Chapter 6- The Development of B Lymphocytes

Immunoglobulin Repertoire

diverse set of sequences via gene rearrangement

Secondary lymphoid tissue

where B cells go to differentiate and activate

Peyer's Patches

helps foster an environment where B cells can encounter an antigen, favor isotope switching

HSC

Hematopoietic stem cell that expresses CD34, picks up more CD markers as it becomes more specialized

CD34

expressed via hematopoietic stem cell, its marker

Pro-B cell (progenitor)

when a B cell is born

early pro B cell- heavy chain rearrangement starts

late pro B cell- heavy chain rearrangement continues

Pre-B cell

large pre B cell- heavy chain is main, mu heavy chain is made

small pre B cell- light chain rearrangement starts, mu chain is in the endoplasmic reticulum

Stromal cells

(non-lymphoid) help the B cells differentiate by using adhesion molecules that maintain contact, releasing growth factors like stem cell factor and IL-7

SCF

stem cell factor, helps development of the B cells

Kit receptor

stem cell receptor, growth factor receptor

IL-7

helps the development of the B cells

IL-7 receptor

on the late pro-B cell and pre-B cell

Non-productive rearrangement

attempt to create a successful rearrangement

Apoptosis

when a cell is signaled to die

Survival signal

when a cell is signaled to survive and become a pre-B cell (only about 50% of cells)

sLC

surrogate light chain - a fake light chain that acts as a place holder for the heavy chain

pre-BCR

sLC and heavy chain form a pre B cell receptor, binding to a ligand means that the B cell will survive

Light chain rearrangement

occurs in the pre-B cell, only one recombination event required (VJ), can have multiple attempts at making a correct assembly (85% success rate), clonal expansion

B cell checkpoints

1) pre-B cell receptor- makes sure there are pre-B cell receptors (pre-BCR), if not, cell goes through apoptosis (after heavy-chain rearrangement)

2) B cell receptor- looks to see if there is a B-cell receptor, if not, cell goes through apoptosis (after light chain rearrangement)

RAG

RAG protein expression is turned on and off (2 times), once for the heavy chain, then again for light chain

Ig alpha and Ig beta

always on until the B cell turns into a plasma cell then turned off

approximate expression patterns of TdT, sLC, RAG, and growth receptors

TdT (N-nucleotide addition) - early pro-B cell phase to small pre-B cell phase

sLC- early pro B cell to immature B cell

RAG (lymphoid-specific recombinase)- early pro-B cell to large pre-B cell, small-pre B cell to mature B cell

Growth receptors:

Kit- stem cell to late pro- B cell

IL-7 receptors- stem cell to small pre-B cell

CD25- late pro B cell-small to pre-B cell

Chromosome translocation

when different chromosomes fuse together by accident

Burkitt's lymphoma

MYC proto-oncogene- the MYC gene normally controls the cell cycle but this control is disrupted with translocation leading to Burkitt's lymphoma

B-1 cells

atypical subset of B cells that are made early in embryonic development

CD5 cell surface protein is a marker

Antibodies are not diverse and tend to bind to more than one antigen

produced in bone marrow in embryo but this stops in adults

In adults- B-1 cells persist in the lymphoid tissue and can self-renew

B cell selection

1) Prepare (Repertoire assembly)

2) Weed out (Negative selection)

3) Promote (Positive selection)

4) Search (Search while recirculating)

5) Activation (Clonal expansion)

6) Attack (Differentiation)

self-reactive B cells

B cells that will die or become inactive when they bind to a self-antigen in the bone marrow, stay in bone marrow to be tweaked

Immature B cells

IgM on the surface, leave bone marrow if they do not react, goes to secondary lymphoid tissue for continued development

Receptor editing

contribute to self tolerance

1) self-reactive B cells reduce IgM BCR levels and maintain expression of RAG proteins

2) light chain is rearranged again to make a new BCR. This leads to two outcomes: New BCR is NOT self-reactive- B cell will develop further, New BCR is self-reactive- rearrangement keeps going until the B cell runs out of attempts

3) Clonal deletion

Clonal deletion

self-reactive B cells eventually die by apoptosis and are cleaned up by macrophages

Anergy

B cells that bind to monovalent and soluble self-antigens in the bone marrow

have a short lifespan (5 days)

come from self-reactive B cells

Primary lymphoid follicle

B cells congregate here from the lymph nodes, continuation of B cell maturation, when B cells enter the primary follicle it will increase their life-span, majority of immature B cells don't enter the primary follicle, Anergic B cells are stuck in the T cell area, some B cells stay in the primary lymphoid follicles

Homing

help B cells enter the lymph, similar to extravasation

-HEV

-stromal/dendritic cells

-naive B cells bind via specific receptor

HEV

high endothelial venule, part of the homing mechanism, leads them to the T cell area

Stromal cells/dendritic cells

secrete chemokines, part of the homing mechanism

Stromal cells - CCL21

Dendritic cells - CCL21, CCL19

FDCs

Follicular Dendritic Cells, in follicles, secrete CSCL13 and BAFF, found in the lymph nodes

CXCL13

secrete chemokine survival, attracts B cells into the primary follicle

BAFF

works with FDCs, differentiation signals, transforms immature B cells that enter follicle to become mature B cells

plasma cells

very specialized- protein synthesis and secretion is highly developed and they lose MHC II and BCR expression, CD4 T cells will help activate B cells directly become plasma cells (secrete IgM)

primary focus

how B cells develop to plasma cells or memory B cells

germinal center

Where B cells undergo affinity maturation and proliferation

B cells will differentiate and reside in the medullary cords, spleen, and bone marrow as plasma cells secreting high-affinity, isotype-switched antibodies; some B cells become long-lived memory B cells that recirculate and rapidly activate after recognizing their antigen

velcade

used to treat multiple myeloma

B cell tumors

many B cell tumors have chromosomal translocations involving immunoglobulin genes, has similar properties equivalent to its developmental stage like location, morphology, and surface receptors

ALL

Acute Lymphoblastic Leukemia, lymphoid stem cell, in the bone marrow and blood, the Ig V gene is unmutated, comes from the lymphoid progenitor, treated with chemotherapy or bone marrow transplant

multiple myeloma

plasma cell origin, comes from plasma cell and various isotypes, from the bone marrow, the Ig V gene is mutated, with no variability within clone