2) Antigen Recep. & Gen. of Div., B Cell Dev., B Cell Activation, Antigen Presentation, NFkB pathways

Question 1

Antigen receptors: TCR contains two transmembrane chains (X) and associates with the (Y) complex

Answer 1

X = Alpha-Beta or Gamma-Delta
Y = CD3

Question 2

Antigen receptors: BCR is a membrane bound form of (X) and associates with the (Y) heterodimer

Answer 2

X = Ig
Y = IgAlpha and IgBeta

Question 3

What does ITAM stand for?

Answer 3

Immunoreceptor Tyrosine based Activation Motifs

Question 4

The BCR and TCR do not directly signal via cytoplasmic signaling molecules. The BCR and TCR complexes include accessory proteins that have cytoplasmic tails containing (X), which are able to initiate cytoplasmic signaling cascades

Answer 4

X = ITAMs

Question 5

TCR Accessory Proteins:
CD3 complex: (X). Each has an (Y) in its tail. The 2 (Z) chains have no significant extracellular domains and form a homodimer. The (A) chains form two heterodimers

Answer 5

X =  δ, (2) ε, (2) ζ, and γ
Y = ITAM
Z = ζ
A = δ, γ and (2) ε

Question 6

What are the 2 BCR Accessory Proteins?

Answer 6

Igα and Igβ

Question 7

What is the ITAM Consensus sequence?

Answer 7

YxxL/Ix(6-8)YxxL/I

Question 8

ITAM signaling. Major signaling pathway is initiated by (X) phosphorylation by (Y)

Answer 8

X = Tyr
Y = Src family kinases

Question 9

B cell Development: Takes place in the ______

Answer 9

Bone Marrow

Question 10

B Cell Development Pathway: 7 cell types in order

Answer 10

HSC
Early Pro B cell
Late Pro B cell
Large Pre-B
Small Pre-B
Immature B cell
Naïve Mature B cell (Follicular B cell)

Question 11

B cell development: Hematopoietic Stem Cell (HSC). What is it?

Answer 11

Multipotent with no surface Ig

Question 12

B cell development: Hematopoietic Stem Cell (HSC). What is the next step?

Answer 12

Common lymphoid progenitor

Question 13

B cell development: Hematopoietic Stem Cell (HSC). If (X) is present (drives proliferation, but is not absolutely required for B cell development in humans- replaced by other factors) (Y) are expressed, turn on (Z) and cell becomes committed to the B cell lineage

Answer 13

X = IL-7
Y = EBF and E2A
Z =  PAX-5

Question 14

B cell development: Hematopoietic Stem Cell (HSC). E2A and EBF induce PAX5 and also what 6 molecules?

Answer 14

RAG1/2. TdT, λ5, VpreB, Igα and Igβ

Question 15

B Cell Development: Early Pro B cell. What is it?

Answer 15

A cell derived from a common lymphoid progenitor committed to the B cell lineage

Question 16

B Cell Development: Early Pro B cell. What is its definable hallmark?

Answer 16

D(H) to J(H) rearrangement

Question 17

B Cell Development: Late Pro B cell. Just a pro-B cell which is attempting (X) rearrangement. If it goes out of frame it dies. If (X) rearrangement is successful it is no longer a pro-B cell

Answer 17

X = V(H)-DJ(H)

Question 18

B Cell Development: Large Pre-B cell. (X) productively rearranged, (Y) expressed at surface with (Z) heavy chain and (A) light chains (B) and in association with (C). This halts IgHC rearrangement (due to allelic exclusion) and leads to (D)

Answer 18

X = VDJ(H)
Y = pre-BCR
Z = μ
A = surrogate
B = VpreB and λ5
C = Igα and Igβ
D = proliferation

Question 19

B Cell Development: Small Pre-B cell. VDJ(H) rearranged, (X) rearranging. Kappa is ALWAYS rearranged (Y)

