2009 01 26 Abbas Chapter 10 Handout

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Abbas Chapter 10:
B Cell Activation
and Antibody Production
Christina Ciaccio, MD
January 26, 2009
Children’s Mercy Hospitals and Clinics
Introduction
Humoral immunity is mediated by 
secreted antibodies (Ab)
Ab function to neutralize and eliminate 
antigens (Ag)
Different types of Ag requires different 
effector mechanisms, mediated by 
different classes of Ab
General Features
B cell activation consists of sequential 
phases
Recognition
Activation
Proliferation
Differentiation
General Features
Ab responses to proteins require Th
Ab responses to multivalent Ag do not 
require Th
Polysaccharides
Lipids
Activated B cells differentiate into Ab-
secreting plasma cells & memory cells
General Features
Heavy chain isotype switching and 
affinity maturation are typically seen in 
Th-dependent humoral response to 
protein Ag
1° and 2° Ab responses to protein 
antigens differ qualitatively and 
quantitatively 
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General Features
Distinct subsets of B cells respond 
preferentially to different types of Ag
Follicular B cells => proteins
Marginal zone B cells => multivalent Ag
B-1 B cells => multivalent Ag
Antigen Recognition and Activation
B cell activation requires Ag 
recognition in lymphoid tissues
Entry into follicles CXCR5 (CXCL13)
BAFF (B cell activating factor of the 
TNF family; aka BLyS B lymphocyte 
stimulator)
APRIL
TACI (Selective IgA def and CVID!)
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Antigen Recognition and Activation
Activation is initiated by binding of Ag 
to membrane Ig molecule
Associated with invariant Igα and Igβ
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Antigen Recognition and Activation
B cell signals when 2 or more receptor 
molecules are cross-linked by 
multivalent Ag
CR2/CD21 Coreceptor
B cell activation is enhanced by signals 
provided by complement proteins
Review: C3 is cleaved => C3b => C3b-
Ag => C3d-Ag
C3d binds to CR2 or CD21 
CD21 is the EBV receptor
CR2/CD19/CD81 complex is coreceptor
Response of B Cell to Ag Recognition
Cross-linking initiate proliferation and 
differentiation
Prepare B cells for interaction with Th
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Th-Dependent Ab Responses
Ab response to protein Ag requires 
recognition by Th AND B cells and 
cooperation between the two
Th stimulate
Clonal expansion
Isotype switching
Affinity maturation
Differentiation
Ag is taken up by DC and presents to Th
Th are activated and express CD40L
Th move toward follicle
B cells are activated by soluble Ag
Alter chemokine profile and migrate 
toward T cell zone
T and B cells interact (CD40L)
B cells migrate back into follicle and 
form germinal centers
Plasma cells are generated and migrate 
to the bone marrow
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Hapten-Carrier Effect
Haptens are small chmicals that can be 
bound by Ab but are not immunogenic 
by themselves
If haptens are coupled to proteins, the 
conjugates induce Ab response
Hapten-Carrier Effect
Require: 
Hapten specific B cells
Carrier specific Th
To stimulate a response hapten-carrier 
must by physically linked
MHC class II restricted
Basis for conjugate vaccines
Germinal Center Reaction
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CD40L:CD40 Interactions
CD40L:CD40 Interactions
(Activated) Th express CD40L that 
engages CD40 on (ALL) B cells
Stimulates B cell proliferation, 
differentiation, and germinal center 
formation
Induces AID (somatic mutation and 
isotype switching)
Induces association of TRAFs (TNF 
receptor-associated factors)
CD40L:CD40 Interactions
Cytoplasmic tail of EBV protein, LMP1, 
associates with TRAF triggering B cell 
proliferation
Activated Th secrete cytokines that act 
with CD40L to stimulate B cell 
production of different isotypes
Isotype Switching
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Switch Recombination
VDJ recombines with a downstream C 
region gene and the DNA in between is 
deleted
Switch Recombination
Activation-induced deaminase (AID) is 
a DNA deaminase that deaminates
cytosines converting C to uracil (U)
Uracil N-glycosylase (UNG) removes 
the U
Ape1 endonuclease cleaves abasic
sites
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Affinity Maturation
Process that leads to increased affinity 
of Ab for a particular Ag
Occurs only in response to Th-
dependent protein Ag
Occurs in dark zone of germinal center
Mechanisms poorly understood (AID)
FDCs display Ag and select high 
affinity B cells to survive
Differentiation into Plasma Cells
Involves major morphologic alterations
Change in Ig heavy chain gene 
expression from membrane to secreted 
form
Change is in MRNA
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