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8th lecture
The collaborations between innate and adaptive immunity.
Antibody types and functions.
THE EFFECTS OF B CELLS ON THE INNATE ARM OF THE IMMUNE SYSTEM
(HUMMORAL IMMUNITY)
Antigen binding
Complement binding site
Placental transfer
Binding to Fc receptors
THE CONSTANT REGION OF AN ANTIBODY CAN BIND Fc RECEPTORS (FcR)
FcR activation occurs when the antibody forms a complex with an antigen
Sequence variability of H/L-chain constant regions
VARIABILITY IN THE CONSTANT REGION HEAVY AND LIGHT CHAINS DETERMINES THE
CLASS OF IMMUNOGLOBULIN
Sequence variability of H/L-chain constant regions
Isotype
• IgG - gamma (γ) heavy chains• IgM - mu (μ) heavy chains• IgA - alpha (α) heavy chains• IgD - delta (δ) heavy chains• IgE - epsilon (ε) heavy chains
HUMAN IMMUNOGLOBULIN CLASSES
Encoded by different structural gene segments (Isotypes)
• kappa (κ)• lambda (λ)
Heavy chain types:
Light chain types:
!
FcγR (gamma) can only bind IgG immunoglobulinsFcαR (alpha) can only bind IgA immunoglobulins
FcεR (epsilon) can only bind IgE immunoglobulins
!
Different cells express different Fc receptors on their surface
Expression of Fc receptors on the surface of cells is relatively constant (INFγ macrophages)
Fc receptors are activated not from a free antibody but by antibody-antigen complex
Antibodies of different isotypes activate different cells and have different effector functions
FcRAffinity for Immunoglobulin Cell Distribution Function
FcγRI (CD64) High (Kd < 10-9 M); binds
IgG1 and IgG3, can bind monomeric IgG
Macrophages, neutrophils; also eosinophils
Phagocytosis; activation of phagocytes
FcγRIIA (CD32) Low (Kd > 10-7 M) Macrophages, neutrophils; eosinophils, platelets
Phagocytosis; cell activation (inefficient)
FcγRIIB (CD32) Low (Kd > 10-7 M) B lymphocytes Feedback inhibition of B cells
FcγRIIC (CD32) Low (Kd > 10-7 M) Macrophages, neutrophils, NK cells
Phagocytosis, cell activation
FcγRIIIA (CD16) Low (Kd > 10-6 M) NK cells Antibody-dependent cell-mediated cytotoxicity
FcγRIIIB (CD16) Low (Kd > 10-6 M); GPI-
linked protein
Neutrophils Phagocytosis (inefficient)
FcεRI High (Kd > 10-10 M);
binds monomeric IgE
Mast cells, basophils, eosinophils
Cell activation (degranulation)
FcεRII (CD23) Low (Kd > 10-7 M) B lymphocytes, eosinophils, Langerhans cells
Unknown
FcαR (CD89) Low (Kd > 10-6 M) Neutrophils, eosinophils, monocytes
Cell activation?
ISOTYPE SWITCHING
Ig isotype Serum concentration
Characteristics, functions
12-14 mg/ml
Major isotype of secondary (memory) immune response
Complexed with antigen activates effector functions (Fc-receptor binding, complement activation
Trace
amounts
The first isotype in B-lymphocyte membrane
Function in serum is not known
Trace amounts
Major isotype in protection against parasites
Mediator of allergic reactions (binds to basophils and mast cells)
3-3,5 mg/ml
Major isotype of secretions (saliva, tear, milk)
Protection of mucosal surfaces
1-2 mg/ml
Major isotype of primary immune responses
Complexed with antigen activates complement
Agglutinates microbes The monomeric form is expressed in
B-lymphocyte membrane as antigen binding receptor
MAIN CHARACTERISTICS OF IMMUNOGLOBULIN ISOTYPES
B CELL ACTIVATION AND THE GERMINAL CENTER
Somatic mutationAffinity maturationIsotype switchingMemory
The progress of these germinal center reactions depend on T cell signals!
ISOTYPE SWITCHING IS T-DEPENDENT
B cell
Helper T cell
IL-2IL-4IL-5
IL-2IL-4IL-5 IgM
IgG
IgA
IgE
IL-2IL-4IL-6IFNγ
IL-5TGFβ
IL-4
B cell proliferation, differentiation and isotype switching
TRANSPORT PROCESSES INVOLVING THE Fc RECEPTORS
Neonatal Fcγ receptor for transport of maternal IgG across
the placenta
Poly Ig receptors for IgA transport across the epithelium to the
mucosal surface
Antigen binding
Complement binding site
Placental transfer
Binding to Fc receptors
FcγRn on the placenta facilitate the transfer of maternal IgG to the
fetus’s circulation, recognizing the constant region of IgGs
Pathological consequences of placental Pathological consequences of placental transport of IgGtransport of IgG
(hemolytic disease of the newborn)(hemolytic disease of the newborn)
Passive anti-D IgG
anti-RhIgM
EFFECTOR FUNCTIONS OF ANTIBODIES
Antibody-mediated immune responses
• Opsonization• Neutralization• Complement fixation• ADCC
ANTIBODY EFFECTOR FUNCTIONS
OPSONIZATION
ANTIBODY EFFECTOR FUNCTIONS
NEUTRALIZATION
ANTIBODY EFFECTOR FUNCTIONS
COMPLEMENT FIXATION
Binding of complement protein 1 to IgG or IgM immunoglobulins on a bacterial surface
ANTIBODY EFFECTOR FUNCTIONS
COMPLEMENT FIXATION
Complement 1 protein and the immunoglobulin bound to the bacteria cause the binding of more complement proteins
ANTIBODY EFFECTOR FUNCTIONS
COMPLEMENT FIXATION
More complement proteins are recruited leading to the death of the extracellular pathogen (bacteria) by forming pores in it
Antibodies target virus infected cells, flagging them for the recognition by natural killer (NK) cells
ANTIBODY EFFECTOR FUNCTIONS
ANTIBODY-DEPENDENT CELL CYTOTOXICITY
THE EFFECTS OF T CELLS ON THE INNATE ARM OF THE IMMUNE SYSTEM
MACROPHAGES
RECEPTORS AND CELL-SURFACE MOLECULES OF MACROPHAGES
TLR4 + CD14
MHCI
MHCII
TLR – pattern recognition Rs
CR1 (CD35)
CR3 (CD11b/CD18)
LFA1 (CD11a/CD18)
FcRIII (CD16)
FcRII (CD32)
FcRI (CD64)
Ag + IgG complex
Mannose receptor
Scavenger receptor
Mϕ
!!
EXTRACELLULAR PATHOGEN PHAGOCYTOSIS AND KILLING
KILLING THROUGH LYSOSOMAL ENZYMES, OXYGEN AND NITROGEN SPECIES
Activation of macrophages
IFN
IL-12IL-18
Th1 cell NK cell activation
Inflammatory cytokines Antimicrobial substances
Microorganism
TNF
IL-6 IL-12
Activation of macrophagesInflammatory cytokines
Leukocyte recruitment
THE LOCATION OF INNATE AND ADAPTIVE INTERACTIONS
KINETICS OF AN IMMUNE RESPONSE AGAINST PATHOGENS