antigen-independent b-cell development 1.dna rearrangements establish the primary repertoire,...
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Antigen-Independent B-Cell Development
1. DNA rearrangements establish theprimary repertoire, creating diversity
2. Allelic exclusion ensures that each clone expresses a single antibody on the surface, establishing specificity
3. Deletion of self-reactive clones establishes tolerance
Bone Marrow
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Bone Marrow Stromal Cells Support Early B Lymphopoiesis
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Ordered Rearrangement of Ig GenesDuring B-Cell Development in the Bone Marrow
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Heavy chain rearrangement occurs first:DJ on both allelesV-DJ on one allele
Productive rearrangement (1/9)
Mu and preBCR (surrogate L.C.)
1. STOP H.C.rearrangement2. Proliferation3. Begin L.C. rearrangement
Non-productive rearr. (8/9)
V-DJ on second allele
Mu and pBCR Non-prod.
DEATH
PRD-J
NPRPR
NPRNPR
(H.C.Alleles)
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Productive rearrangement produces IgM and theB CELL RECEPTOR on the surface
Light Chain Rearrangement: 4 possible alleles, eachwith 1/3 chance of a productive rearrangement
Kappa usually precedes lambda
STOP further L.C. rearrangement
PR,GLGL,GL
NPR,PR
GL,GL
NPR,NPR
PR,GL
NPR,NPR NPR,NPR
NPR,NPRNPR,PR
DEATHCONTINUE DEVELOPMENT
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Rearrangement of Ig alleles is orderedand regulated to achieve allelic exclusion
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Checkpoints which confer allelic exclusion
pBCR
BCR
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THE B CELL RECEPTOR
1. Bound antigen is inter- nalized and presented to T cells.
2. Bound antigen gives signals to the B cell to proliferate and differentiate.
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Signalling from the BCR
Lack of Btkcauses Bruton’sXLA
(blocked at preBstage)
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No self recognition1. Proliferation2. Maturation3. Exit to periphery
IgM on B Cell Surface
L.C. editing
Recognition of self
DEATH
Recognition of self
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Light Chain Receptor Editing to Change theSpecificity of Self-reactive Clones
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Ig GeneStatus atDifferent StagesOf
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Antigen-Independent B-Cell Development
1. DNA rearrangements establish theprimary repertoire, creating diversity
2. Allelic exclusion ensures that each clone expresses a single antibody on the surface, establishing specificity
3. Deletion of self-reactive clones establishes tolerance
Bone Marrow
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Antigen-Dependent B Cell Development
In Periphery (spleen and LN)
Antigen and TH cells give B cells two signals: 1) proliferate 2) differentiate
T-cell dependent responses are refined two ways: 1) higher affinity antibodies
2) IgG/A/E (“switched”) isotypes
Two products of B cell development:1) plasma cells secrete Ig (final effector)
2) memory cells respond to IIo antigen
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Marginal Zone
Germinal Center
Naïve ImmigrantFrom Marrow
Low affinity IgM
High affinity IgG
Memory Cell
antigen
IgM
MHCII
IgG
2. FDC-
1. Ag-sp T cell1.Affinity Maturation
2. Isotype Switching
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B CellActivationBy T-CellDependent And T-CellIndependentAntigens
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The Germinal Center
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T Cell-B Cell Communication
1. Cell-cell signals from CD40L/CD40 andother surface molecules.
2. Secreted cytokines
(B cells signal T cells by presenting Ag inassociation with MHC II)
T cells provide 2 kinds of help to B cells:
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T Cell:B CellSynapse
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The Germinal Center
1. Affinity maturationa. Somatic hypermutationb. Selection for high affinity clones
2. Isotype switch recombination
4. Final maturation to memory or plasma cell.
3. Peripheral tolerance
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Proliferation
Ag(FDC) + T cell help
(Iterative cycles)
SURVIVAL
butT help and no Ag(eliminates low affinity clones)
orAg and no T help(eliminates self-reactive clones, giving tolerance)
DEATH
+ Somatic Hypermutation
AFFINITY MATURATION IN THE GC
Darkzone
Lightzone
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Pattern of V Gene Mutations Provides EvidenceOf Cyclical Mutation and Selection Events
Random mutation combined with selection.
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B Cells MakingIg with HighAffinity for Antigen AreSelectivelyProtected fromApoptosis inthe GerminalCenter.
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SELECTIVE SURVIVAL IN GC
1. Selects clones producing high affinityantibody--i.e.affinity maturation
2. Eliminates self-reactive clones--peripheral tolerance.
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Hyper IgM Syndrome
1. Mutations in CD40L
2. Mutations in CD40
3. Mutations in AID (or repair enzymes downstream of AID)
4. One or more other genes defined by human disease!
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Marginal Zone
Germinal Center
Naïve ImmigrantFrom Marrow
Low affinity IgM
High affinity IgG
Memory Cell
antigen
IgM
MHCII
IgG
antigen
FDC
Ag-spec. T cell1. Affinity Maturation
2. Isotype Switching
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1. Memory B cells
Surface Ig, usually IgGHigh affinity for antigenLong-lived, even in the absence of antigenRespond rapidly to secondary stimulation
2. Plasma Cells
Secrete copious amounts of Ig, no surface IgNon-dividingSome are short-lived, some become long-lived in the bone marrow
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Different Ig Isotypes
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Ig Isotypes Have Different Functions and Distributions
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Secreted AntibodiesFunction in Various WaysTo EliminateForeign Invaders
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AntibodiesCan NeutralizePathogens
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AntibodiesActivate NKCell Killing by Engaging FcReceptors
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AntibodiesActivateComplement-Mediated Lysis
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Opsonization ofPathogens by Antibodies
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IgE, residentOn Mast Cells,Causes De-Granulation WhenAntigen Is Encountered