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63 Cards in this Set
- Front
- Back
Pluripotent hematopoeitic stem cells express _______ that marks them
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CD34
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Earliest identifiable cells of B-cell lineage is ___________
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pro-B cells
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What is the main event during the pro-B cell phase?
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Heavy chain rearrangement
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What are the 6 stages of B Cell Development?
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1) Repertoire assembly: Generation of diverse and clonally expressed BCRs in bone marrow
2) Negative selection: Getting rid of BCRs that are self-reactive 3) Positive selection: Promotion of a fraction of immature B cells to become mature B Cells in secondary lymphoid tissue 4) Searching for infection - get circulated btwn lymph, blood and secondary lymphoid tissues 5) Finding infection: Activation and clonal expansion of B cells by pathogen-derived antigens in 2ndary lymphoid tissue 6) Attacking infection: Differentiation to plasma cells and memory B cells in 2ndary lymphoid tissue |
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What is a critical cytokine expressed on B-cell precursor?
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IL 7
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Where is the site of B cell development?
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Bone marrow. primary lymphoid tissue
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Once a B cell expresses the heavy chain it is known as _________
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pre-B cell
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What is the main event during the pre-B cell phase?
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Light-chain rearrangement
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What are 2 roles the stromal cells play in development of b cells? the growth factors
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1) Make contacts with developing cells thru the interaction of adhesion molecules and their ligands
2) Make growth factors that act on the B cells they're attached to |
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What is stem-cell factor?
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A growth factor expressed by stromal cells, recognized by Kit (a receptor on maturing B cells)
Responsible for induction of IL7 receptor |
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What is VLA-4?
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An integrin stem cells and pro B cells use to bind to adhesion molecule VCAM-1 on stromal cells.
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What is VCAM-1?
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The cell adhesion molecule (CAM) on stromal cells that VLA-4 (integrin on stem cells and pro B cells) binds to
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What role do cell adhesion molecules (CAM)s and integrins play in B-cell development?
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Interactions between these promote binding of stem cell to stromal cell, which causes the cell to proliferate. Cells at different stages require stimulation of different things to grow.
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Non-productive rearrangements result from_________________
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Introduction of stop codons during joining --> no functional protein would be expressed
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Productive rearrangements result in_________
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generation of function protein
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What happens if developing B cells make nonproductive rearrangements at both copies of the heavy-chain gene loci?
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They lose their potential to make Ig; they die by neglect
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What two rearrangements in heavy chains must occur? What are the relative efficiencies?
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1) D-J : very efficient
2) DJ-V: less efficient, 50/50 chance (there are two chances) |
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What genes must an early pro-B cell express to rearrange the Ig H chain genes?
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Recombination Activating Genes (RAG 1 and 2
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What is pre-BCR made of?
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The heavy chain and surrogate light chain (VpreB and λ5)
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What is the surrogate light chain made of?
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VpreB and λ5
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T/F pre-BCR expression required for B cell development
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True. The pre-BCR lets the cell show it can make a H chain that combines with light chain. Its presence sends signal that allows a pro B cell to become a pre B cell.
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What sends signal that allows a pro B cell to become a pre B cell? (stop heavy chain rearrangement)
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Presence of a pre-B-cell receptor
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What is allelic exclusion?
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cell expresses only one of its two copies of a gene. Responsible for in B cells monospecificity.
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What is the advantage of allelic exclusion?
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Results in homogeneous BCRs with high-avidity binding.
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T/F Light chains are more rearrangeable
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T. It's relatively more efficient.
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What are the implications for having multiple rearrangement opportunities?
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Increases the likelihood of forming a BCR (after H chains are made)
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What is light chain isotype exclusion?
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There are two isotypes of light chain (κ and λ); only one can be expressed
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How many chances to rearrange does the L chain have?
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4.
Two κ genes and Two λ genes. |
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What are the two checkpoints that B cells have to pass in development in bone marrow?
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1) Check to make sure H chain works by formation of functional pre-BCR (with final H chain and surrogate light chain)
2) Check to make sure the L chain works with the (already checked for function) H chain - make sure they can produce a functional BCR. |
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When are RAG genes turned on?
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During H and L chain rearrangement (NOT between these times)
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When are terminal deoxynucleotidyl transferase (TdT, the one responsible for adding the nucleotides resulting in junctional diversity) genes turned on? (What's implication?)
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Mostly during pro-B Cell stage, less so during pre B cell;
Implications are that all VD and DJ joints of rearranged H chains show N nucleotides; BUT only about half of VJ joint of rearranged L chains do. |
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Junctional diversity occurs most commonly in H or L chains?
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H. Due to activation of TdT genes.
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How do gene rearrangements affect transcription in the Ig locus?
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The promotor upstream of the variable region is brought closer to the enhancer after rearrangement, resulting in increased transcription.
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What does X-linked agammaglobulinemia result from?
