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Antigen-independent development of B cells
B cell subsets and development
Fetus liver：B1 B
Bone Marrow：
HSC
proB
mB
spleen：NF B
FO B
FP
MZ B
preB
imB
three major naive peripheral B-cell populations
B cell
High-affinity IgG
Immunol Rev 2004; 197:206
INSTITUTE FOR IMMUNOBIOLOGY
B cell and B cell-mediated
humoral immune response
Part II
Department of Immunology
Fudan University
Wei Xu, Ph.D
021-54237749
[email protected]
Overview of the humoral immune response against bacterial
B cells
plasma cells
Significance of humoral immunity
eliminate extracellular bacterium and toxin
eliminate extracellular virus
B cells and humoral immune response
1.
Recognition of the specific Ag
2.
Activation, proliferation,
differentiation
2. Germinal center: later event
3. General feature of Ab response
thymus-dependent (TD) antigens
B response to TD Ag requires direct contact with Th cells,
thymus-independent (TI) antigens
TI- 1 Ag
bacterial cell-wall components,
lipopolysaccharide (LPS),
TI-2 Ag
highly repetitious molecules,
bacterial flagellin
bacterial cell-wall polysaccharides with repeating units.
Recognition of TD Ag
Directly recognize Ag
(B cell epitope)
No MHC involvement
surfaced displayed
B cell-epitopes
Ab (BCR) binds the B-cell epitope directly,
TCR binds with a self-MHC-T-cell-epitope complex
BCR-Iga/Igb -coreceptor complex
B cell epitope
（CD21-CD19-CD81）
coreceptor
B cell epitope
Ag-C3d
BCR
CR2
Iga/b
CD19
Signal
Signal
+
+
B cell activation
+++
B cells and humoral immune response
1.
Recognition of the specific Ag
2.
Activation, proliferation,
differentiation
2. Germinal center: later event
3. General feature of Ab response
1) activation
A. 2-signal activation model
B. the help from Th cell
2) Signal transduction
3) Proliferation and differentiation
the 2-signal
rule
signal 1：BCR － B cell epitope
signal 2：CD40 － CD40 L
B
B7
survive
Th
CD40L
survive
Co-sti mol
B cell activation requires 2 signals
Signal 3: IL-4
Signal 1 From antigen
Recognition of
B cell epitope
Receptor-mediated Ag endocytosis
T cell epitope-MHC II presentation
BCR serves 2 roles:
1.
Ag-induced clustering of BCRs
delivers signals that initiate the
activation process.
2.
BCR internalize the Ag into
endosome, process and present on
surface for T recognition
Signal 1
From antigen
Signal 3
From Th
Signal 2
From Th
Antigen crosslinks mIg(BCR), generating signal 1, which leads to
increased expression of class II MHC and costimulatory B7.
Antigen–BCR complexes are internalized by receptor-mediated
endocytosis and degraded to peptides, which are bound by class II
MHC and presented as peptide–MHC complexes.
Th cell recognizes Ag–class II MHC and B7-CD28 co-stimulation on Bcell membrane which activates TH cell.
Th cell begins to express CD40L.
Interaction of CD40 and CD40L provides signal 2.
Th cell release large quantities of cytokines(IL-4) signal 3 to
support the progression of the B cell replication and differentiation.
Signal 3
Th-secreting cytokines
Regulate B cell
differentiation
B cells and humoral immune response
1. Recognition of the specific Ag
2. Activation, proliferation, differentiation
1) 2-signal activation
2) signal transduction
2. Germinal center: later event
3. General feature of Ab response
Tyrosine kinase
phosphorylation
cascade
PTK Src family
immunoreceptor
tyrosine-based
activation motif
(ITAM)
Bruton’s disease
a genetically determined immunodeficiency disease
inability to synthesize all classes of antibody.
discovered in 1952 by O. C. Bruton.
Case:
a young boy who had mumps 3 times and experienced 19 different
episodes of serious bacterial infections during 4 years.
Do not raise Abs to any vaccines.
1937，Tiselius use Electrophoresis to analyze the serum proteins
Which comprised of 5 components：
albumin、a1、a2、b、g globulin
anode
Antibody，IgG
albumin
a globulin
b globulin
g globulin
cathode
Electrophoresis
Serum of unimmunized
person
Pathogenesis: failures in B-cell development.
inhibition pro–B to pre–B-cell transition
In 1990s, the gene was cloned which
encodes Bruton’s tyrosine kinase (Btk).