Answer 19

X = V(k)->J(k)
Y = first

Question 20

B Cell Development: Immature B cell. VDJ(H) and VJ(L) rearranged. (X) expressed at the surface

Answer 20

X = IgM

Question 21

B Cell Development: Immature B cell. Selection for self-tolerance is next. What happens if BCR recognizes self-peptides too strongly?
If the cell sees self antigen strongly, receptor editing occurs at (X). The cell then re-expresses (Y) genes and undergoes further κ
rearrangement. If it fails on κ it then tries (Z) (there are four possible alleles, 2κ and 2 (Z), for test of whether the (X) is in-frame and no longer self-reactve: If all the possible rearrangements are self-reactive, the cell dies. (A) is a back up mechanism of central tolerance.
(B) signaling keeps B cells alive

Answer 21

X = IgLC
Y = RAG
Z = λ
A = Clonal deletion
B = Tonic

Question 22

B Cell Development: Naïve Mature B cell (Follicular B cell). (X)+ and circulating in the periphery, looking for antigen. Kept alive
by (Y)

Answer 22

X = IgM+ IgD+
Y = tonic signaling and BAFF

Question 23

What are the 5 functions of the Pre-BCR?

Answer 23

1. Survival
2. proliferation
3. shutting off H-chain rearrangement (allelic
   exclusion)
4. shutting off of surrogate light chain transcription
5. opening kappa locus

Question 24

An X-linked gene downstream of pre-BCR is (X), a tyrosine kinase. Absence of (X) results in failure of pro-B to pre-B transition, and failure to make B cells, therefore no antibodies. (Y) is the disease

Answer 24

X = Btk
Y = X-linked
agammaglobulinemia

Question 25

B cell activation: Stimulation by T cell DEPENDENT antigens i. The BCR signal is transduced via (X) ITAMs ii. (Y) (lyn, fyn, blk) phosphorylate the ITAMs iii. (Z) bind to the phosphorylated ITAMs and subsequently get phosphorylated themselves iv. A number of cascades are initiated, they can include (A) giving signaling for development, proliferation, etc. v. After initial stimulation by T cell dependent antigen (with (B) interaction)

Answer 25

``` X = Igα and Igβ Y = Src family kinases Z = Syk family kinases (syk) A = NFκB, NFAT and AP-1 B = CD40L-CD40 ```

Question 26

Is isotype switching (B cell activation), what is the fundamental or original Ab type?

Answer 26

IgM

Question 27

Isotype switching: Only the (X) region changes. Requires signals via (Y)

Answer 27

``` X = Fc (constant) "tail" Y = CD40 ```

Question 28

Isotype switching: Cytokine environment determines outcome: IL4 gives (X), TGF-β gives (Y)

Answer 28

``` X = IgE Y = IgA ```

Question 29

Isotype switching: Mechanism: There are switch regions and (X) upstream of each constant region, and when a particular isotype is selected (based on cytokine environment, etc) there is transcription from the (X) through the selected constant region and then (Y) leads to incorporation of the new constant region.

Answer 29

``` X = I exons Y = splicing ```

Question 30

B cell activation Step 2: Proliferation in the (X) and (Y) with eventual development of a B cell memory population 1. (Y) occurs in dark zones of (X) in the (Z, organs) 2. The mutations begin (A) of the rearranged V region and end (B) of that region 3. This generates a set of B cells with diverse affinities for the instigating antigen—those with the highest affinity are selected on (C, cell type) to survive and proliferate (the others die)

Answer 30

``` X = germinal center Y = somatic hypermutation Z = lymph nodes/spleen A = 5’ B = 3’ C = follicular dendritic cells (FDCs) ```

Question 31

Somatic Hypermutation only changes the (X) regions, not the (Y) region

Answer 31

``` X = variable Y = Fc ```

Question 32

B cell activation Step 3: From plasma cells: secreted antibody due to selection of alternate (X) site which eliminates the (Y)