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A tyrosine kinase that's essential for BCR development beyond pre B cell stage. Result in almost no circulating antibodies because their B cells are blocked at this stage.
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How can aberrant rearrangements lead to B cell tumors?
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Ig genes can get spliced onto other chromosomes, juxtaposing Ig with a proto-oncogenes (something involved in cell growth or proliferation) ---> may get turned on all the time resulting in a tumor.
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What chromosomal rearrangement occurs in Burkitt's lymphoma?
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Proto-oncogene MYC gets juxtaposed with Ig locus --> comes under control of Ig locus --> gets turned on all the time.
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What characteristic marker do B1 cells express?
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CD5
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What do B1 cells do?
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Characteristics of innate and adaptive systems. Not an extensive repertoire, "neither here nor there" cells
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How are B1 cell antibodies different from conventional B cells?
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Exhibit polyspecificity - they bind with lower affinity to more things.
They make IgM but doesn't improve response (no hypermutation or junctional diversity) |
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What are most cases of chronic lymphocytic leukemia caused by?
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B-1 cells, might stem directly from their capacity for self-renewal.
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How do non-self and self-reactive B cells in bone marrow have different fates?
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A) non-self-reactive B cells express mIgD and exit to blood
B) self-reactive cells are retained in bone marrow and get a second chance |
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How do self-reactive B cells maintained in bone marrow get a second chance?
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When self-antigen ligates immature B cells IgM, the cell continues to rearrange L chain genes. The cell makes a new L chain and thus has new IgM with a new specificity.
If: A) New IgM isn't self-reactive anymore --> B cells leave bone marrow B) New IgM still is self-reactive, L chain genes keep rearranging until no further rearrangements are possible and cell apotoses. <b>The second chance comes from rearrangement of the L chain while still in bone marrow.</b> |
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What is anergy? When does it happen?
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State of inactivation and non-responsiveness to their specific antigen. Half life is shortened.
Happens when IgM of immature B cell binds soluble self-antigen |
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Maturation and survival of B cells requires access to_____________
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Lymphoid follicles
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What are follicular dendritic cells (FDCs)?
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network of specialized stroma with the primary lymphoid follicle of lymph node (not related to conventional dendritic cells). They attract B cells into the follicle via a chemokine, which is a survival signal
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What is the general route of B-cell circulation thru a lymphoid tissue?
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1) B Cells in blood come in to lymph node via a HEV
2) The pass into primary lymphoid follicle 3) If they don't encounter their antigen they leave the follicle and exit from the lymph node in the efferent lymph. |
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What is the key survival step of B cells into lymphoid tissue?
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Entry into a primary follicle. this step is competitive and results in survival signal.
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What things regulate B cell circulation and development?
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A variety of cytokines and chemokines
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Generally, how do cytokines/chemokines regulate B cell circulation and development?
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1) Naive B cells have receptors for chemokines secreted by stromal cells and dendritic cells
2) FDCs make an attractive chemokine 3) FDCs stimulate B cell survival via antigen or cytokines |
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What are the fates of antigen-stimulated B cells?
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B cells that find antigen form a primary focus in T cell zone, some mature to plasma cells.
Once in the primary focus they can enter follicle and form a <b>germinal center</b> leading to isotype switching, affinity maturation, and memory cell development. |
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What mainly comprises a primary lymphoid follicle?
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B cells enmeshed in a network of follicular dendritic cells.
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What is stage in development/normal cell equivalent to: <b>Acute lymphoblastic leukemia</b>
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Lymphoid progenitor
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What is stage in development/normal cell equivalent to: <b>Pre-B-Cell Leukemia</b>
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Pre-B cell
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What is stage in development/normal cell equivalent to: <b>Mantle Cell Lymphoma</b>
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Resting, naive B cell
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What is stage in development/normal cell equivalent to: <b>Chronic lymphocytic leukemia</b>
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Activated or memory B cell
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What is stage in development/normal cell equivalent to: <b>Follicular center cell lymphoma/Burkitt's lymphoma</b>
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Mature, memory B cell (resembles germinal center cell)
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What is stage in development/normal cell equivalent to: <b>Hodgkin's lymphoma</b>
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Germinal center B cell
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What is stage in development/normal cell equivalent to: <b>Waldenstrom's macroglobulinemia</b>
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IgM-secreting B cell
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What is stage in development/normal cell equivalent to: <b>Multiple myeloma</b>
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Plasma cell
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T/F B cells specific for self-antigens not encountered in bone marrow (eg., the periphery) can also undergo receptor editing/rearrangement of light chains
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F. They either die by apoptosis or by anergy
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before entering follicle, what are B cells expressing?
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IgD (little) and IgM (mostly)
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after entering follicle, what are B cells expressing?
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IgD (mostly) and IgM (little)
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When leaving bone marrow, B cells only express _________ at surface.
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IgM
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