BIOL 1104 Lecture Notes - B-Cell Linker, Germinal Center, Cd24
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Published on 30 Jan 2013
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IMMUNOLOGY
B CELL DEVELOPMENT
Overview of hematopoiesis
-Hematopoietic stem cells (HSC) in bone marrow are source of all blood cell lineages
-long term reconstitution potential (bone marrow transplants)
-ability to “self renew” = long term reconstitution
-Diff.. due to loss of reconstitution and differentiation potential (ex:MPP can differentiate but not self
renew)
1. Antigen Independent Differentiation
-generate large pool of B lymphocytes with unique antigen receptor (diversity generator) (bone marrow)
-weed out B cells that react against self (bone marrow and peripheral lymphoid organs, spleen)
2. Clonal Selection
-antigen exposure selects few B cells to mount an immune response
Step 1: Generating the Repertoire
CD 19 marker of beginning differentiation (only IL-7 does this alone)
-Common Lymphoid progenitor (CLP) expresses IL-7Rα (last multipotent progenitor)
-Pre-Pro B cells-(committed) –needs E2A and EBF gene expression (1st Ig gene rearrangements)
Accessibility Hypothesis
all rearrangeable genes cant be acted upon by recombinase machinery b/c of chromatin strucute constraints
-constrains can be removed by enhancers/promoters and regulated by cis acting sequences
-rearrangement mediated by several proteins RAG1/RAG2
-RAGs recognize and cleave recombination signal sequence (RSS) associated with rearranging gene
segments
IgH locus 1)DJ 2)VDJ NO VD
IgH genes rearrange first followed by IgL genes!
Fraction A/B (pre-pro-B cells) D J
1st step of DhDJh occur when CLP receive an IL-7 signal and the cells express E2A and EBF
-When Dh and Jh gene segments are accessible to recombinase machinery, Vh genes are inaccessible
5’DhRSS
INVERSION 3’DhRSS
Deletion (most)
-Domain turned on by (1) Eμ enhancer between Jh and Cμ
(2)Pq promoter (5’ of 3’ most Dh gene segment)
-However can be deleted and still have recombination: SOMETHING ELSE ACTIVATES DOMAIN
Note: D
J recombination not a hallmark of cells committed to B lineage (Doesn’t ensure B cell
lineage)
Fraction C (late-pro B cells) V DJ
-5’ and 3’ end of V locus are independently regulated
Evidence
1. proximal V favored in fetus but “swamped out” by more numerous distal (5’) V gene in the adult (needs
IL-7)
2. differential regulation of prox. and distal V genes in Pax-5 and Ezh-2 deficient mice
Note: Pax5 transcriptional factor necessary for commitment of developing cells to B lineage but not
for
initiating B cell development (activates B specific genes/suppresses myeloid specific genes)
Ezh-2 encodes a histone methyl transferase to methylate K27 of histone H3
K/O have normal D
J but reduced Vdistal
DJ