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• Complement pathways and effects
• Antibody structure
• How B cell response is controlled
B-cell, Antibody, Complement
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Measles
Active immunization Infection Vaccination
Protective immunity by antibody
Passive immunization Maternal antibodies Antibody injection (toxin, virus, lymphoma, PDL1)
Broadly Neutralizing Antibodies (bNAbs)
HIV
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Selection of protective epitope: Structurally mapping antibody
repertoires Computational prediction and
modelling
Antigen-antibody generator
Epitope
Epitope is the antigen part that an antibody binds
Epitope determines efficacy of antibody
Sequence Conformation
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Edward Jenner
Cross-reactivity of antibody
Rheumatic fever M-Protein on group A Streptococcus Myocardial and muscle proteins
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Antibody structure
On February 2019, FDA approved the first Nanobody-based medicine.
A dimer of dimerVH, CH
VL, CL
Nanobody Penetration Small epitope
Constant region
Light chain
Heavy chain
Variable region
19081972
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Antibody structure
Immunoglobulin: IgM, IgD, IgG, IgA, IgE
CH chains: μ, δ, γ, α, ε
Light chains: κ and λ (VL and CL )
Light chain
Heavy chain
Heavy chainconstant region
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Antibody classes
Immunoglobulin: IgM, IgD, IgG, IgA, IgE
Memory B cell generation
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B cell receptor (BCR)
Membrane bound immunoglobulin +Igα/β
BTK (Bruton tyrosine kinase)X-linked agammaglobulinemia
BTK
Signal transduction
Cytoplasmic domain
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B cell development and migration
Bone marrow
Secondary lymphoid organs (SLO)
Chemokine: small protein attracting immune cells
CXCR4/ CXCL12 CXCR5/ CXCL13
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Naive mature B cells
BCR
BAFF
CD20
CD19
Spleen
B1 B cellB1 B cell
IgM
CD5
Peritoneal & pleural cavity
Marginal zone
Follicle
T cellzone
White pulp
Red pulp
Rituximab Anti-CD20Lymphoma
BelimumabAnti-BAFFSLE
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T helper cell and B cell activation
TI antigen
SpleenBlood born antigen
Lymph node Spleen follicle
TD antigen
B cell works as APCs T cell deficiency causes
antibody impairment
Th2 cell
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B cell/ T cell
Lymph node
British Society for Immunology
T cell zone
Germinal centre
B cell follicle
Tfh cellB cell
T follicular helper (TFH) cells
Where does B-T interaction take place?
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T follicular helper (TFH) cells
T follicular helper (TFH) cells: Expressing B cell chemokine receptor-CXCR5 CD4 T cell subset that supports germinal center in B cell follicles
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B cell activation in the germinal centre (GC)
Germinal centre : proliferation, somatic mutation, class switch recombination, affinity selection
BT cell zone
B
B
B
B
Dark zone
Light zone
Apoptosis/ Nucleus
GC
FDC/ Nucleus
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Antibody diversification
Generation of antibody diversity
Nature Reviews Molecular Cell Biology, (2001)
Somatic mutation• Activation-nduced cytidine deaminase
(AID)• Common variable immunodeficiency
(CVID)
Class switch recombination• AID• X linked hyper-IgM syndrome• Selective IgA deficiency
VDJ rearrangement• Recombination-activating gene
(RAG)• Severe combined immune deficiency
(SCID)
1987
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Allelic exclusion, clonal selection and monoclonal antibody
Only one of the allelic forms of a gene is permitted 1984
Allelic exclusion Polyclonal & Monoclonal Antibody
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Opsonization by antibody and complement
Phagocytes
Antibody
Complement
Antibody+complement
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Opsonization by antibody and complement
Classical pathway Lectin pathway
C3b
C3
C3 convertase
Alternative pathway
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Complement pathway, cascade and effectBacteria surface
C3a, C5a = Cytokine &
Chemokine like
MAC
Bacteria lysis by membrane attack complex (MAC)
Inflammation
Termination
Phagocytosis
Rate-limitingstep
opsonization
Amplication
Lectin pathway
Ag-Abcomplex
CarbohydratesPAMP recognition
Initiation
Spontaneous hydrolysis of C3
Alternative pathway
Classical pathway
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Summary
Antibody Epitope (Cross-reactivity) Antibody structure Antibody classes B cell receptor signaling
B-cell (space and time) B cell development (BM and SLO) Naive mature B cell (MZ and FO) T-B interaction (TI and TD) Tfh cells and GC reaction (T and B cell zone) Antibody diversification Allelic exclusion and clonal selection
Complement Opsonization Complement pathways Complement functions
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