Week 4

Question 1

Which region of an antibody binds to its antigen?

Answer 1

The variable region

Question 2

Which signaling molecules are associated with B cell receptors?

Answer 2

Ig alpha and Ig beta

Question 3

Which Ig isotypes have four constant domains on the heavy chain?

Answer 3

M and E

Question 4

Which Ig isotype exists in a pentameric form?

Answer 4

IgM

Question 5

Which Ig isotype exists in a dimeric form?

Answer 5

IgA

Question 6

Which Ig isotype can cross the placenta?

Answer 6

IgG

Question 7

Which Ig isotype is found in breast milk? Where else is it found?

Answer 7

dimeric IgA

Also found in secretions like tears, saliva, and on mucosal surfaces

Question 8

Which Ig isotype is primarily found bound to mast cells and basophils in the tissues?

Answer 8

IgE

Question 9

Describe the signaling molecules associated with T cell receptors and describe what they do.

Answer 9

4 CD3 chains
2 zeta chains with cytoplasmic ITAMs
CD4 or CD8
Lck that associates with the cytoplasmic tail of CD4 or CD8

When the TCR binds MHC + peptide, Lck phosphorylates the ITAMs on zeta –> Zap-70 –> PLC cleavage of PIP2 to DAG and IP3 –> Ca2+ release –> elevated calcineurin –> activation of transcription factors like NFAT –> upregulation of IL-2 and IL-2 receptor

Question 10

What does RAG1 and RAG2 do?

Answer 10

Involved in cutting heavy chain loci during VDJ recombination (for both antibody/BCR recombination and TCR recombination)

Question 11

Name the four ways in which antibody diversity is generated.

Answer 11

1. Germline: mix-and-match of V, D, and J from parents.
2. Combinatorial: different permutations of V, D, and J.
3. Junctional: imprecise joining of V, D, J segments (done by terminal deoxytibonucleotidyl transferase TdT).
4. Somatic hypermutation.

Question 12

What do terminal deoxytibonucleotidyl transferases (TdTs) do?

Answer 12

They randomly add nucleotides to the cut ends of genes during VDJ recombination

Question 13

Describe somatic hypermutation.

Answer 13

After antigen stimulation, there are rapid point mutations in the Ab variable region genes that result in changes in affinity for the antigen. The Abs have the highest affinity for the antigen will be stimulated to expand. Activation induced cytidine deaminase (AID) is involved for both BCRs and antibodies.

Question 14

With regards to T cell development, what happens in the thymic cortex?

What happens in the thymic medulla?

Answer 14

Positive selection (making sure the TCR binds to MHCs), and the first round of negative selection.

Second round of negative selection happens in the medulla - TCRs that bind tightly to MHC + tissue-specific peptides will be killed.

Question 15

Double negative T cells enter the thymus at the ___________ junction, then make their way to the outer edge of the cortex as they proliferate and undergo TCR gene rearrangement to become ________ _______ T cells prior to positive selection.

Answer 15

T cell progenitors enter the thymus at the corticomedullary junction, proliferate, move up to the cortex, and undergo TCR gene rearrangement to become double positive T cells prior to positive selection.

Question 16

Defects in AIRE result in which disease? Why?

Answer 16

Autoimmune polyendocrine syndrome type 1 because AIRE is the TF that allows medullary epithelial cells to express tissue-specific proteins in their MHCs during negative selection in the thymic medulla.

Question 17

Describe the clinical manifestations of DiGeorge syndrome.

Answer 17

CATCH 22 syndrome

Cardiac defects
Abnormal facies
Thymic aplasia
Cleft palate
Hypocalcemia/hypoparathyroidism

Question 18

What are the three activation signals that are required to activate a naive T cell?

Answer 18

1. TCR signal
2. Co-receptor signal
3. Cytokines

Question 19

What types of cells express MHC I?

Answer 19

All nucleated cells!

Question 20

What types of cells express MHC II?

Answer 20

Antigen-presenting cells

Question 21

What cells are antigen presenting cells?

Answer 21

Macrophages, dendritic cells, B lymphocytes!

Question 22

What is the major growth factor for naive T cells after activation? What do signals 1 and 2 do regarding this growth factor?

Answer 22

IL-2!

TCR and co-stimulator activation results in upregulation of IL-2 and IL-2 receptor (co-stimulators like CD28 are thought to enhance the stability of IL-2 mRNA), and it also puts existing IL-2 receptors into a high affinity state.

Question 23

What is the major inhibitory T cell co-stimulator? How does it work?

Answer 23

CTLA-4. It binds with higher affinity to B7 on APCs than CD28 does.

Question 24

Name two co-stimulator-ligand pairs for APCs and T cells.

