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MICB 302 (2)
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Department
Microbiology
Course
MICB 302
Professor
Tracy Kion
Semester
Fall

Description
MICB 302 Week 4 Notes Antigen independent phase in bone marrow, fetal liver VDJ rearrangements Alternative splicing of mRNA to make IgM/IgD Abs Pro B>Pre B>immature B>mature B Ag dependent phase in spleen, lymph node Class switching, somatic hypermutation Alternative splicing of mRNA to make sIg instead of mIg B cell activation, diff to form memory B cells and plasma cells Lymphoid progenitor: 1) Committed T cell progenitor, double positive thymocyte, single positive thymocyte, mature T cell 2) Pro B, Pre B, Immature B, Mature B B Cell Development B cell activation = secrete Ig into body fluids Synthesis of H and L chains of Ig necessary for development Officially B cell = µ(H) and L chains expressed on membrane Development begins in fetal liver, continue bone marrow through life, migrate from outer part of marrow to core during development Lymphoid Progenitor produced by stem cells in outer part of marrow Immature B (easily killed by recog. of self antigen) until expression of IgD on membrane. Mature B moves into the periphery and activated by antigen to become plasma cell or memory B cell. Apoptosis occurs when failure to complete B cell development - can occur at several stages of development. Default pathway unless survival signal given. e.g. failure to make productive rearrangements and express Ig at appropriate times Somatic recombination(SR)- productive, synthesis of functional H or L chain - nonproductive, stop codon b/c of frame-shift mutation *genes encoding proteins for SR and receptor expression turned on and off at set times during development Key Steps: 1) Lymphoid progenitor cell to early pro-B cell Lymphoid progenitors - signal from marrow stromal cells to begin development Adhesion molecules involved - stem cell factor (SCF) on stromal cell membrane and Kit on lymphocyte membrane. Kit activation = lymphocyte proliferation. Cytokines released from stromal cells induce RAG-1/RAG-2/TdT synthesis. RAG reads RSS and recombine gene segments, TdT adds N-nucleotides. DNA repair enzymes also expressed. D-J joining on both H chain chromosome → early pro-B cells Rearrangement very efficient → D gene segments read in all 3 reading frames Key events: commit to B cell lineage D-J joining 2) Early pro-B to late pro-B Joining of V segment to DJ completes late pro B stage Rearrangement targeted to 1 chromosome, if productive, other chromosome no rearrangement. If V → DJ unsuccessful on 1st chromosome, 2nd chromosome rearranges. 50% pro B make functional H chain → survival signal → dividing pre B producing µ H chains. pre B cells also express Igα/Igβ. Remaining cells → no functional µ H chain → apoptosis Productive = transcribed, mRNA translated, functional protein product Non-productive = a stop codon 1) P + N nt 2) frameshift mutation → non functional Test whether µ H chain made is functional e.g. able to pair with L chain: Synthesis of surrogate light chain → VpreB (like V region) and λ5 (like C region) 1st Checkpoint: µ H chain, VpreB, λ5, and Ig-α/Ig-β assemble to form structure that resembles B cell receptor. pre-B receptor in vesicles of pre B; successful expression sends signal to stop µ H chain gene rearrangements → non functional = apoptosis (select for functional H chains) Key Events: V → DJ joining H chain synthesis successful pairing with VpreB, λ5, and Igα/Igβ→ func pre B receptor cessation of rearrangement of H chain genes 2 opportunities for apoptosis: fail to rearrange V-DJ on both chromosomes fail to express func preα B receptor 3) Late pro B to small pre B developing cell express IL-7 receptor and recieve IL-7 from bone marrow stromal cell to stimulate growth/proliferation several rounds of division → transition to pre B stage, RAG/TdT gene expression off Key events: proliferation, expansion of pre B cells with same µ H chain 4) pre-B to immature B cell pre B stop surrogate L chain → rearrangement of L chain genes → RAG/TdT re-expressed κ and λ light chains located on diff chromosomes L chain V-J joining first on κ chain → productive rearrangement →κ chain made and become immature B cell expressing membrane IgM(κ) BCR. B cells able to repeat V-J joining several times: First attempts are nonproductive = light chain rescue process can happen because only 1 joining event is required for L chain rearrange If κ genes not successfully rearranged on either chromosome →λ genes are rearranged → success leads to prod of IgM(λ) BCR If neither κ nor λ is productive → apoptosis in marrow Little less than 50% of B lineage cells in marrow end up prod func Ig H and L chains 2nd Checkpoint: µ chain, L chain (κ or λ), and Igα/Igβ assemble to form BCR BCR on cell surface → shut down L chain gene rearrangement (select for functional L chains) Cannot pair H chain with L chain → problem with L chain L chain gene rearrangement continue until functional L chain made, or no more rearrangements possible → Apoptosis (no func BCR) Key points: V to J L chain joining synthesis κ or λ light chain protein successful pairing with H chain for func BCR stop rearrangement L chain genes 2 opportunities for apoptosis: fail to rearrange V-J for L chain fail to express func BCR Allelic and isotopic exclusion: Somatic recombination leads to allelic exclusion for H and L chains since each B cell productively recombines only 1 H and 1 L chain gene ONLY ONE IS PRODUCTIVE, even if more recombination attempts made Allelic exclusion ensures B cell makes BCR of 1 Ag specificity Isotopic exclusion for L chains → individual B cells only have either κ or λ light chain PROTEINS MENTIONED IN CLASS: Kit, IL-7 receptor, RAG-1/2, TdT, λ5, VpreB, Igα/Igβ Negative Selection: B/T cells undergo positive/negative selection in PLO B cell: (+) selection when pre-B receptor binds ligand and get survival signal e.g. survival signal for pre B receptor, and membrane IgM expression (-) selection when receptor binding result in death or inactivation e.g. Immature B (-) selected if bind Self-Antigen in marrow/periphery  No self-Ag binding = leave marrow and enter periphery, start to express IgM/IgD on membrane, fully mature B when they get to SLOs  self-Ag binding = 1 of 3 fates: 1) killed or inactivated (negatively selected) in marrow 2) given another opportunity to rearrange L chain genes to make BCR not self reactive = receptor editing. Apoptosis if use up all rearrangement chances. 3) Immature B with BCR specific to soluble, univalent self-Ag = become anergic (unresponsive). These cells make IgM/IgD with only IgD on membrane → IgD binding doesn't activate B cell, short life-span 1-5 days Immature B with BCR binding self-Ag outside of marrow →Apoptosis or Anergic  Receptor Editing unavailable → recombinases turned off Bone marrow is very busy! Billions of B cells die/day, neutrophils made/day, T cells... After escaping negative selection, immature B cell goes through rite of passage Immature B cell → Mostly IgM with little IgD Mature B cell → Little IgM and mostly IgD Competing with mature B cells in lymph node: Stromal cells = chemokine CCL21 (attract immature B to HEV to enter lymph node) Dendritic Cells = chemokines CCL21 + CCL19 (attract B cells into lymph node) Follicular DCs = chemokine CXCL13 (attract immature Bs to primary follicle) Immature B compete with Mature B to access limited follicular sites At these sites, (im)mature B cells and fDCs have "chemical chat" beneficial to both  fDCs and cytokines drive maturation of immature B cells  Immature B that fail to access follicular site die within few days of entering periphery/blood → competition favors mature B cells Mature B cells recirculate between lymph, blood, and secondary lymphoid tissues. Life span = 100 days Naive B cells make IgM and IgD with same antigen specificity On mature/immature B cell surface → some BCRs with IgM and some with IgD Both IgM
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