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BIOL 1104 (30)

Cell Development Overview

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Carleton University
BIOL 1104
Tamy Superle

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 (1 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)DJ 2)VDJ NO VD IgH genes rearrange first followed by IgL genes! Fraction A/B (pre-pro-B cells) DJ 1 step of DhDJh 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 -chromatin structure of distal V gene under control of IL-7!! -DJ signal to turn on these genes (DJ brings proximal V genes under +ve reg. influence of JC part of the locus: -Proximal Vh gene activation is allele specific 3. V gene recombination susceptible to feedback inhibition (allelic exclusion) Selection of Functional IgH rearrangements (v. non functional rearrangements) -VDJ recombination is not precise (out of frame) so many pro-B cells cant make IgH proteins. Making Immunoglobulin (H + L) is a hallmark of B cells -Only cells able to express IgH will be selected from pool for further differentiation (done by pre-BCR) -VpreBCR has surrogate light chain (λ5 and Vpre B)= not rearranged waiting to test heavy chain recombination -randomly produced IgH also “judged” by association with signal transducing proteins Igα and Igβ Signals from pre-BCR CHECK POINT IN B CELL DEVT -doesn’t require ligand b/c hooked up to cytosolic components 1. Rescue from apoptosis 2. Proliferation (through Ras/Erk pathway) (down regulates SLC/IL-7R, which inhibit proliferation) Same signal that increases IL-7R responsiveness also decreases it??? 3. Stop IgH rearrangements (feedback inhibition) -degrade RAG proteins in S phase, then make IL-7R refractory -loss of IL-7 signals render them inactive in pre-B cells to stop recombination 4. Activate light chain rearrangements Allelic exclusion or Feedback Inhibition of IgH rearrangement -Mature B cells express only one of 2 possible I
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