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61 Cards in this Set
- Front
- Back
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What is lymphopoiesis?
Where does it occur? (B cells and T cells?) |
Lymphocyte development
Occurs in the central lymphoid organs: B cells: Bone marrow (liver:fetus, Spleen:neonatal) T cells: Thymus |
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What is the difference between lymphopoiesis in B cells and T cells?
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In B cells, production continues throughout life
T cells: Production slows down after puberty |
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Where is the thymus located?
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Upper anterior thorax
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Which cell generates all the cells of the immune system?
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Pluripotent hematopoietic stem cell (HSC)
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What kind of cells do HSC make?
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Cells with progressively more limited potential
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Which cells made directly from the HSC?
How is this cell more limited than an HSC? |
MPP (multipotent progenitor)
Has lost all its stem cell properties, has lost the capability of self renewal |
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What does MPP branch into?
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CFU-GEMM (common granulocyte/megakaryocyte/erythrocyte progenitor): erythoid and myeloid potential
ELP (early lymphocyte progenitor): lymphoid potential |
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What will the CFU-GEMM eventually give rise to?
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Gives rise to all th non-lymphoid cellular blood elements
(circulating monocytes and granulocytes, macrophages and dendritic cells that live in tissues/2ry lymph organs) |
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What will the ELP eventually develop?
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NK, B and T-cells from:
CLP: common lymphocyte progenitor ETP: Early T-lineage precursor |
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What does the CLP make?
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Precursor NK cells (which become NK cells)
Precursor B cells (that become B cells) |
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What will ETP make?
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Thymocytes that will become T cells
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What are the 4 phases of B cell development?
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1) Progenitor B cells rearrange there Ig genes
2)Immature B cells carries the Ag receptor in the form of IgM to the cell surface. Negative selection takes place 3) Immature B cells enter the periphery and mature, expressing IgM and IgD, can be activated in a secondary lymph organ 4) Activated B cells proliferate and differentiate into Ab secreting cells (plasma cells) or memory cells |
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What happens in phase 1?
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rearrangement of Ig genes in B-cell precursor
Generation of B-cell receptors in the bone marrow Independent of Ag Creation of immature B cell |
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What happens in phase 2?
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Immature B cell carries Ag receptor in the form of cell-surface IgM, which can interact with Ag
Negative selection: kill/inactivate B cells that are strongly stimulated by Ag |
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What happens in phase 3?
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The immature B cells go to the periphery and mature, expressing IgD/M
They can be activated by their specific foreign antigen in a secondary lymphoid organ |
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What happens in phase 4?
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Mature B cells make plasma cells or memory cells
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How does B cell dev'l occur?
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In Ordered stages, chracterized by:
1) sequential steps in the rearrangement of the Ag-receptor genes and the expression of their ptns products** 2)changes in exprssion of cell surface molec |
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Which genes need to be rearranged to make Ag receptors for B and T cells?
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V, D & J
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Where do these rearrangements occur in B cells?
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2 dif loci:
Heavy chain Light chain (kappa/lamda) |
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Why is the reaarangement process imprecise?
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Not all the V-(D)-J rearrangements make a DNA seq that is in frame and can be made nto a ptn
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What is a nonproductive rearrangement? Productive rearrangement?
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Nonprod: unsuccessful rearrangements that don't make a ptn
Productive: successful rearrangements that produce a ptn |
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How many gene loci can be rearanged at a time?
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Just 1
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What is the first gene locus to be rearranged?
What is the 2nd? |
D (on the heavy chain) (D => J)
then V => DJ |
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What happens if the heavy chain has a productive rearrangement?
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Heavy chain ptn is expressed, pairs with a surrogate light chain that the B cell produces, to form a pre-BCR on the cell surface
Receptor makes intracell signals to stop rearrangement at the locus and induce cell division Then get rearrangement at light chain locus |
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What happens when the light chain rearranges?
