Term
| Phases of B cell development |
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Definition
Repertoire assembly: generation of diverse, clonally expressed B-cell R in BM
Negative selection: alteration, elimination, or inactivation of BCR that bind to components of the human body
Positive selection: promotion of a fraction of immature B cells to become mature B cells in secondary lymphoid tissue
Searching for infxn: recirculation of mature B cells b/t lymph, blood, and secondary lymphoid tissue
Finding infxn: activation, clonal expansion of B cells by pathogen-derived Ag in secondary lymphoid tissue
Attacking infxn: differentiation to Ab-secreting plasma cells & memory B cells in secondary lymphoid tissue |
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Term
| Describe the process of allelic exclusion |
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Definition
results in B cells expressing surface Ig with one specificity, high-avidity binding
no allelic exclusion gives heterogenous BCR with low-avidity binding |
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Term
| Discuss why chromosomal translocations can be associated with B cell tumors |
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Definition
Burkitt's lymphoma
translocation of IgM gene on 14 & MYC gene on 8 |
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Term
Discuss the different types of B cell tumors: normal cell equiv/stage in development, location, status of Ig V genes
-acute lymphoblastic leukemia (ALL)
-pre-B-cell leukemia
-mantle cell lymphoma
-chronic lymphocytic leukemia
-follicular center cell lymphoma (Burkitt's lympoma)
-Hodgkin's lymphoma
-Waldenstrom's macroglobulinemia
-multiple myeloma |
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Definition
-(ALL): lymphoid progenitor, BM & blood, unmutated
-pre-B-cell leukemia: pre-B cell, BM & blood, unmutated
-mantle cell lymphoma: resting, naive B cell, periphery, unmutated
-chronic lymphocytic leukemia: activated or memory B cell, periphery, usually unmutated
-follicular center cell lymphoma (Burkitt's lympoma): mature memory B cell resembles germinal center B cell, periphery, mutated, intraclonal variability
-Hodgkin's lymphoma: germinal center B cell, periphery, mutated, +/- intraclonal variability
-Waldenstrom's macroglobulinemia: IgM-secreting B cell, periphery, mutated, no variability within clone
-multiple myeloma: plasma cell, various isotypes, BM, mutated, no variablity within clone |
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Term
State the differences between B-1 and B-2 cells
-when first produced?
-N-regions in VDJ junctions?
-V-region repertoire
-primary location
-mode of renewal
-spontaneous production of Ig
-Isotypes secreted
-requirement for T-cell help
-somatic hypermutation
-memory development |
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Definition
B-1 CELLS
-when first produced? FETUS
-N-regions in VDJ junctions? FEW
-V-region repertoire RESTRICTED
-primary location PERITONEAL & PLEURAL CAVITIES
-mode of renewal SELF-RENEWING
-spontaneous production of Ig HIGH
-Isotypes secreted IgM >> IgG
-requirement for T-cell help NONE
-somatic hypermutation LOW-NONE
-memory development LITTLE-NONE
-produce mainly Ab against bacterial polysaccharides
B-2 CELLS
-when first produced? AFTER BIRTH
-N-regions in VDJ junctions? EXTENSIVE
-V-region repertoire DIVERSE
-primary location SECONDARY LYMPHOID ORGANS
-mode of renewal REPLACED FROM BM
-spontaneous production of Ig LOW
-Isotypes secreted IgG > IgM
-requirement for T-cell help YES
-somatic hypermutation HIGH
-memory development YES |
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Term
| Discuss the selection and further development of B cell repertoires |
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Definition
B cells that bind to multivalent self Ag are retained in BM
-receptor editing can rescue a self-reactive B cell by inducing rearrangement of L chain genes
B cells that bind to univalent self Ag become anergic
-signaled to make IgD, become unresponsive to Ag, enters peripheral circulation, lives ~5 days
-if immature B cells don't gain access to a primary lymphoid follicle, they die
-isotype switching, somatic hypermutation occur in germinal centers |
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Term
| Discuss the different types of central tolerance for B cells |
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Definition
Developed in a primary lymphoid organ (for B cells: the bone marrow)
B cells reactive to self antigens in BM experience one of three fates:
-receptor editing: gets rid of self-reactivity
-die by apoptosis
-become anergic |
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Term
| Discuss the role of the thymus in T cell development |
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Definition
T cell precursors migrate from BM
selects for alphabeta T cells that can recognize self MHC I or II, but don't bind too tightly
positive selection (ensures self-MHC restriction)
negative selection (removes auto-reactive T cells)
gammadelta-T cells leave thymus once TCR has productively rearranged |
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Term
| Discuss the stages of T cell development in the thymus |
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Definition
thymocytes: immature T cells
Notch expression, signaling results in commitment to T cell lineage
IL-7 R expression is req'd for T cell development
Double negative (committed progenitor, rearrange b/g/d, first checkpoint/pre-TCR, proliferating pre-T cells/pTalpha)
Double-positive (rearrange a/g/d/CD4&CD8, second checkpoint/TCR) |
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Term
| Explain the interactions that lead to positive and negative selection of developing T cells |
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Definition
Positive:
a:b TCR which bind to self MHC are selected, ensures peripheral T cells can recognize Ag presented in context of self-MHC (<2% of ++ thymocytes can bind self-MHC)
thymic cortical epi express MHCI&II complexed with self peptides
a-chain can rearrange if TCR doesn't bind MHC
