Lymphocyte receptor development and antigen receptor gene rearrangement Flashcards
At what stage in development does a B cell begin DH to JH rearrangement?
Pro-B cell
At what stage in development does a B cell complete VJ rearrangement for kappa and/or lamba chains?
Immature B cell
At what stage in development does a B cell complete VH to DJH rearrangement?
Pre-B cell
At what stage in development does a B cell begin to express IgM?
Immature B cell
At what stage in development does a B cell begin to express IgD?
Mature B cell
Which surface marker(s) are present on B stem cells?
CD43+
Which surface marker(s) are present on pro-B cells?
CD43+, CD19+, CD10+
Which surface marker(s) are present on pre-B cells?
B220lo, CD43+
Which surface marker(s) are present on mature B cells?
IgM+ and IgDhi
Which surface marker(s) are present on immature B cells?
IgM+, CD43-
At what stage in development does a T cell begin DB to JB gene rearrangement?
Pro-T cell
At what stage in development does a T cell complete Va to Ja gene rearrangement?
Double positive T cell
At what stage in development does a T cell complete VB to DJB gene rearrangement?
Pre-T cell
At what stage in development does a T cell begin to express aB TCR?
Double positive T cell
Which surface marker(s) are present on T stem cells?
c-KIT+
CD44+
CD25-
Which surface marker(s) are present on pro-T cells?
c-KIT+
CD44+
CD25+
Which surface marker(s) are present on pre-T cells?
c-KIT+
CD44-
CD25+
Which surface marker(s) are present on double positive T cells?
CD4+/CD8+
TCR/CD3lo
Which transcription factors are associated with B lineage hematopoiesis?
EBF, E2A, and PAX5
Which transcription factors are associated with T lineage hematopoiesis?
Notch 1 and GATA3
Which transcription factors are associated with innate lymphoid cell hematopoiesis?
Id2
What are the components of the pre-BCR?
u heavy chain, invariant surrogate light chains (v pre-B protein and lamba5 protein), and signal-transducing Iga and IgB
What are the components of the pre-TCR?
TCR B chain, invariant pre-T alpha (pTa) chain and signal-transducing CD3 and zeta proteins
What are the signals propagated by the pre-BCR?
- Proliferation of pre-B cells
- Inhibition of H chain recombination (allelic exclusion)
- Stimulation of kappa light chain recombination
- Shut off surrogate light chain transcription
What are the signals propagated by the pre-TCR?
- Proliferation of pre-T cells
- Inhibition of B chain gene recombination
- Stimulation of alpha chain rearangement
- Shut off pre-Ta chain transcription
- Expression of CD4 and CD8
What is the pathophysiology of X-linked agammaglobulinemia?
Mutations in Bruton tyrosine kinase prevent delivery of signals from BCR that mediate survival, proliferation and maturation beyond the pre-B cell stage.
What is somatic hypermutation?
High frequency point mutations in Ig heavy and light chains that occur in germinal center B cells in response to signals from Tfh cells. It is present in B cells only. Mutations are clustered in V regions, mostly in CDRs.
Which enzyme mediates somatic hypermutation?
AID
What is receptor editing?
Inducement of further Ig gene rearrangements in strongly self-reactive immature B cells
Which enzyme in the thymus induces expression of self antigens usually only expressed in specific peripheral organs?
autoimmune regulator (AIRE)
What is the end result of positive selection of T cells?
Cells with TCRs that recognize MHC
Expression of coreceptor (CD4 , CD8) complementary to MHC recognized
What is the end result of negative selection of T cells?
Elimination of cells with high affinity for self antigens (clonal deletion)
What is the end result of positive selection of B cells?
Cells with functional BCRs
What is the end result of negative selection of B cells?
Induction of further Ig gene rearrangements in self-reactive cells
Elimination of cells whose rearrangements continue to contribute to formation of self-reactive cells (clonal deletion)
Where do positive and negative selection of B cells occur?
Bone marrow
Where does positive selection of T cells occur?
Thymic cortex
Where does negative selection of T cells occur?
Thymic medulla
In which order do positive and negative selection of B and T cells occur?
Positive selection occurs first, followed by negative selection
What are the four steps of VDJ rearrangement?
- Synapsis
- Cleavage
- Hairpin opening and end-processing
- Joining
Describe synapsis in V(D)J recombination.
Coding segments and adjacent recombination signal sequences (RSSs) brought together by chromosomal looping event
Describe cleavage in V(D)J recombination.
V(D)J recombinase (RAG1 and RAG2) creates double stranded breaks at RSS-coding sequence junctions.
Describe hairpin opening and end-processing in V(D)J recombination.
ARTEMIS opens hairpins. Terminyl deoxynucleotidyl transferase (Tdt) adds nucleotides to broken DNA ends.
Describe joining in V(D)J recombination.
DNA-dependent protein kinase (DNA-PK) and DNA ligase join segments together.
Describe the 12/23 rule.
Recombination only occurs between two segments if one segment is flanked by a 12-nucleotide spacer and the other by a 23-nucleotide spacer. 12- and 23- nucleotide spacers correspond to 1 or 2 turns of a DNA helix and ensure that two RSSs are brought close to each other for recombination.
