Lecture 14 - Lecture 14- B Cell Development: p. 275-290...

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Lecture 14- B Cell Development: p. 275-290 Baby Joe Case Near absence of B/T cells Reduced number of WBC’s Mutation in RAG genes: genetic mutation in either RAGs will cause a disease Severe Combined Immunodeficiency (SCID) The most sever of the primary immunodeficiency diseases; result of absence of adaptive immunity Unless treated, SCID is lethal before the child’s first or second birthday; treat via bone marrow transplant Classified by detection of T, B and NK cells: T- B- NK- (most severe) T- B+ NK- (most common) T- B+ NK+ T-B- NK+ (Baby Joe’s case) Creation of functional T and B cells requires VDJ recombination via RAG Development of Common Lymphocyte Progenitor Cells All blood cells are generated from hematopoietic stem cells; can divide for a life time Common lymphocyte progenitor cell arises from multpotent progenitor and gives rise to precursor stages of NK, B and thymocytes; these mature into NK, B and T cells Lymphoid progenitor cells are derived from the hematopoietic stem cell; progeny are progenitor B cells, T cells and NK cells Proliferation/differentiation regulated by txn factors and cytokines/cytokine receptors Cytokines/Receptors involved in Early Lymphocyte Development IL-7, FL (Flt3 ligand) and SCF (stem cell factor) are low MW, soluble proteins produced by stromal cells in the bone marrow, and by other cell types when required; act on receptors on developing B cells These proteins interact non-covalently with receptors on the surface of the developing progenitor cells SFC receptor: c-KIT (encoded by the white spotting gene—required for melanocyte development) FL receptor: Flt3 (fms-like tyrosine kinase receptor-3) IL-7 receptor: heterodimer of alpha and common gamma chain (2 molecules); promotes survival and cell proliferation and maybe differentiations Mutations in genes encoding IL-7 is a main cause of SCID (30%) Flt3 ligand= ligand for FL receptor; growth factor; produced by stromal cells and imp. for survival and proliferation SCF also acts to induce survival and proliferation in early B cells The IL-7 Receptor is required for development of the immune system IL-7Rα can bind IL-7 weakly on its own but can’t send signal; common gamma chain cannot bind IL-7 on its own Together IL-7Rα/γc form a high affinity receptor ( common gamma chain delivers the signal into the cell) In mice IL-7, IL7Rα and γc are absolutely required for lymphoid development; mutations in any one results in loss of B and T cell development Expression of IL-7Rα is a marker for commitment to the lymphoid lineage Mutation of γc= accounts for almost half of all SCID cases; cannot transmit signals through IL-7 receptor; severe defects for early lymphoid progenitors to proliferate; this is an attractive target for gene therapy B Cell Development The hallmark of B cell development is rearrangement of the Ig genes to generate a B cell receptor; Ig rearrangement
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Lecture 14 - Lecture 14- B Cell Development: p. 275-290...

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