Class Notes (806,507)
Canada (492,261)
UOIT (1,636)
Biology (294)
BIOL 1010U (101)
Ani (35)


4 Pages
Unlock Document

BIOL 1010U

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
More Less

Related notes for BIOL 1010U

Log In


Don't have an account?

Join OneClass

Access over 10 million pages of study
documents for 1.3 million courses.

Sign up

Join to view


By registering, I agree to the Terms and Privacy Policies
Already have an account?
Just a few more details

So we can recommend you notes for your school.

Reset Password

Please enter below the email address you registered with and we will send you a link to reset your password.

Add your courses

Get notes from the top students in your class.