chain loci

Front 20

Y. idiotype

Back 20

These regulatory processes ensure that each B cell expresses antibody with only one antigenic specificity (only one idiotype).

Front 21

Z. class switch recombination

Back 21

One of the puzzles in the molecular genetics of antibody production was how different antibody classes (heavy chain isotypes, i.e. IgG1, IgA, IgM, etc.) of identical antigenic specificity (identical idiotype) could be produced. The exact mechanism of this class switch (CS) recombination is still not fully understood. In CS recombination the previously recombined IGH variable region is moved to a new location that is directly upstream of a different IGH constant region gene segment.

Front 23

Where are antigens concentrated?

Back 23

peripheral lymphoid organs (lymph nodes and spleen)

Front 24

How do antigens arrive in the lymph nodes?

Back 24

via lymph or DCs

Front 25

How do antigens arrive in the spleen?

Back 25

blood

Front 26

Where do immature DCs reside?

Back 26

epithelia and most organs

Front 27

Are immature DCs phagocytic?

Back 27

yes

Front 28

Do immature DCs express PRRs(TLRs)?

Back 28

yes

Front 29

What do DCs phagocytose?

Back 29

microbes

Front 30

How are DCs activated?

Back 30

signaling through their PRRs

Front 31

Where are chemokines recognized by CCR7 produced/

Back 31

in the paracortex

Front 32

What does CCR7 do?

Back 32

causes DCs to travel through the lymph to the lymph node paracortex and to secrete IL-12

Front 33

What do DCs do as they travel to the paracortex? What do they arrive secreting

Back 33

mature (they arrive secreting cytokines like IL12)

Front 34

What are required to activate naïve T cells?

Back 34

mature DCs

Front 35

Are Mature DCs potent antigen presenting cells?

Back 35

yes

Front 36

What activates T cells?

Back 36

DCs

Front 37

Are mature DCS required to initiate T-dependent adaptive immune responses?

Back 37

yes

Front 38

When does an adaptive immune response begin?

Back 38

when the antigen receptors of lymphocytes bind antigens

Front 39

Where do T cell antigen (TCRs) receptors bind peptides?

Back 39

in Major HistoCompatibility (MHC) molecules on antigen presenting cells

Front 40

Do TCRs make contact with both the peptide and MHC?

Back 40

Yes

Front 41

What are MHC molecules also called?

Back 41

human leukocyte antigens (HLAs)

Front 42

Where are MHC molecules ecpressed?

Back 42

on cell surface

Front 43

What is the function of an MHC molecule?

Back 43

to present peptides from antigens to T cells

Front 44

What is the structure of MHC 1?

Back 44

Peptide-binding cleft formed by single chain (alpha). Invariant molecule, b2M, completes structure. Binds small peptides (8-11 amino acids long)

Front 45

What is the structure of MHC 2?

Back 45

Peptide-binding cleft formed by two chains (alpha and beta). Binds larger peptides (10-30 amino acids long)

Front 46

What are CDs

Back 46

Cluster of Differentiation (really means nothing)

Front 47

What is the MHC 1/peptide complex bound by?

Back 47

CD8+ cytotoxic T cells

Front 48

Where does CD8+ bind to MHC 1?

Back 48

on the a3 domain

Front 49

What does MHC2/peptide complex bind?

Back 49

CD4+ helper T cells

Front 50

Where does CD4 bind?

Back 50

B2 domain

Front 51

Each MHC molecule binds :(3)

Back 51

only peptides from antigens (not whole antigens), many different peptides, only one peptide at a time

Front 52

Peptides bound to MHC: (3)

Back 52

are acquired during assembly, stabilize MHC moleculre for transport to cell surface, have slow off rate at the surface

Front 53

MHC 1 =

Back 53

HLA-A, B and C

Front 54

MHC 2 =

Back 54

HLA-D (DR, DP, and DQ)

Front 55

Where are MHC 1 and MHC 2 molecules encoded?