Answer 24

B7 on APC – CD28 on T cell

CD40 on APC – CD40 ligand on T cell

Question 25

Name three effector T cell types. Under what general conditions are each activated?

Answer 25

TH1 cells help during intracellular infection.

TH2 cells help during infection with parasites, helminth worms, and are involved in allergic reaction.

TH17 cells help during infection with extracellular fungi and extracellular bacteria.

Question 26

Which chemokine and chemokine receptor is used for lymphocyte migration through a HEV into a lymph node?

Answer 26

CCR7 receptor on T cells binds CCL21 chemokine

Question 27

What does Bruton’s tyrosine kinase (Btk) do?

Answer 27

It is involved in B-cell receptor signaling. If it is defective, the BCR won’t transmit a proper signal during B cell development and therefore B cells will be halted from developing further.

Question 28

At which stage in B cell development does heavy chain rearrangement occur? What is the next step?

Answer 28

Pre-B cells undergo heavy chain rearrangement. Next step is to use a dummy light chain to see if the heavy chain works. If so, light chain rearrangement happens, generating an immature B cell.

Question 29

Developing thymocytes interact with _______ ________ _______ in the thymic cortex during positive selection.

Answer 29

thymic epithelial cells (TECs)

Question 30

Describe the two methods by which CD8+ cells can be activated.

Answer 30

Direct: intracellular pathogen —> DC makes IL-12 —> Th1 polarization —> IFN-gamma and IL-2 production —> IL-2 activates CD8+ cells.

Indirect: activated CD4+ cells stimulate APCs –> APCs activate CD8+ cells with cytokines and CD40-CD40L binding

Question 31

Which terminally-differentiated T cell type makes IL-4 and what does IL-4 do?

Answer 31

Made by Th2 cells in response to parasitic or helminthic infection.

1. Tells B cells to switch to IgE
2. Activates M2 macrophages
3. Stimulates peristalsis in the GI tract
4. Stimulates recruitment of eosinophils

Note that IL-13 is made by Th2 cells also, and does mostly the same stuff except promoting the switch to IgE, and it promotes mucus secretion.

Question 32

Which terminally-differentiated T cell type makes IL-5 and what does IL-5 do?

Answer 32

Made by Th2 cells in response to parasitic or helminthic infection.

IL-5 is the major eosinophil growth factor and activator and it tells B cells to make IgA

Question 33

What cells make IL-10? What does it do?

Answer 33

IL-10 is made by monocytes, Th2 cells, and Treg cells.

It is an inhibitory cytokine that…

1. Blocks NFkB —> no more TNF!
2. Downregulates expression of Th1 cytokines, MHC II, and co-stimulatory molecules on macrophages
3. Enhances B cell survival and antibody production

Question 34

Which terminally-differentiated T cell type makes IL-17 and what does IL-17 do?

Answer 34

Th17 cells make them in response to extracellular bacteria or fungi.

It tells epithelial and stromal cells to make chemokines for neutrophils like IL-8 and antimicrobial substances like defensins.

Question 35

Explain how carbohydrate antigens generate a T cell-independent antibody response.

Answer 35

The carbs circulate in the body until they get to the marginal zone of the spleen.

The long, repeating units on the carbs cross-link BCRs on marginal zone B cells and activates them –> differentiation into plasma cells that make IgG and IgM and IgA (these plasma cells will live in the red pulp in the spleen making Abs for ~months).

Note there is no T-cell directed B cell germinal center expansion, so immunity doesn’t last for more than several months

Question 36

Which receptor do effector T cells use to help them get out of secondary lymphoid organs so they can get out and fight infection?

Answer 36

Egress receptors like the sphingosine-1-phosphate receptor

Question 37

How do CD8+ T cells kill other cells?

Answer 37

By binding to infected cell (via MHC I), releasing perforin and granzyme —> pore formation, induction of apoptosis. 2nd apoptotic signal comes from Fas-FasL

Question 38

What is cross-presentation?

Answer 38

When antigen-presenting cells take up exogenous antigens and present them on MHC class I to CD8+ cells in order to activate them so they can kill infected cells.

Question 39

Should you give a PPD test to a patient with RA that you’re thinking about giving a TNF-a blocker to?

Answer 39

Yeah! You want to make sure they don’t have latent TB infection that will progress to active TB after administration of TNF-a blockers.

Question 40

What is AID?

Answer 40

Activation-induced cytidine deaminase: a protein involved in BCR/antibody class-switch recombination and somatic hypermutation

Question 41

Describe the adhesion molecules involved in low-affinity and high-affinity binding during T cell activation with an APC.

Answer 41

Low affinity binding is mediated by ICAM on the APC binding to LFA-1 on the T cell.

High affinity binding is mediated by integrins, making an immunologic synapse.