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3-4 - Pre-B cell receptor is a quality control step for IgH...

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Unformatted text preview: Pre-B cell receptor is a quality control step for IgH. Expansion and further maturation Blocked in further maturation If an IgH chain can form a functional pre-BCR with SLC, it may generate a functional BCR with IgL chain later in maturation. Functional pre-BCR Non-functional pre-BCR Pre-BCR activates IgL locus for V(D)J recombination. Accessibility model of V(D)J recombination RSS accessible to Rag-1, Rag-2 IgH locus in an open chromatin structure IgL locus in closed chromatin structure RSS inaccessible to Rag-1, Rag-2 pro-B cell Pre-BCR IgH locus closed IgL locus open Pre-B cell Pre-BCR induces cell proliferation. Pre-BCR shuts off SLC expression. Pre-BCR is diluted during cell division. Rag + Rag-1 and Rag-2 genes are reactivated for IgL V(D)J recombination. Cell proliferation stops (small pre-B cells). Large pre-B cells Rag + Rag + Rag + Rag + Rag + Rag + Rag + Small pre-B cells IgL rearrangement Pre-BCR is a key transition point during B cell maturation. pro-B cells IgH undergoes V(D)J recombination pre-B cells pre-BCR Shut off Rag-1, Rag-2 genes Close IgH locus Allelic exclusion Open IgL locus Prepare for IgL rearrangement pre-BCR Expansion of precursor population Pre-BCR Negative feedback Loss of pre-BCR Re-expression of Rag-1, Rag-2 IgL rearrangement Stop proliferation Flow cytometry analysis of BM from normal people and patients with λ 5 de¡ciency (agammaglobulinemia) λ 5 de¡ciency blocks B cell maturation. Phosphorylation of ITAM by Src family of tyrosine kinase pre-BCR Ig α Ig β P P Syk Activation of Syk SFK Btk P PLC- γ PLC- γ P PIP 2 IP 3 DAG Ca 2+ P P Fc γ RIII γ 2 Syk SFK Btk P PLC- γ PLC- γ P PIP 2 IP 3 DAG Ca 2+ Similar to Fc...
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3-4 - Pre-B cell receptor is a quality control step for IgH...

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