Chapter 08 Flashcards
1
Q
What are the subtypes of B cells and their function?
A
- B-1 cells occupy and protect body cavities
- B-2 B cells makeup majority of B cells that survey and combat infections after they become activated in secondary lymphoid tissues
- Marginal-zone B cells are found the in the spleen and protect against bloodborne pathogens
2
Q
What are the concentrations of isotypes of B-cell subtypes?
A
- B-1 B cells have high IgM and low IgD; they secrete IgM
- B-2 (follicular) B cells have low IgM and high IgD; they secrete all isotypes
- Marginal-zone B cells have high IgM and low IgD; they secrete IgM and IgG
3
Q
How do the locations of B-cell development differ between adults and early embryo?
A
- B-cell development occurs in the bone marrow and spleen of adults
- B-cell development changes depending on the site of HSC production
4
Q
What is the timeline and location for fetal HSC production?
A
- Yolk sack
- The placenta and AGM until day 40
- Liver starts making pre-B cells
- HSC begins to occur in bone marrow about day 75
5
Q
What is the difference between HSC division in fetal liver and adult bone marrow?
A
- HSCs produced in the fetus continuously divide
- HSCs produced in the adult require activation signals to proliferate and divide
6
Q
What is the pathway from fetal B-1 B cells to daughter B-1 B cells?
A
B-1 B cells become pleural or peritoneal B-1 B cell lines, which are able to divide and produce daughter B-1 B cells
7
Q
What are the characteristics of B-1 B cells?
A
- cross-reactive antibodies that can recognize multiple carbohydrates
- express low levels of terminal deoxynucleotidyl transferase (TdT)
- V(D)J recombinase uses only a subset of variable V, D, and J segments
- self-renewing in the pleural and peritoneal cavities
8
Q
What happens to the B-cells in late fetal development?
A
- moves from the liver to the bone marrow
- B cells developed in the bone marrow become B-2 B cells
9
Q
What are the characteristics of HSCs?
A
- multipotent and self-renewing
- less-organized nucleosome structure and chromosome packing
- acetylation and methylation of histone proteins, promote gene transcription found near acetyl and methyl groups
- use transcription factors to activate genes in progression to a common lymphoid progenitor cell
10
Q
How do HSCs interact with stromal cells, and why?
A
- c-Kit (expressed by HSCs) bind to stem cell factor (on stromal cells)
- maintains contact between HSCs and stromal cells
- drives HSCs into differentiation into multipotent progenitor cells
11
Q
What do HSCs differentiate into, and what are the functions?
A
- HSCs differentiate into multipotent progenitor cells, ultimately, lymphoid-primed multipotent progenitor cells
- No longer self-renewing cells
- Begin to express unique molecules:
- CD34: cell-surface receptor is detectable
- CXCR4: interacts with stromal cell cytokine CXCL12 to maintain population of progenitor cells in the correct location as differentiation continues
12
Q
What is the mechanism from lymphoid-primed multipotent progenitor cells to lymphocyte?
A
- fms-related tyrosine kinase 3 receptor (flt-3) binds to cell-surface ligand found on bone marrow stromal cells
- the signal causes the lymphoid-primed multipotent progenitor cell to express IL-7 receptor
- IL-7 secreted by bone marrow stromal cells promotes B cell differentiation through early pro, pro, and pre-B stages of development
- Lymphoid-primed multipotentn progenitor cell begin to express RAG1, RAG2, and TdT
13
Q
What are the two pathways progenitor cells are destined?
A
- Progenitor cells that remain in the bone marrow become B cells
- Progenitor cells that migrate to the thymus become T cells
14
Q
What happens when lymphoid-primed progenitor cells bind to IL-7?
A
- cells that bind will progress towards B-cell development
- Binding of IL-7 promotes chromatin remodeling, allowing access to the immunoglobulin genes to the V(D)J recombinase
15
Q
What is the pathway for B-cell development in adults?
A
- Signals provided by bone marrow stromal cells (IL-7) initiate the differentiation of common lymphoid progenitor cells into B cells
- Key immunoglobulin rearrangement occur during the early and late pro-B cell stages and the pre-B cell stage before the cell becomes an immature B cell
- Within the bone marrow, further selection of the immature B cell occurs to promote central tolerance
- Within the spleen, the immature B cell continues through transitional stages (T1 and T2) and ultimately becomes a mature B cell
16
Q
What are the four developmental stages in bone marrow?
A
- Early pro-B cells
- Pro-B cells
- Pre-B cells
- Immature B cells
17
Q
What are the two major functions of the spleen?
A
- filter and cleanse the blood
- lymphocyte proliferation and positive and negative selection of B cells
18
Q
What are the two types of transitional B cells?
A
- T1 transitional B cells undergo negative selection
- T2 transitional B cells receive a survival signal, enabling them to transition into mature B cells
19
Q
How to B cells differ from T cells in their developmental checkpoint?
A
B cells can only produce one functional type of immunoglobulin, in contrast to the two possible forms of T-cell receptors
20
Q
What are the two checkpoints a developing B cell must pass to continue development?