if recognized, thymocyte is signaled to continue maturation
apoptosis occurs if MHC not recognized
controls expression of CD4 or CD8 co-R
ensures self-MHC restriction, determines co-R specificity
Negative:
removes auto-reactive T cells in the thymus
T cells with a TCR that binds too tightly to self-MHC I on dendritic cells, macrophages, others in thymus are signaled to die
In periphery:
-T cells that are self-reactive and bind to self-peptides and MHC don't receive co-stim from APC --> anergy
-CD4+ Treg can suppress proliferation of naive self-reactive T cells |
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Term
Describe the role of the AIRE molecule during T cell development
-what does its lack result in? |
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Definition
transxn factor
responsible for expression of tissue specific proteins in the thymus, imp in negative selection
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED)
-T cells specific for tissue-specific antigens aren't eliminated by negative selection; they mature and enter peripheral circulation & attack tissue cells |
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Term
| State differences between ab and gd-T cells |
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Definition
CD34 (uncommitted progenitor) -> CD2 (committed double-neg T-cell progenitor)
rearrangement of delta, gamma, beta chain genes
some cells commit to gd T-cell lineage
-leave thymus
-dominant T cell pop in epithelial tissues
-don't require MHC for Ag recognition
-can recognize bact products, heat shock or stress proteins
-immune response regulation, maintenance of mucosal epithelial integrity, innate immunity
some rearrange b gene first, halts rearrangement
-alpha, gamma, delta rearrangement resumes
-productive alpha chain rearrangements --> CD4+CD8+ a:b cells
-minority of double-positives --> more g:d T cells |
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Term
| Describe further differentiation states of ab-T cells after activation |
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Definition
naive T cells travel b/t circulation and secondary lymphoid tissues
activation leads to further development, differentiation
-CD8+ T cells: activated cytotoxic
-CD4+ Th
-Th1: cell mediated, macrophages
-Th2: humoral, produce Ab
-Th17: inflammatory
-effector and memory T cells can migrate to sites of infection |
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Term
What does B cell development require in the BM?
-how do they interact? |
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Definition
Stromal cells
-are nonlymphoid
-interact with developing B cells via adhesion molecules & L, GF
-Stem cell factor on stromal cells interacts with Kit on developing cells (promotes proliferation)
-IL-7 made by stromal cells stimulates growth & proliferation of late pro-B cells and pre-B cells |
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Term
| B cell development checkpoints |
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Definition
Early pro-B cell - commits to B-cell lineage
H chain rearrangement
First CP: selection for functional H chains
-BCR -> progresses
-no BCR -> apoptosis
L chain rearrangement: makes L-chain gene diversity in B cell pop
2nd CP: selects for functional L chains
-BCR -> progresses
-no BCR -> apoptosis
Immature B cell: makes functional IgM |
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Term
| B cells: Gene rearrangements leading to surface Ig |
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Definition
early pro-B cell undergoes H chain gene rearrangement, D-J rearrangements on both csomes
late pro-B cell undergoes further H chain rearrangement.
-if successful V-DJ rearrangement doesn't happen on either csomes, apoptosis
pro-B cell undergoes L-chain rearrangement
-if one csome is successful kappa, cell is mu/kappa IgM
-if one csome is successful lambda, cell is mu/lambda IgM
-if neither csome is successful in either one, apoptosis |
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Term
| Summary of B cell development: 6 stages in BM, 6 stages in secondary lymphoid organs |
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Definition
BM:
stem cell - mu germline, kappa/lambda germline
early pro B cell - m germline, k/l germline
late pro B cell - mDJ, k/l germline
large & small pre B cell - mVDJ, k/l germline
immature B cell - mVDJ, k/l VJ
Secondary lymphoid organs & circulation:
immature B cell - IgM+, IgD-, leaves BM & enters peripheral circulation
immature - IgMhigh, IgDlow, alternative splicing to give delta & mu chains, gains access to primary lymphoid follicle & matures
mature naive - IgMlow, IgDhigh, enters circulation & binds specific Ag in lymphoid tissue draining infxn
Ag-activated B lymphoblast - alt splicing to secrete Ig, isotype switching, somatic hypermutation
Ab-secreting plasma cell - IgM & IgG, fighting infxn
Memory cell - IgG, preparing for future infxn |
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Term
2 populations of TCR:
alpha beta-T cells
gamma delta-T cells |
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Definition
recognize peptides bound to self MHC
-CD4 T cells: MHC II restricted
-CD8 T cells: MHC I restricted
not MHC restricted |
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Term
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Definition
thymus fails to develop, T cells absent
patient is susceptible to a wide range of opportunistic infxns |
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Term
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Definition
lack of MHC I or MHC II molecules by lymphocytes and thymic epithelial cells
-no MHCI: have CD4, no CD8
-no MHCII: have CD8, a few abnormal CD4 |
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Term
| Immune dysregulation, polyendocrinopathy, enterophaty, X-linked syndrome (IPEX) |
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Definition
Lacking Treg
Caused by lack of FoxP3 --> autoimmunity in a variety of tissues, esp gut, thyroid, pancreatic beta cells, skin --> recurrent infxn
Tx: BM transplant from an HLA-identical sibling |
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