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V=>J
If tis is productive, light chain pairs with the heavy chain and the B cell expresses a BCR |
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What happens if the rearrangements at either of the loci is unsuccessful?
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The cell dies by apoptosis
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What is required for dev'l of immature B cells from B cell progenitors?
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interaction of B-cell progenitors with stromal cells of bone marrow
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How do bone marrow stromal cells interact with the progenitor B cells?
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MPP express FLT3 (tyr kinase receptor) which binds to its ligand on stromal cells. MPP require FLT3 signallling to differentiate into CLP
CLP express IL7 receptor and can bind the IL7 made from stromal cells and that is required for dev'l of B-cells (growth and survival) Stromal cells secree CXCL12, a chemokine needed to retain HSC and lymphoid progenitos in the BM Stromal cells have VCAM-1, an adhesion molec, that promotes binding of the Kit receptor of progenitor B cells to SCF (stem cell factor) on the BM Signalling by Kit induces the proliferation of pro-B cells |
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What are the stages in B cell dev'l? (7)
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Stem cell
Early pro-B ecll Late pro-B cell Large pre-B cell Small pre-B cell Immature B cell Mature B cell |
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In what stages does heavy chain rearrangement take place?
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D->J : early pro-B cell
V-> DJ: late pro-B cell |
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What happens in the large pre-B cell stage?
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Express heavy chain (its VDJ have been rearranged)
Get pre-BCR expression if successful rearrangement (µ chain transiently at surface) Proliferation of large pre-B cells Express surrogate light chain |
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When does the light chain start to rearrange?
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pre-B cell stage
V-> J (heavy chain rearrangement has now stopped) (also express intracellular µ chain) |
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What happens at the immature B cell stage?
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Heavy and light chains have been rearranged
IgM is expressed on cell surface |
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What happens in a mature B cell?
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IgD and IgM are made from alternatively spliced H chain transcripts
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What happens during the rearrangement of Ig gene segments?
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Addition/deletion of nucleotides during the formation of the junctions btw the gen segments
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What is the chance that a V->DJ or a V-> J rearrangement results in an in-frame downstream seq?
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1 in 3
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Why do mature B cells only produce 1 specificity of CR if they have 2 alleles for each Ig locus in a diploid genome?
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2 mechanisms:
1) Rearrangement of V->J or V-> DJ occurs on one CHR at a time 2) As soon as the allele has rearranged, the productive joins are checked and if they lead to a fctnal ptn: ptn is assembled into a receptor that signals the cell to stop rearrangement at that locus |
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What are the chances of generating a pre-B cell?
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5/9 (55%)
(1/3 that a good rearrangement of CHR 1, and 2/3 x 1/3 get a good rearrangement on CHR2 .: 1/3 +2/9 = 5/9) |
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What happens when a productive rearrangement tales place on 1 allele of the heavy chain locus?
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Express the µ heavy chain ptn at the pre-B cell stage
Ass't with surrogate light chain |
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Which 2 proteins make up the surrogate light chain? What do they ass't with?
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λ5 and VpreB
Ass't with Igα and Igβ |
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What is the pre-BCR complex composed of?
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λ5 VpreB Igα Igβ
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What happens when the pre-BCR is expressed?
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1) Stop rearrangement at the heavy chain locus: can do this by dec RAG/2
2) Induce proliferation: all the progeny will have same H chain but can have many dif light chains due to different rearrangements .: can make many dif Ag specificities from a single pre-B cell) |
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Is it more likely to make a fctnal light chain or fctnal heavy chain? Why?
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Fctnal light chain
1-Nonproductive light chain rearrangements can be rescued by further gene rearrangement 5 fctnal Jk segments so can combine a 5'Vk with any of the 3'Jk if a nonfctnal ptn forms (can't do this at heavy chain locus because there's only one DJ for V to rcombine with) 2- Existence of 2 light chain gene loci (k and λ) |
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Where are more cells lost: pre-B -> immature B or pro-B -> pre-B?