Answer 32

``` X = poly-A Y = transmembrane exons ```

Question 33

B cell activation: What does AID stand for?

Answer 33

activation induced cytidine deaminase (DNA deaminase)

Question 34

B cell activation: What is the role of AID?

Answer 34

Required for class-switching and somatic hypermutation

Question 35

B cell activation: Stimulation by T cell INDEPENDENT antigens: carbohydrates with repeating patterns—signaling is almost identical. 1. No isotype switching, somatic hypermutation or memory response (so always (X)!) 2. (Y) antigen binds BCR and crosslinks the BCR 3. Co-receptor complex (Z) (A): Complement fragment (B) bound antigen binds to both the BCR and the nearby (A) (complement receptor), thus clustering it with the BCR

Answer 35

``` X = IgM Y = Multivalent Z = (CD19/CD21/ less so CD81, unclear role) A = CR2/CD21 B = C3d ```

Question 36

Antigen Presentation: What are the human and mouse versions of Class I MHC?

Answer 36

``` human = HLA-A, B, C mouse = H2-K, D, L ```

Question 37

What is a Class I MHC complex made of?

Answer 37

α chain (transmembrane) and β-2 microglobulin (β2m, non-transmembrane) chain

Question 38

Class I MHC is expressed on (X) cell types, presents (mostly) (Y) protein, and is recognized by (Z) cells

Answer 38

``` X = all nucleated Y = cytosolic Z = CD8+ T ```

Question 39

Antigen Presentation: What are the human and mouse versions of Class II MHC?

Answer 39

``` human = HLA-DR, DP and DQ mouse = I-A, I-E ```

Question 40

What is a Class II MHC complex made of?

Answer 40

α chain and β chain (both transmembrane)

Question 41

Class II MHC presents mostly (X) antigens and is recognized by (Y) cells

Answer 41

``` X = exogenous Y = CD4+ T ```

Question 42

Class I MHC Antigen Processing: i. α and β2m synthesized in (X), associate with (Y) ii. α and β2m associate with each other and (Z) iii. In the cytosol, proteins to be degraded are (A) iv. The proteasome is augmented with three new β subunits in the context of inflammation by IFN γ, (B). This new proteasome creates peptides MHC I presentation ending with the appropriate type of C-termini (mainly (C)) that can be recognized by (Z) v. (Z) transports peptides from the cytosol to the (X) vi. The peptides then associate with MHC I in the (X), increasing the stability of the MHC I complex, which is then transported to the cell surface

Answer 42

``` X = ER Y = chaperones Z = TAP A = ubiquitinated B = iβ1, iβ2 and iβ5 C = aromatic amino acids ```

Question 43

Class II MHC Antigen Processing. i. (X) are synthesized in the ER and associate with each other and an (Y) which prevents proteins from binding to the MHC-II complex ii. The complex moves out of the ER to the Golgi and is targeted by the (Y) tail into acidic (Z) iii. Proteases in the (Z) digest away most of the (Y), leaving only the “(A)” fragment in the peptide cleft of the MHC II iv. (A) is then dislodged by (B) and antigen peptides can bind to the MHC II complex v. MHC II complexes are then transported to the cell surface

Answer 43

``` X = α and β chains Y = invariant chain (Ii) trimer Z = late endosomes/lysosomes A = CLIP B = HLA-DM ```

Question 44

NFkB Signaling: 1) (X) (Receptors) signal to/release... 2) (Y) which interacts with... 3) (Z) (α,β,γ subunit —γ subunit = NEMO) 4) (Z) then degrades (A) releasing NFkB to the nucleus, inducing transcription of inflammatory genes

Answer 44

``` X = CD40, IL6-R, TNF-R, TLR Y = TRAF Z = IκB kinase A = IκB ```

Question 45

TRAFs are (X) ligases that (Y) a target which leads to (Z) of a kinase upstream of Ikk (and DOES NOT drive proteosome mediated destruction unlike other instances of ubiquitination)

Answer 45

``` X = E3 Ubiquitin Y = polyubiquitinate Z = activation ```