Back 55

close together on human chromosome 6 (inherited as a unit)

Front 56

How are MHC molecules expressed?

Back 56

codominantly (both haplotypes are expressed)

Front 57

Are MHC genes polymorphic?

Back 57

Very

Front 58

Macrophages and MHCs

Back 58

Macrophages in tissues phagocytose microbes and display peptides from these antigens on MHC II to CD4+ effector or memory (not naïve) helper T (TH) cells

Front 59

Are viruses intracellular or extracellular antigens?

Back 59

intracellular

Front 60

B cells and MHCs

Back 60

B cells take up antigens by receptor-mediated endocytosis and display peptides from these antigens on MHC II to CD4+ effector or memory helper T (TH) cells in peripheral lymphoid tissues (i.e. lymph nodes)

Front 61

Any nucleated cell and MHCs

Back 61

Any nucleated cell can present peptides derived from intracellular antigens (i.e. viruses) on MHC I to CD8+ effector or memory cytotoxic T cells (CTLs)

Front 62

What cells express MHC2?

Back 62

DCs, macrophages, and B cells

Front 63

Can other cells be induced to express MHC 2?

Back 63

yes

Front 64

Where is MHC 1 expressed?

Back 64

on all nucleated cells and platelets

Front 65

Where are peptides from extracellular microbes presented?

Back 65

on MHC II to CD4+ helper T (TH) cells

Front 66

Where are peptides from intracellular microbes presented?

Back 66

on MHC I to CD8+ cytotoxic T cells (CTLs)

Front 67

Describe the MHC 2 pathway

Back 67

During MHC II molecule synthesis, CLass II Invariant chain Peptide (CLIP) binds/blocks peptide binding cleft until MHCIIs arrive in vesicles containing peptides from extracellular microbes. —Lysosomal enzymes (called cathepsins) break down incoming microbes into peptides. HLA-DM* removes CLIP so these exogenously derived peptides can load onto MHCIIs

Front 68

Describe the MHC 1 pathway

Back 68

Proteins from intracellular microbes (i.e. virus), produced in cytosol, are degraded by proteosome into peptides. Transporter associated with Antigen Processing (TAP) injects peptides into endoplasmic reticulum (ER). Aminopeptidases trim peptides to correct size. Peptides are loaded onto MHCIs as they are synthesized

Front 69

Describe pathway differences

Front 70

Presentation of MHC2 results in

Back 70

antigen-specific helper CD4+ T (TH) cells which produce cytokines that activate macrophages and stimulate B cells to produce antibodies. (extracellular microbes like Group A Strep)

Front 71

Presentation by MHC1 results in

Back 71

antigen-specific CD8+ cytotoxic T cells (CTLs) which can directly kill infected cells. (intracellular microbes like Rhinovirus)

Front 72

Cross presentation by DCs

Front 73

How are DCs special in relation to antigen presentation?

Back 73

do not have to be virally infected to present viral peptides on MHC I

Front 74

Are both CD4 and CD8 T cells activated or "primed" by DCs

Back 74

Yes

Front 75

What kind of response to viruses are produced by DCs?

Back 75

Both antibody and CTL(cytotoxic lymphocyte)

Front 76

Pro-avtivation of NK cells

Back 76

molecules on stressed cells bind NK cell activating receptors

Front 77

Anti-activation of NK cells

Back 77

MHC1 molecules on target cells bind to Killer Inhibotory Receptors (KIRs) (to protect host cells)

Front 78

How is NK cell activation balanced?

Back 78

?????????? Stress signals are expressed on virally infected cells. The virus decreases MHC 1 expression. The NK cell can detect the decrease in MHC1 and the increase in stress molecules on the cell surface.

Front 79

What does the inhibitory receptor on NK cells recognize?

Back 79

MHC1

Front 80

Back 80

Front 81

Back 81

Front 82

Back 82

Front 83

Back 83

.