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pro-B to pre-B cuz more chances of making non productive Heavy chain then light chain
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What happens once the light chain has been rearranged?
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Make the light chain and combine it with the heavy chain µ to make an intact IgM
Form BCR by expressing IgM at surface with Igα and Igβ BCR sends signal to stop rearrangithe light chain and to continue maturation |
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What is allelic exclusion?
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Only 1 of the 2 alleles of a given fene in a diploid genome is expressed (this takes place in both heavy and light chain loci)
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What is isotypic exclusion?
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expression of a light chain from only one of the 2 light chain loci (k or λ) in each individual B cell
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How do these 2 types of exclusion take place?
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Signalling from the BCR
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What is the clonal selection theory?
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An individual B cell produced only one specificity of Ab.
The monospecificity of B lymphocytes is achieved by the regulated program of Ig gene rearrangements in which a productive Ig gene rearrangement suppreses further rearrangement at the same locus |
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What are the 4 possible fates of immature B cells in the bone marrow?
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1)BCR does not recognize self-molec: migration to spleen=> mature B cells
2)BCR is strongly reactive to self: Receptor Editing or Deletion 3) BCR recognizes self with medium affinity: Anergenic mature B cells (migrate to periphery but won't react, frozen state) 4) BCR recgnizes self with low affinity: Clonally ignorant; migration to spleen=> mature B cells |
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When are immature self reactive B cells eliminated?
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When their BCR recognizes a multivalent self-Ag (get extensive cross-linking of the BCR)
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What is clonal deletion?
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Ag induced loss of cells from B cell population
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What happens if u add a rearranged transgene (heavy chain) into a mouse?
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Inhibit rearrangement of the corresponding endogenous Ig locus
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What happens when light and havy chain transgenes that are already rearranged are inserted into mice?
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nearly all the devloping B cells express thesame specificity
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What is receptor editing?
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Some B cells make further light-chain gene rearrangements to make new receptor specificities (if the new BCR doesn't bind to self in the bone marrow, the immature B cell can reach the spleen and mature)
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What happens when there is a strong liation of the IgM by self antigen?
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-RAG ptn expression continues
-Stop B-cell dev'l and continue light chain rearrangement (low cell sureface IgM) -A new receptor specificity is expressed --> If the new receptor is still self reactive, rearrangement continues until the V and J sgments are exhausted, if its still self-reactive, the B cell undergoes apoptosis -->If the new receptor is not self reactive anymore, the immature B cell migrtes to the periphery and matures |
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What is anergy induction of self-reactive Immature B cells?
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Immature B cells that recognize more weakly cross-linking self-Ags (soluble ptn) (i.e soluble ptn in the bone marrow)
->these Bcel have low IgM on their surface, mostly intracellular ->Non-reactive state=ANERGY there was no proliferation of these cells, they could not cross link |
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What are the differences between anergic and non anergic B cells?
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Non-anergic:
-Have IgD -Migrate to the spleen -Migrate to the lymphoid follicles -Have a half-life of months Anergic: -Have IgD (x-linking IgD=Anergy, block in signal transduction through the BCR) -Migrate to the spleen (not deleted) -Don't migrate to the lymphoid follicles (follicular exclusion) -Half life is short (3-4 days) |
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What happens to B cells that recognize a low affinity non-crosslinking self Ag?
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Normal migration to the periphery
Remain in state of ignorance of their self-Ag because: ->self-Ag interacts weakly with the BCR, low intracellular signalling is generated ->the self Ag is not expressed in the bone marrow |
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What happens to mature B cells that recognize self-Ag in the peripheral lymphoid organs? (bone marrow does not express every self Ag!)
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Self tolerance can be induced at the mature B-cell stage
->Clonal deletion (NO receptor editing) ->Anergy of mature B cells |
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What are the mechanism o self tolerance in the B cell compartment of central tolerance? Peripheral tolerance?
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Central: Clonal deletion, Receptor editing, Anergy
Peripheral: Clonl deletion, Anergy |
