Download Lecture 6: The Humoral Immune Response

Lecture 6: The Humoral Immune Response
(based on lecture by Dr. Matthew Scharff, Einstein)
Progenitor
B cell
Pluripotent
stem cell
Immature
B cell
antigen
mature B
B
cell
activation
Pre-B cell
centroblast
AID
Th
AID
Dark
Zone
AID
centrocyte
SHM
CSR
Light
Zone
FDC
selection
memory
B cell
apoptotic
cell
plasma
B cell
anergic
B cell
modified from Luo, Ronai, and Scharff. J Allergy Clin Immunol. 2004
and Harrison’s Principles of Internal Medicine 16th ed Ch. 97.
Questions to Consider






How can we make antibody to every possible
pathogen-i.e. Diversity
How do we avoid making autoantibodies-i.e.
Specificity
How do we rapidly increase amount of antibody-i.e.
Mobilization
How do we switch from making IgM to IgG- i.e.
Isotype Switching
How do we increase the the affinity of antibody-i.e.
Affinity maturation
How do we generate memory
Humoral Immune Response
Class Switch Recombination
IgM
IgG / IgE / IgA
Antigen-binding site
Effector arm
Somatic Hypermutation
Low affinity
high affinity
Janeway and Travers, Immunobiology
Antibody Mediated Functions
IgM is Polymeric Which Increases
Its Avidity
Neutralization of Viruses
Antibodies Neutralize Toxins
Binding of Antigen to Surface Ig Triggers The
Proliferation And Differentiation of B Cells
Generation of Antibodies To Polysaccharides by
Conjugation to Proteins (Glycoconjugate Vaccines)
Circulating Antibodies Reflect Somatic Mutation
And Isotype Switching
HaveAre
Different
C Region Structures
Ig Isotypes
Isotype
Encoded
by
Unique Constant Regions
Isotypes Mediate Different Effector Functions
Ig Isotypes Have Different Functions
Due to Their Unique Constant Regions
IgM And IgA Are Polymeric
Which Increases Their Avidity
Binding of Antigen to Surface Ig Triggers The
Proliferation And Differentiation of B Cells
Different Cytokines Secreted By T Cells Induce
Switching To Different Isotypes
Different Cytokines Signal Transcription Of
Different C-regions (Sterile Transcripts)
Activation-induced
Cytidine Deaminase (AID)
NLS
N alpha helix
Deficiency causes
Hyper IgM type II
F15X
NES
active site
PS
CSR C
H56Y
W68X C87R L106P
C147X R174S
R24W
M139V
L59F
W80R W84X R112C
F151S L181
R112H
P182
C
U
G
Luo, Ronai, and Scharff. J Allergy Clin Immunol. 2004
• AID is a cytidine deaminase whose in vitro substrate is ssDNA
• AID may associate with RPA, RNAP II &? others
• Transcription is required for somatic SHM and CSR
R190X
Activation-induced Cytidine Deaminase
(AID) Mediates Class Switching
Isotype Switching Requires Recombination
Between Different Switch Regions
The Poly-Ig Receptor Mediates the Transcytosis
Of IgA Into Mucosal Secretions
Cells Express Multiple Fc Receptors
With Unique Functions
Antibody Complexed To Antigen Binds to FcR’s
and Activates Macrophages
Antibody Complexed To Tumor Cells Targeting
Their Killing by NK Cells Through FcRs
IgE Complexed To Antigen Binds to FcR’s on
Mast Cells and Mediates The Release Of Granules
Questions to Consider






How can we make antibody to every possible
pathogen-i.e. Diversity
How do we avoid making autoantibodies-i.e.
Specificity
How do we rapidly increase amount of antibody-i.e.
Mobilization
How do we switch from making IgM to IgG- i.e.
Isotype Switching
How do we increase the the affinity of antibody-i.e.
Affinity maturation
How do we generate memory