Lecture 19: Early Lymphocyte Maturation - B cells Flashcards
Describe B lymphocytes.
B Cells mature in the ______________.
bone marrow (in birds in the Bursa of Fabricius)
______________ ensures that one B ccells only makes one antibody.
. Successful rearrangements at both heavy-chain alleles could result in a B cell producing two receptors of different antigen specificities. To prevent this, signalling by the pre-B-cell receptor enforces allelic exclusion, the state in which only one of the two alleles of a gene is expressed in a diploid cell.
Recall the overview of B cell development.
B cells develop in the _____________, but can also develop in ______________ and ________________.
bone marrow, neonatal spleen, liver
______ is not self-renewing. ________ can develop into both T and B cells, Transition through the various differentiation steps requires ____________. ______________ in the bone marrow are critical for B cell development.
What are antibodies?
Antibodies are soluble forms of their membrane-bound antigen receptors that are critical for opsonization, neutralization and complement activation
Default of developing B cells is ______ unless they are rescued by ___________.
Default of developing B cells is ‘death’ unless they are rescued by a positive signal
Recall the importance of Pre-BCR signalling in B cell development.
Pre-BCR is formed by __________ pairing with ___________.
H µ-chains, surrogate chains (E2A-induced l5, VpreB; Iga, Igb)
Recall B cell development events after successful heavy chain rearrangement
Recall the overview of light chain rearrangement in B cell development.
Recall how nonproductive light-chain gene rearrangements can be rescued by further rearrangement.
The organization of the light-chain loci in mice and humans offers many opportunities for the rescue of pre-B cells that initially make an out-of-frame rearrangement. If the first rearrangement is nonproductive, a 5’ Vκ gene segment can recombine with a 3’ Jκ gene segment to remove the out-of-frame join and replace it with a new rearrangement. In principle, this can happen up to five times on each chromosome, because there are five functional Jκ gene segments in humans. If all rearrangements of κ-chain genes fail to yield a productive light-chain join, λ-chain gene rearrangement may succeed
Recall isotypic exclusion.
As well as allelic exclusion, light chains also display isotypic exclusion, that is, the expression of only one type of light chain—κ or λ—by an individual B cell
Recall allelic exclusion in B cell development.
In B lymphocytes, successful heavy chain gene rearrangement of the genetic material from one chromosome results in the shutting down of rearrangement of genetic material from the second chromosome. If no successful rearrangement occurs, rearrangement of genetic material on the second chromosome takes place. If no successful rearrangement occurs on either chromosome, the cell dies.
Recall the selection of immature B cells.
If an immature B cell encounters a strongly cross-linking antigen in the bone marrow, its development is arrested and the cell dies (clonal deletion/negative selection). Since RAG expression is still active at this stage, receptor editing can rescue such cells from clonal deletion (continuing light chain rearrangements)
Recall the outcomes of the selection of immature B cells
- Normal
- When developing B cells express receptors that recognize multivalent ligands, such as MHC, these receptors are deleted from the repertoire. The B cells either undergo receptor editing, thereby eliminating the self-reactive receptor, or the cells themselves undergo programmed cell death (apoptosis)
- Immature B cells that bind soluble self-antigens able to cross-link the B-cell receptor are rendered unresponsive to the antigen (anergic) and bear little surface IgM.
- Immature B cells whose antigen is inaccessible to them, or which bind monovalent or soluble self-antigens with low affinity, do not receive any signal and mature normally.
Recall the checkpoints of B cell development
Recall RAG expression during B cell developmental stages.
Signaling from the pre-B-cell receptor promotes heavy-chain allelic exclusion in three ways. First, it reduces V(D)J recombinase activity by directly reducing the expression of the RAG-1 and RAG-2 genes. Second, it further reduces levels of RAG-2 by indirectly causing this protein to be targeted for degradation, which occurs when RAG-2 is phosphorylated in response to the entry of the pro-B cell into S phase (the DNA synthesis phase) of the cell cycle.
RAG proteins will again be expressed in order to carry out light-chain locus rearrangement, but at that point the heavy-chain locus does not undergo further rearrangement
