G.2014-immuno~ (10a.humoral immunity'bcell'-jyh)
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Transcript of G.2014-immuno~ (10a.humoral immunity'bcell'-jyh)
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Surface markers on B lymphocytes and their function
Subsets of B lymphocytes
Function of B lymphocytes
Contents
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Surface Markers on B Lymphocytes and Their Functions
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1. B cell receptor--BCR
• Membrane immunoglobulin(mIg) on B cell
• Recognize and bind antigen specifically
Part I B cell receptor complex and its associated molecules
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2. BCR complex• BCR and Ig-(heterodimer) Ig(CD79a) , Ig(CD79b) • Participate in BCR formation• ITAM------bind to tyrosine kinase• Transmit activating signal
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3. B cell co-receptor complex ----CD19, CD21, CD81
CD21
CD19CD81
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CD21
CD19CD81
Antigen
C3d
CD21 occurs in a complex with CD19, CD81 . CD21 binds to the C3d fragment of complement. Complement-coated antigens therefore can cross-link CD21 with the BCR.
Co-crosslinking of CD21 with the BCR introduces more CD19 into the BCR and increases the signal through the BCR.
CD21
CD21: receptor of C3d,C3d and iC3b ----Enhance the binding of BCR and antigen and pass activating signal to CD19
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CD19
CD19 is a transmembrane protein with a very large cytoplasmic domain. It is present on follicular dendritic cells and on B cells from the early pre-B stage until plasma cell differentiation. It is found associated with the BCR, or with CD21, or on its own in the plasma membrane.
The cytoplasmic domain has multiple tyrosines which are phosphorylated following BCR ligation. CD19 acts as a adaptor molecule and amplifies BCR signals.
****
sykCD79CD79
****
CD79CD79
*****
CD19: Transmit activating signal into B cell
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CD21
CD19CD81
Antigen
C3d
CD81 occurs in a complex with CD19, CD21 . CD81: a transmembrane protein, stable CD21and CD19
CD81
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Src family kinases then bind the phosphorylated CD19
Antigen recognition
C3d opsonized bacterium
• mIg and CD21 are cross-linked by antigen that has activated complement
C3d binds to CD21,
P P
• CD21 is phosphorylated and receptor-associated kinases phosphorylate CD19
P P
• Phosphorylated CD19 activates more Src family kinases• CD 81 and CD 21 also play a role as a coreceptor for the BCR
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Transmission of signals from the cellsurface to the nucleus
• B cell-specific parts of the signalling cascade are associated with receptors unique to B cells - mIg, CD19 etc.
• Subsequent signals that transmit signals to the nucleus are common to many different types of cell.
• The ultimate goal is to activate the transcription of genes, the products of which mediate host defence, proliferation, differentiation etc.
Once the B cell-specific parts of the cascade are complete, signalling tothe nucleus continues via three common signalling pathways via:
1.The mitogen-activated protein kinase (MAP kinase) pathway2. Increase in intracellular Ca2+ mediated by IP3
3.The activation of Protein Kinase C mediated by DAG
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1. CD40----co-stimulatory receptor• CD40 on B cell binds to CD40L on
activated T cell• Transmit an important co-stimulatory signal to B cells• Upregulate expression of B7 on B cells • Participate in class switching of antibody
Part II B cell Accessory molecules
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CD40
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2. B7• B7-1 (CD80) and B7-2 (CD86) • Expressed on B cells or other APC• B7-CD28• B7-CTLA-4
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4. CD80/CD86(B7-1,B7-2
B
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3. MHC molecules• Class , MHC moleculesⅠ Ⅱ
4. Mitogen receptor• SPA, LPS• PWM
5. Cytokine receptor• IL-4R, IL-5R, IL-6R
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Part III Development and differentiation of B cells
Differentiation of B cells in Bone marrow
Differentiation of B cells in peripheral lymphoid tissue
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1. Differentiation of B cells in Bone marrow----Ag independent
• Hematopoietic stem cells • Lymphoid progenitor • Pro-B cells( chain rearrangement) • Pre-B cell( chain + surrogate light chain ) • Immature B(mIgM, chain +κchain orλchain)
• Mature B(mIgM, mIgD) • Functional B repertoire
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Overview of B-cell development
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Peripheral
Stages of B cell development
Stem Cell Early pro-B cell Late pro-B cell Large pre-B cell
Small pre-B cell Immature B cell Mature B cell
Each stage of development is defined by rearrangements of IgH chain genes, IgL chain genes, expression of surface Ig, expression of adhesion molecules and cytokine receptors
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Organization of Ig gene segments in the mouse V-variable
D-diversity
J-joining
C-constant
L-leader
V gene
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Heavy-chain gene rearrangement and RNA processing
RAG1/RAG2
RAG1/RAG2
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Stages of differentiation in the bone marrow aredefined by Ig gene rearrangement
B CELL STAGE
IgH GENECONFIGURATION
Stem cell Early pro-B Late pro-B Large pre-B
Germline DH to JH VH to DHJH VHDHJH