A
- heavy chain: tests the rearrangement event of the heavy chain variable region
- test for productive rearrangement of the immunoglobulin light chain locus
21
Q
What happens during the early pro-B cell stage?
A
somatic recombination occurs at the immunoglobulin heavy chain locus, first recombining a D and J segment.
22
Q
What happens during the late pro-B cell stage?
A
recombining a V segment with the DJ segment in the late pro-B cell stage
23
Q
How are heavy chains tested?
A
the heavy chain is tested using a surrogate light chain, known as a pre-B cell receptor
24
Q
What are the components of the surrogate light chain/ pre-B cell receptor?
A
- two proteins: VpreB (mimics the variable region of the light chain) and λ5 (mimics the constant region of the light chain)
- two immunoglobulin coreceptors: Igα and Igβ (ensures complex can assemble)
25
What prevents another heavy chain from forming?
* After immunoglobulin heavy chain is rearranged and a pre-B cell receptor is formed, RAG1 and RAG2 activity is shut down.
* allelic exclusion: one allele is silenced
26
What happens after the heavy chain checkpoint?
* cells that successfully cross the heavy chain checkpoint become large-pre B cells
* undergo allelic exclusion and cell proliferation
* somatic recombination in the light chain loci is then activated in small pre-B cells
27
What happens during the small pre-B cell stage?
* recombination events occur at the immunoglobulin light chain loci
* somatic recombination of the light chains begins at a random λ or κ light chain locus
* there are four different opportunities to be successful
28
How are light chains tested?
rearrangements of V and J variable segments at any of these loci are tested for the ability to form a functional immunoglobulin at the surface of the developing B cell
29
What are the three possible fates for self-reactive immature B cells?
* clonal deletion
* receptor deletion
* anergy
30
What is clonal deletion?
* removal of self-reactive B cells through an immunoglobulin mediated activation of apoptosis
* leads to central tolerance of the B-cell repertoire within the organism
31
What is receptor editing?
* reactivation of somatic recombination at the light chain locus can occur in self-reactive B cells
* if a new, productive rearrangement of the light chain is successful, it can lead to an alteration in the specificity of the immunoglobulin
* if editing does not work, the B cell dies through clonal deletion
32
What is anergy?
* self reactive B cells that recognize soluble monovalent antigens may not be removed through clonal deletion or through receptor editing
* these cells are placed into an arrested state known as anergy, in which they do not respond to antigen (2-10 days)
33
Why is negative selection for B cells less stringent?
self-reactive B cells still require follicular helper T-cell activity to become activated. The helper T cell would also have to be self-reactive to the same antigen, and since the stringency of negative selection of T cells is high, self-reactive T cells tend to be limited within the circulation.
34
What are the ratios of B cells traveling to secondary lymphoid tissues versus the spleen:
1:4
35
What are the characteristics of T1 transitional B cells?
* high IgM levels
* low IgD levels
* CD24
* CD93
* low levels of BAFF receptor
36
What is BAFF?
B-cell activation factor or B-cell survival factor that promotes the survival of B cells capable of mounting a humoral adaptive immune response
37
What happens to T1 transitional B cells?
* immature B cells enter the spleen, transition into T1 cells and migrate to the T-cell zone of the spleen
* undergo further testing and negative selection to promote peripheral tolerance
38
What are the characteristics of T2 transitional B cells
* IgM level is higher than IgD
* IgD levels increase
* CD21
* CD23
* Higher levels of BAFF receptor
39
What happens to T2 transitional B cells?
* signaling through the immunoglobulin receptor stimulates survival signals from BAFF-R
* those T2 cells that do not undergo positive selection are deleted
* T2 cells that survive become mature B-2 B cells
40
What is the pathway of mature B cells?
1. B cells travel through the circulatory system and enter the secondary lymhpoid tissues through a high endothelial venule (HEV)
2. they migrate to a primary lymphoid follicle to scan for antigen
3. if the B cell recognizes a specific antigen present, it will go through activation and begin proliferation; if no, it exits the lymph node via the efferent lymphatic system and cirulates to another secondary lymphoid tissue
41
What are the characteristics of B-1 B cells?
* reside and patrol in the pleural and peritoneal cavities
* have limited immunoglobulin diversity
* signals that drive negative selection of T1 transitional B-2 cells are required for positive selection of B-1 B cells
42
What is the difference between B-1 B cell development and B-2 B cell development?
* B-1 B cell development occurs independently of the B-cell survival factor BAFF
* B-1 B cells regenerate in the periphery of the organism
* B-2 B cells regenerate through the developmental processes that start in the bone marrow
43
What are the characteristics of marginal-zone B cells?
* high level of IgM
* low level of CD23 and IgD
* membrane-bound adhesion molecules for adherence to other cells
44
How are marignal-zone B cells and B-1 B cells similar?
* both require strong self-antigen recognition by their immunoglobulin to survive
* strong positive selection of T2 transitional B cells is a requirement
* require Notch signaling to differentiate
