humoral immunity and complement robert beatty mcb150
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Humoral Immunity and Complement
Robert Beatty
MCB150
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Humoral Immunity
Transfer of non-cell components of blood-- antibodies, complement
Humoral immunity = antibody mediated
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T-cell dependent antigens T-cell independent antigens
T cell dependent B cell antigensMajority of antigens. Most protein antigens. T cell help required for B cell activation and antibody production.
B cell AntigensT cell independent Do not require thymus.No memory.
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B Cell Activation of T-dependent antigens
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B Cell Activation T-dependent antigens
Linked Recognition
Need T cell epitope along with B cell epitope to get antibody response.
B cells get help from T cells,
help = CD40Ligand and IL-4.
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Location of B Cell Activation
Antigen activated B cells remainin T cell zones of LN.
Maximize contact of B cells with T cells.
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Affinity maturation
Clonal proliferationIn Follicles
Somatic hypermutation
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Isotype Switching
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B-1 cells Activated by repeating CHO epitopes that provide crosslinkingto induce antigen uptake and activation.
Antigen specific immune response Lower affinity, lower numbers, no memory. Primarily IgM.
T cell Independent Antigens
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B cell mitogens (e.g. LPS)At low levels normal immune response to LPSAt high levels LPS can cause non-antigen specific activation of B cells. Mitogen effect
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Antibody Effector Functions Neutralization
Neutralizing antibodies are usually high affinity and primarily IgG.
Neutralizing abs block active site for adherence, entry into host cell, or active site of toxin
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Enhancement of phagocytosis
OpsonizationAntibody Effector Functions
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Antibody-dependent cell-mediated cytotoxicity (ADCC)
Antibody Effector Functions
Antibody binds to pathogen or infected target cell. Fc portion of antibody binds to Fc receptors of a cytotoxic cell.
ADCC of target cell with bound antibody by activated NK cells
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Complement ActivationAntibody Effector Functions
Antibody binds to antigen…….complement binds. Kill, kill, kill…….
Which we will talk about in great detail----very shortly.
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Location of Antibody Isotype Influences Function
IgA Mucosal
IgG Tissues/blood crosses placenta
IgE Parasitic, mast cells
IgM Peritoneum, tissues,
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Control of Antibody Effector FunctionsFc Receptors
Fc Receptors– opsonization and ADCC
FcR1 for IgA – opsonization and ADCC
FcR1 on Mast cells – can prolong life of IgE (role in hypersensitivity)
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Complement Pathways
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Complement
Classical Pathway
C1q binds to 1 IgM molecule
OR
2 IgG molecules
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Complement
Classical Pathway
C1q binds to
2 IgG molecules
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Classical PathwayQ: Why don't Complement proteins bind to antibodies in serum or lymph fluid?
Answer: Antibodies only expose Fc domain forComplement binding when bound to antigen.
Planar form of IgMStaple form of IgM
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C1qr2s2Classical Pathway
Once C1q binds to antibodies it provides site for serine proteases C1s and C1r to bind. Full C1 molecule is made of 1 C1q with 2C1r and 2 C1s molecules.
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Classical Pathway
C1 cleaves C4 and C2. C4b and C2b stay bound to cell surface to form C3 convertase (cleaving C3).
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Formation of Membrane Attack Complex
Once C5b is bound then C6, C7, C8 all bind to attract multiple C9s.C9is pore-forming protein.
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Membrane Attack Complex (MAC)
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Alternate Pathway
C3 spontaneously cleaves. C3b is bound.
Factor B binds C3b-B is cleaved by D forms C3bBb.
C3bBb is a C3 convertase stabilized by Properdin.
Amplification making more C3b.
C3bBb3b is C5 convertase.
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Biological Functions of C'
Lysis of pathogen of infected cell
Complement Receptors initiate other functions of C'
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Biological Functions of C'Opsonization
CRs vs FcRs
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Biological Functions of C'Clearance of Immune complexes
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Biological Functions of C'Inflammation
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Proteins that Regulate and InhibitComplement
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Proteins that Regulate and InhibitComplement