Ch. 10

Question 1

What is the first, second, & third site of hematopoiesis in a developing embryo/fetus?

Answer 1

Yolk sac, then the AGM, then placenta and fetal liver, and finally the bone marrow

Question 2

What is the predominant subtype of B cells made in a developing embryo/fetus?

Answer 2

• B cells generated from the fetal liver are predominantly B-1 cells

Question 3

How do the B-1 cells differ from the predominant subtype made in adult bone marrow?

Answer 3

o Look similar, but have different receptors
o Abs from B-1 cells are cross-reactive and bind to carbohydrate antigens found on many pathogenic species
 Minimal receptor diversity
o Primarily located in body cavities (protect the gut and lungs)
o Self-renewing, even outside of bone marrow

Question 4

By the age of 18, where are the major sites of hematopoiesis?

Answer 4

By 18, the major sites of hematopoiesis are in the tibia, femur, pelvis, ribs, and sternum

Question 5

How does the hematopoiesis ability change over time as we age?

Answer 5

The ability to make B cells declines with age due to…

1. Stromal cells less effective in secreting cytokines
2. B-cell progenitors less able to respond to cytokines
3. Stem cells start to lose self-renewal ability
4. Rag1/2 and surrogate light-chain λ5 expression goes down
5. A lifetime of B-cell activations diminishes room in follicles

Question 6

What are the three goals of B-cell development?

Answer 6

1. Generate a diverse antigen receptor
2. Alter or eliminate self-reactive B-cells/B-cell receptors
3. Promote foreign reactive B cells to become mature B cells in the secondary lymphoid tissues

Question 7

What factors are produced by bone marrow stromal cells that facilitate B-cell development?

Answer 7

1. Make contact with cells through cell-adhesion molecules (CAMs), VLA-4/VCAM
2. Produce growth factors for the attached CLP
   a. IL-7, stem cell factor (SCF) c-KIT

Question 8

What is the 1st checkpoint of B-cell development?

Answer 8

Large pre-B cell is an important stage, where the heavy chain is expressed with surrogate light chain as a pre-B-cell receptor
• Successful signaling= proliferation
o Why is this a good thing?
 Trying to maximize success; it is hard to make heavy chain recombination work, most will die.

Question 9

What is the 2nd checkpoint of B-cell development?

Answer 9

Loci failures result in additional loci being attempted
•	Light chain gene rearrangement
o	Rearrange k on 1st chromosome
o	Rearrange k on 2nd chromosome
o	Rearrange λ on 1st chromosome
o	Rearrange on λ 2nd chromosome
•	If fail, apoptosis.

Question 10

What three possible outcomes occur when B cells are autoreactive?

Answer 10

1. Autoreactive B cells may undergo receptor editing
   a. Reactivation of recombination machinery
2. Clonal deletion of strongly autoreactive cells
   a. Through apoptosis
   b. Termed central tolerance (bone marrow) or peripheral tolerance (spleen)
   c. 55-75% of immature autoreactive B cells lost this way
3. Anergy- autoreactive T1 B cells that leave bone marrow can become anergic
   a. Bind to antigen without costimulatory signals  induction of nonresponsiveness to further stimuli (even self-antigen stimuli)

Question 11

What results when central tolerance & peripheral tolerance mechanisms fail?

Answer 11

When tolerance mechanisms fail, autoreactive B cells can cause autoimmune diseases

Question 12

The upregulation of BAFF & Bcl-XL are hallmarks of T2 cells as they mature into B-2 cells. What do these proteins do in cells?

Answer 12

• No longer die in response to these stimuli due to increase in anti-apoptotic molecule Bcl-XL
• Unknown molecule delivers a stimulatory signal that positively selects T2 cells to increase BAFF receptor (B-cell survival/activating factor)

Question 13

Where in the spleen are T1 B cells located?

Answer 13

periarteriolar lymphoid sheath (PALs)

Question 14

Where are T2 B cells located?

Answer 14

follicles of spleen

Question 15

Where would you find mature B-2 cells in SLOs?

Answer 15

secondary lymphoid follicles (follicular B cells)

Question 16

Where would you find the largest populations of B-2 cells?

Answer 16

secondary lymphoid organs

Question 17

Where would you find the largest populations of B-1 cells?

Answer 17

peritoneal and pleural cavities

Question 18

Where would you find the largest populations of MZ B cells?

Answer 18

marginal zones of spleen

Question 19

Where is the source of new B cells in adults for B-1 cells?

Answer 19

self-renewing (division of existing B-1 cells)

Question 19

Where is the source of new B cells in adults for B-2 cells?

Answer 19

HSC in bone marrow

Question 20

Where is the source of new B cells in adults for MZ B cells?

Answer 20

from HSCs in bone marrow, long lived

Question 21

Which B cell subset has high mIgD expression

Answer 21

B-2 B cells

Question 22

Which B cell subset(s) have high mIgM expression?

Answer 22

B-1 B cells and MZ B cells

Question 23

What is the main difference between B-1a and B-1b cells?

Answer 23

B-1a cells develop in the fetal liver whereas B-1b cells develop in adults

Question 24

Where do B-1a and B-1b B cells reside?

Answer 24

populate different anatomic niches than B-2 cells; 30-50% in pleural and peritoneal cavities in mice; 2% of splenic B-cell population

Question 25

Which B cell subset(s) primarilysecrete IgM in response to stimulation?

Answer 25

B-1 B cells and MZ B cells

Question 26

Which B cell subset(s) primarily secrete IgG in response to stimulation?

Answer 26

B-2 B cells

Question 27

Which B cell subset is likely the first to respond to a blood-borne bacterial infection?

Answer 27

MZ Bcells because they primarily make IgMantibody to blood borne antigens and can also activate without T cell help

Question 28

Which B cell subset is likely the first to respond to a bacterial infection in your peritoneum?

Answer 28

B-1 B cells because they reside within peritoneal and pleural cavities

Question 29

What are ways in which B- and T-cell development is different?

Answer 29

• Location of maturation and screening
o T cells= first stages in bone marrow, but then travel to mature in thymus
o B cells=most in bone marrow, but then mature in spleen
• Screening processes used
o T cells= positive and negative selection
o B cells= negative selection
• Specific arrangements and identities of gene segments recombined together
o T cells= heavy chain, kappa and lambda light chains
o B cells= delta and gamma
• T cells require presentation and differentiate into helper or killer subsets
• Only some B cells require T-cell help and all secrete antibodies
o Only B-2 requires T-cell help

Question 30

What are ways in which B- and T-cell development is similar?

Answer 30

• Share early phases of their developmental program (HSC to CLP)
• Rearrangement of gene loci for receptors
• Screening processes to avoid self-reactivity
o Ex. Negative selection
• Production of small subsets with discrete functions
o T cells= cytotoxic, helper, regulatory
o B cells= B-1, B-2, and MZ B cells
• Production of more innate, “general purpose” subsets
o T cells= regulatory cells
o B cells= B-1b or MZ B cells

Question 31

Where do B-1a and B-1b cells reside in the body?

Answer 31

Populate different anatomic niches (body cavities) than B-2 cells; 30-50% in pleural and peritoneal cavities in mice s; 2% of splenic B-cell population

Question 32

B-1 cell BCR diversity

Answer 32

B-1 B cells have a relatively limited receptor repertoire
• Some heavy- and light- chain gene segments predominantly rearranged and low TdT expression leads to lack of N-nucleotide diversity
• Receptors tend to bind microbial carbohydrate antigens
o Similar to PRRs of innate immunity