chapter 6 - development of B lymphocytes

test 3

what are the 6 phases of B cell development?

1. repertoire assembly
2. negative selection
3. positive selection
4. searching for infection
5. finding infection
6. attacking infection
(1-3 happen in bone marrow, 4-6 happen in secondary lymphoid tissues)

B cell development: pluripotent hematopoietic stem cell (CD34 marker) → ______ → ______ → ______

common lymphoid progenitor (CD34, and CD10) → B-cell precursor (CD34, CD10, and CD127) → pro-B cell (CD34, CD10, CD127, and CD19)

what marker is primarily used to distinguish B cells from other cells?

CD19

what happens during phase 1 of B cell development?

• early stages of development in the bone marrow are defined by rearrangement and expression of Ig genes

• heavy chain is rearranged before light chain

• kappa light chains are rearranged before lambda light chains

b-cell development is stimulated by what kind of cells?

bone marrow stromal cells

bone marrow stromal cells

• establish specific contact through the cell-addition molecules (CAMs)

• also produce growth factors for the bound B cells so they can progress through different stages; ex: stem cell factor (SCF) and IL-7

how does rearrangement of the heavy chain locus by pro-B cells occur?

productive rearrangement

if functional rearranged gene is produced, cell progresses to next step of development

nonproductive rearrangement

if gene rearrangement is not functional, cell tries again on second chromosome; if second rearrangement is not functional, cell undergoes apoptosis

what percentage of developing B cells are signaled to die by apoptosis?

50%

surrogate light chain

• a protein in pre-B cells, made up of two subunits, VpreB and λ5

• pairs with a full-length heavy chain and the Igα and Igβ signaling subunits

• is formed in low abundance

• has extensions that form dimerization to enhance signaling in cell → termination of further H chain rearrangement

• also provides survival signals for survival of pre-B cell

allelic exclusion

• only one type of heavy chain and one type of light chain are produced in each B-cell

• gives homogenous B-cell receptors with high-avidity binding

• occurs in all B cells, but not in all T cells

how does rearrangement of the light chain locus in pre-B cells occur?

• rearrange K gene on first chromosome

• rearrangement K gene on second chromsome

• rearrange λ gene on first chromosome

• rearrange λ gene on second chromosome

• apoptosis

what are the two checkpoints that developing B cells pass in the bone marrow?

all occur within phase 1 of B cell development

• 1: pre BCR check to make sure BCR is structurally correct and will signal properly

• 2: auto-reactivity - the ability to bind to the body’s own molecules

  • if the BCR fails this step, it will undergo apoptosis

list the specific proteins involved in the following in B cells:
1) signaling
2) growth factor receptors
3) lymphoid-specific recombinase
4) N-nucleotide addition
5) surrogate light chain components
6) signal transduction
7) differentiation markers
8) transcription factors

1) signaling: FLT3
2) growth factor receptors: Kit, IL-7 receptor, CD25
3) lymphoid-specific recombinase: RAG-1 and RAG-2
4) N-nucleotide addition: TdT
5) surrogate light chain components: lambda5 and VpreB
6) signal transduction: Igalpha and Igbeta, Btk, CD19, CD45R
7) differentiation markers: CD43, CD24, BP-1
8) transcription factors: E1A and EBF, Pax-5

which transcription factor is exclusive to B cells?

Pax-5

many B-cell tumors carry chromosomal translocations, which are...

the transfer of DNA between non-homologous chromosomes

proto-oncogenes

normal cellular genes that are important regulators of normal cellular processes; they promote growth

oncogenes

genes that cause cancer by blocking the normal controls on cell reproduction

chromosomal rearragements in Burkitt's lymphoma

occurs between MYC gene on chromosome 8 and Ig gene on chromosome 14 (look at image on slide 17 of notes)

B-1 cells vs B-2 cells

summary of gene rearrangements in B cell development

early pro-B cell → late pro-B cell → pre-B cell → immature B cell

what happens if B cells react with self antigens? what happens if there is no reaction?

• immature B cells that do not react with self antigen move to the blood and express IgD and IgM

• immature B cells that react with self antigen are retained in the bone marrow

autoreactive immature B cells undergo receptor editing

if B cells react with self antigens → undergo additional modification to L chain → if still binding to self, undergo apoptosis (look at diagram on slide 22)

anergic B cell

immature B cells specific for monovalent self antigens are made nonresponsive to antigen (will still recognize self antigen, but will not activate immune system upon recognition)

maturation and survival of B cells requires access to ______ ______.

lymphoid follicles

maturation of B cells in secondary lymphoid tissues

look at notes on slide 25 (and understand info on chart)

what leads to the differentiation of activated B cells into plasma cells and memory B cells?

encounter with antigen

b-cell tumors

• represent uncontrolled growth of single transformed B cell

• associated with all stages of development

• tumors retain characteristics of cell type and location

Hodgkin's lymphoma

originate from the germinal center in lymphoid tissue

multiple myeloma

plasma cell in bone marrow

waldenstrom's macroglobulinemia

IgM secreting B cells in lymphoid tissue

different types of B-cell tumors reflect B cells at different...

stages of development

b-lymphocyte tumors

caused by mutations in genes that regulate cell growth

what are the two main types of genes that regulate cell growth? how?

1) proto-oncogenes: promote cell growth
2) tumor suppressor genes: inhibit cell growth

what happens when there are mutations in cell growth regulating genes?

cells transform into oncogenes (cancer-causing genes)

summary of B cell development