CD8+ T cels Maturation/ Differentiation/ Development Flashcards
B cells come from
lymphoid progenitors in bone marrow for central tolerance
Autoreactive mIg on B cell surface =
anergy or destruction= central tolerance
Expression of other cell surface molecules play a role in
B cell activation
All naive mature B cells express
IgM or IgD on cell surface
BCR+ CD79a/ CD79b links
to intracellular signaling cascade
BCR=
two identical light chains and heavy chains with a constant and variable region that is a cell surface membrane immunoglobulin that recognizes and interacts with intact antigen but is not linked to any signal transduction pathways.
Light chain and heavy chain variable regions
Light- V,J Heavy- V,D,J
Multiple germline genes =
many gene segments for V, D J
Combinatorial diversity
combine VDJ in any combination
Junctional Diversity
insert nucleotides at junctions if no open reading frame
Random Selection/association happens with
light and heavy chains
Step 1 Somatic recombination
DNA encoding variable regions is cut and recombined so that intact genes can encode light and heavy chain varible regions
Step 2 somatic recombination
Recombinases RAG-1 and RAG2 trigger somatic recombination process
Step 3 somatic recombination
Gene rearrangement of VJ in light chain and VDJ in heavy chain
Step 4 Somatic recombination
during recombination, unselected VDJ’s are deleted
Step 5 Somatic recombination
DNA nucleotides are deleted, inserted in order to maintain an open reading frame
Step 6 Somatic recombination
Insertion is mediated by Terminal Deoxynucleotidyl transfeast Tdt
Step 7 Somatic Recombination
constructed variable and constant regions are transcribed to hnRNA that is spliced to mRNA
Step 8 Somatic Recombination
translated light and heavy chain expressing both a variable and a constant region
successful rearrangement of heavy chain variable regions from one chromosome inhibits
the somatic recombination of the heavy chain on the other member of the chromosome pair.
all mIgs present on the surface of any one B cell will have
the same heavy chain variable region
Pro-B cell stage
1, Transcription of RAG-1, RAG-2, CD19, Tdt and CD79a/b –2.CD19 is expressed throughout all stages of B cell development –3. Btk is expressed in the transition from Pro-B to Pre-B cells stages
Pre BCR complex
Pre-BCR, CD79a/b heterodimer
Pre BCR=
two heavy mu chains paired with two invariant pseudo light cahins
interaction of pBCR with
ligands in bone marrow drives B cell differentiation
CD20 is expressed in
the Pre-B cell stage and thereafter
Somatic recombination of light chain variable region happens
during Pre-Bcell stage with
Somatic recombination of B cell heavy stage and cell surface expression happens during
the immature B cell stage
BCR=
assembly of light and heavy chains
Pre- BCR is changed to BCR on the cell surface during
the Immature B cell stage
destruction of autoreactive B cells takes place during
the immature B Cell stage
Tolerance induction marks
the immature B cell stage
Immature B cells that survive tolerance induction go
to the spleen
Maturation of B cell happens
in the spleen during the Naive Mature B cell stage
alternative splicing of hnRNa leads to
surface expression of IgM and IgD during the naive, mature B cell stage
CD40 and others are expressed
in transition from immature to mature B cell stage
Naive, Mature B cells circulate and
migrate to the other secondary lymphoid tissues.
Btk=
Bruton’s tyrosine kinase
Btk mutation is associated with
X linked agammagloulinemia
Btk plays a critical role in
B cell activation, differentiation, and proliferation
initial block of formation of Btk happens
at the pro-B to Pre- B cell transition
Pre B cells that form during Btk mutation are defective and so
maturation is halted at this point
in the blood of an XLA patient you will find
a small number of B cell numbers (Leaky B cells)
XLA patients have
reduced B cells in peripheral blood and reduced serum Ig levels of all classes
there may be a compensatory pathway that
can at least parly take over the role of Btk in human B cells.
light chain constant regions are called
kappa and lambda
pseudolight chains are invariant and
do not have VJ segments.