U3L2: B cell responses

For which antibody chains does VDJ recombination occur?

heavy and light chains

What is the B cell receptor complex composed of?

The heavy and light chains (two each) and CD79a (Igalpha) and CD79b (Igbeta)

where are B cells located when their receptors are being generated?

bone marrow

where does BCR negative selection occur

in the bone marrow

how do bone stromal cells contribute to B cell development

give signals to promote survival and BRC rearrangement

In the bone marrow, what happens to B cells whose receptor reacts to self antigen

they are removed by further Ig gene editing or they undergo apoptosis

What happens to B cells once they do not recognize self antigen in the bone marrow?

the migrate through the circulatory system to the lymphoid organs where they can encounter cognate antigen

what are the key cytokines from bone stromal cells that are important for progenitor B cell differentiation and survival

Flt3L and IL-7

what is FLT3 signaling crucial for

CLP differentiation in developing B cells and upregulation in B cells of IL-7 receptor

how do progenitor B cells bind to stroomal cells

via VCAM-1 on stromal cells through B cell integrin VLA-4 AND interactions between Kit (on pro-B cell) and SCF (on stromal cell)

CLP

common lymphoid progenitor

What transcription factor is required for CLP differentiation into Pro-B cell

PU.1

Expression of ___ is essential for pro-B cell commitment and it requires ___ and ______

E2A; Ikaros; PU.1

Role of E2A in B cell development

induces expression of early B cell factor EBF

together, what do E2A and EBF promote?

expression of Pax5 and Rag1/2

function of Rag1/2 in B cell development

regulates formation of the BCR

function of Pax5 expression in developing B cells

promote expression of CD19 and Iga

what are the two ways VDJ creates BCR diversity

combinatorial diversity and junctional diversity

Stages of development a B cell goes through

1. stem cell

2. Early Pro-B cells (i.e. pre-pro B cells)

3. Late pro B cell

4. Large Pre-B cell

5. Small Pre-B cell

6. immature B cell

7. Mature B cell

At what point in B cell development if the heavy chain first fully rearranged

Large pre-B cell

When does the heavy chain start rearranging

Early Pre-B cell

When does the light chain start rearranging

small pre-B cell

What BCR proteins are expressed in a large pre-B cell

Pre-B receptor composed of rearranged heavy chain and surrogate light chain

What is the surrogate light chain composed of

VpreB and lambda5

does the pre-BCR provide signaling?

YES! this is different from T cells and pre-BCR signaling provides survival signaling, initiates allelic exclusion, and stimulates rapid proliferation of B cell clones

allelic exclusion

triggered by pre-BCR signaling, prevents other Ig heavy chain gene on the other allele from rearranging by terminating the RAG protein expression and inducing degradation of RAG proteins

When does the early B cell re-express RAG genes after they were turned off during allelic exclusion?

after the Pre-B cell has proliferated → RAG genes cause the light chains to undergo VJ rearrangement

order of light chains in which VJ rearrangement is attempted

the kappa chain attempts first, followed by lambda if kappa was unsuccessful

When does a B cell “earn” the designation of immature B cell?

when the light chain successfully rearranges into a complete membrane-bound IgM BCT

What is the first isotype made by B cells?

membrane bound IgM

what happens if a B cell expressing a sucessfully rearranged IgM does not react to any antigen in bone marrow?

the cell is permitted to leave where it then expresses the rearrangedIg as membrane bound IgD and IgM

what happens if a B cell expressing a sucessfully rearranged IgM binds to multivalent self antigen?

the BCRs cluster together and form a strong signal and this cell is retained in the bone marrow where it undergoes apoptosis or receptor editing

what happens if a B cell expressing a sucessfully rearranged IgM binds soluble self antigein in the bone marrow?

The BCR is cross-linked and permitted to leave the bone marrow, but it receives instructions to make very little IgM and mostly IgD → this cell is anergic and nonfunctional

what happens if a B cell expressing a sucessfully rearranged IgM binds monovalent or soluble antigen with low affinity

this is incapable of causing the BCR to cluster and this cell is permitted to leave the bone marrow and is a POTENTIAL SOURCE OF AUTOREACTIVITY LATER IN LIFE

Process that takes place after a BCR reacts to self antigen in the bone marrow

arrest of B cell development and continued light chain rearrangements as long as there are additional VJ options still available in the genome → if still self-reactive, it undergoes apoptosis/if no longer self-reactive, it migrates to the periphery and matures

what can improper negative selection of B cells lead to?

auto immune diseases and lymphomas

Where do mature B cells develop

secondary lymphoid organs

what is the difference in producing transmembrane and secreted forms of Igs?

they are derived from the same heavy chain sequence that undergoes alternative RNA processing → exons M1 and M2 encode for the cytoplasmic tail and transmembrane form/the last C-domain exon has a secretion coding sequence