Btk play important roles in B-cell signaling
vital to the function of mature B cells
Absence of Btk results in the failure of B
activation and Ab generation
B cells and humoral immune response
1. Recognition of the specific Ag
2. Activation, proliferation, differentiation
1) 2-signal activation
2) signal transduction
3) proliferation
2. Germinal center: later event
3. General feature of Ab response
Early and late event in Ab response to TD antigen
Early events：
follicle（B）-paracortex（T）border,
B activation and T-B activation
Small amounts of Ab production
Late events：
At the germinal center
Presence of Ag and Th
Affinity maturation
Ig class switch (IgM
Memory B
IgG)
（T cell）
Affinity
maturation
late event in Ab response to TD antigen in LN
Ag
Th
1、somatic hypermutation
2、affinity maturation
3、Ig class switch
Un-activated lymphocyte
（mantle zone）
Light
zone
Dark
zone
Follicular DC (FDC)
No MHC II
Bind with Ag-Ab （IC ）by FcR，maintain Ag for long
Provide persistent Ag signal for B cells
1、somatic hypermutation
In presence of Ag , by Th’s co-stimulation
Point Mutation of CDR in the Ig V region
Affinity-enhanced BCR(B cell) is selected
affinity maturation
2、affinity maturation
Result of somatic hypermutation of B cell
B cells with high affinity would survive
Affinity enhancement
3、Ig class (isotype) switch
In response to CD40-CD40L signal and IL-4 from Th cell, the activated
B cells undergo the process of heavy chain isotype (class) switching
leading to production of Abs with different class of heavy chain.
cytokine determined
occur in single B cell
during RNA transcription
ligation of various C gene
the V region of Ig remains,
the C region changed
Without Th
With Th’ help
Th cell-secreting cytokines determines the Ig class switch
No Th
CD40L signal、IL-4 from Th
The V gene
would
recombine
with a
downstream C
region gene
and the other
DNA deleted
IgM
IgG
late event in Ab response to TD antigen in BM
Ag
Th
1、somatic hypermutation
2、affinity maturation
3、Ig class switch (Th’s help)
5) Fate of the activated B cell
plasma cell，PC
move to BM? Secret high level of Abs
memory B cell
maintain in BM? Never die?
1．plasma cell
marginal-zone B
plasma cells
Early stage
follicular B
later
plasma cells
short-lived
form a germinal centre
Th
plasma cells
follicle
Bm
long-lived plasma cell
Bone Marrow
Formation of plasma cells
Nat Rev Immunol 2005; 5:232
Long-lived plasma cells in the bone marrow
somatic mutation
class-switch
Germinal
Center
CXCR4
plasma cells
crucial survival
signals (BM)
BAFF- BCMA
IL-6- IL-6R
B-cellactivating
factor
survival signals
内皮细胞选择素
血管细胞黏附分子
retention of plasma cells in BM
BCMA： receptor B-cell
maturation antigen
B cell response to TI antigen
CD5＋B1
Low-affinity IgM
No help from Th
No class switch (no IgG)
Mitogen
receptor
Signal 1：Ag
Signal 2：mitogen
Polyclonal strong B activation
BCR
Mitogen receptor
B cell response to TI-2 antigen
Repetitive units
Signal 1：cross-linking of
lots of BCR
By polymeric saccharide
B cells and humoral immune response
1. Recognition of the specific Ag
2. Activation, proliferation, differentiation
2. Germinal center: later event
3. General feature of Ab response
The general feature of humoral immunity
primary response
Mostly IgM with low affinity，IgG
secondary response
Mostly IgG with high affinity and high level
primary immune response
Mostly IgM, later IgG, low level and affinity
①
lag phase: long
5－10 days
②
log phase
③ plateu phase
short
④ decline phase
quickly
secondary immune response
mB act as APC，with high mB7，and high-affinity BCR,
small amounts of Ag can stimulate mB
① long
Lag phase: short, 1-3 days，quickly to the top
② strong
The Ab level is 10 times more than that of the primary
response
③ most IgG
enhanced affinity
5-10 days
1-3 days
4、受体修正 (receptor revision)
生发中心内 识别自身抗原的 B 细胞
发生 Ig V(D)J 基因的二次重排，
使 BCR 被修正为针对非自身抗原。
清除自身反应性 B 细胞
使针对外来抗原的 BCR 具有更广泛的多样性。
Where do Th and B cell encounter
？
follicle（B）-paracortex（T）boundary
（T cell）
滤泡区：B
Ag特异性 T （蓝色）
向滤泡边缘移动
副皮质区：T
B
T
Ag特异性 B （蓝色）
向滤泡边缘移动
Ag特异性 T （棕色）
Ag特异性 B （蓝色）
在滤泡边缘相遇