Lecture 6: The Humoral Immune Response(based on lecture by Dr. Matthew Scharff, Einstein)

centrocyteFDC

B Th

activation

centroblast Dark Zone

LightZone

selection

antigen

memory B cell plasma

B cell

apoptotic 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.

Pluripotent stem cell

Progenitor B cell

Pre-B cell

Immature B cell

mature B cell

SHMCSR

AID

AIDAID

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

Janeway and Travers, Immunobiology

Somatic HypermutationLow affinity high affinity

Class Switch Recombination

IgM IgG / IgE / IgA

Effector arm

Antigen-binding site

Humoral Immune Response

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

Isotypes Have Different C Region StructuresIg Isotype Are Encoded by Unique Constant Regions

Isotypes Mediate Different Effector FunctionsIg 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-inducedCytidine Deaminase (AID)

• 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

CUG

P182

CNESNLS

F15XR24W

H56Y

L59F

W68X

W80R

C87R

W84X

L106P

R112CR112H

M139VC147X

F151S

R174S R190X

L181

N alpha helix active site PS CSR

Deficiency causes Hyper IgM type II

Luo, Ronai, and Scharff. J Allergy Clin Immunol. 2004

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