Pre-B cellreceptor
expressed
Ig light chain gene has not yet rearranged
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Kappa light-chain gene
rearrangement and RNA processing
RAG1/RAG2
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V D J C
D JV CD J
V CD JV
Germline
DH-JH joining
VH-DHJH joining
V J C
V CJV
Germline
VL-JL joining
light chain rearrangement
Largepre-B
Smallpre-B
Y ImmatureB cell
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Peripheral
Checkpoint in B cell development
Stem Cell Early pro-B cell Late pro-B cell Large pre-B cell
Small pre-B cell Immature B cell Mature B cell
Y
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B cell receptor
Expressed when VHDHJH CH is productively rearranged
VpreB/5 - the surrogate light chain, is required for surface expression
Ig & Ig signaltransductionmolecules
CH
Heavy chainVHDHJH
Light chainVLJLCL
VpreB
5
Pre-
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LargePre-B
LargePre-B
LargePre-B
LargePre-B Large
Pre-BLargePre-B Large
Pre-BLargePre-B Large
Pre-BLargePre-B
Proliferation
Y ImmatureB cell
Light chain expressedIgM displayed on surface
IgM
Ligation of the pre-B cell receptor triggers entry into the cell cycle
Largepre-B
Many large pre-B cells with identical pre-B receptors
Large pre-B
Intracellular VDJCH chainVL-JL rearranges
Proliferation stops
Small pre-B
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B cell receptor
Ig & Ig signaltransductionmolecules
CH
Heavy chainVHDHJH
Light chainVLJLCL
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Diversity of BCR Combinatorial diversity (2.5x108)
Junctional diversity Somatic hypermutation
Total: 1014
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2. Events in the differentiation of B cells:
Gene rearrangement of Ig
Clonal deletion
Immature B cells : mIgM--self antigen mIgM X self antigen
apoptosis or anergy surviving to develop
mature B cells
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Y
Y
Y Y
B
Immature B cellCell surface Ig expressed
Able to sense Ag environment
Can now be checked for self-reactivity
Acquisition of antigen specificity creates a need
to check for recognition of self antigens
1. Physical removal from the repertoire DELETION2. Paralysis of function ANERGY3. Alteration of specificity RECEPTOR EDITING
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B cell self tolerance: clonal deletion
Immature B cell recognizesMULTIVALENT
self Ag
B
Clonal deletion byapoptosis
YYBImmatureB
BSmallpre-B
Small pre-B cellassembles Ig
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Y
B cell self tolerance: Anergy
B
YY
YB
Anergic B cell
IgD normal IgM low
Immature B cell recognizessoluble self Ag
No cross-linking
YYB
ImmatureB
BSmallpre-B
Small pre-B cellassembles Ig
IgM
IgD
IgD
IgD
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Receptor editingA rearrangement encoding a self specific receptor can be replaced
V CD JVV V
Y
BB!!Receptorrecognizes
self antigen!!
B Apoptosisor anergy
YBB
Edited receptor now recognizesa different antigen and can be
rechecked for specificity
CD JVV VV
Arrest developmentAnd reactivate
RAG-1 and RAG-2
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YYY
YYY
Mature B cellexported to the
periphery
Y
Y
B cell self tolerance: export of self tolerant B cells
IgD and IgM normal
IgMIgD
IgD
IgD
IgD
IgMIgM
IgM
Immature B cell doesn’t recognize any
self Ag
YYB
ImmatureB
BSmallpre-B
Small pre-B cellassembles Ig
B
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2. Differentiation of B cells in peripheral lymphoid tissue----Ag
dependant
• Plasma cell Ab• Memory B cell secondary
immune response
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B cell recognizesnon-self antigen
in periphery
Ig-secreting plasma cell
Differentiation in the periphery
YY Y YY YYY Y
BY Y
YYYYY
BY Y
YY
YYYB
Mature peripheralB cell
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Control of Affinity & Affinity Maturation
Five B cell antigenreceptors - all specificfor , but withdifferent affinitiesdue to somatichypermutationof Ig genes in the germinal center B B B B B
Only this cell, that has a high affinity for antigenOnly this cell is rescued from apoptosis
The cells with lower affinity receptors die of apoptosis by neglect
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Isotype Switching Under the Influence of HelperT Cell-Derived Cytokines
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Mechanism of Ig Isotype Switching
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Plasma cells
Surface Surface High rate Growth Somatic Isotype Ig MHC II Ig secretion hypermutation switch
B
BMature B cell
Plasma cell
High Yes No Yes Yes Yes
Low No Yes No No No
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B cell subpopulations
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According to expression of CD5 or notB1 cell (CD5+) B2 cell (CD5-)
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CD5
Two B cell lineages
B
B cell precursor
B
Mature B cell
B2 B cells
Plasma cell
YY Y YY YYY Y
PC
IgG
BYYYYYYYYYY
YYYYY YYYYY
IgM - no other isotypes
B
Distinct B cellprecursor
B1 B cells‘Primitive’ B cells found in pleura and peritoneum
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Comparison of B1 and B2 cells B1 B2
Development early late BCR mIgM mIgM and mIgD CD5 + - Reproduction self-renewing from pre-B cell in BM Recognized Ag TI-Ag and auto-Ag TD-Ag Ab type IgM >IgG IgG >IgM Ab avidity low high Second IR - + Function innate immunity adaptive immunity
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Function of B cell
Produce the antibody----HI Present antigen----APC Participate in immunological regulation