Humoral Immunity

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Humoral Immunity Immunoglobulin Structure and
Function

• Dr. Adel Almogren

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• Adaptive Immunity
• _at_ Humoral Immunity
• (Antibody mediated response)
• _at_ Cellular Mediated Immunity (CMI)

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• Humoral (Antibody-Mediated) Immunity
• Involves production of antibodies against
  foreign antigens.
• Antibodies are produced by a subset of
  lymphocytes called B cells.
• B cells that are stimulated will actively
  secrete antibodies and are called plasma cells.
• Antibodies are found in extracellular fluids
  (blood plasma, lymph, mucus, etc.) and the
  surface of B cells.
• Defense against bacteria, bacterial toxins, and
  viruses that circulate freely in body fluids,
  before they enter cells.
• Also cause certain reactions against
  transplanted tissue.

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Some responses require T help whereas other do not
B cell activation
T-independent antibody response generally have1.
no memory2. no isotype switching3. no
somatic mutations
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Immunoglobulin (Antibody) Structure and Function
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Immunoglobulin Structure-Function Relationship

• Cell surface antigen receptor on B cells
• Secreted antibody

Immunoglobulins are Bi-functional proteins
Ag binding Fc receptor Complement protein binding
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Domain Structure of Immunoglobulins
Domains are folded, compact, protease resistant
structures
Light chain C domains k or l
Heavy chain C domains a, d, e, g, or m
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CH3
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CH2
CH3
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CH1
CH2
CH3
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VH1
CH1
CH2
CH3
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VH1
CH1
CL
CH2
CH3
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VH1
CH1
VL
CL
CH2
CH3
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VH1
CH1
VL
CL
CH2
CH3
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VH
CH1
CL
VL
CH2
Elbow
Hinge
CH3
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Flexibility and motion of immunoglobulins
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Hypervariable regions

• Most hypervariable regions coincided with antigen
  contact points - the COMPLEMENTARITY DETERMINING
  REGIONS (CDRs)

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Hypervariable CDRs are located on loops at the
end of the Fv regions
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Hypervariable loops and framework Summary

• The sequences of the hypervariable loops are
  highly variable amongst antibodies of different
  specificities
• Variable amino acid sequence in the hypervariable
  loops accounts for the diversity of antigens that
  can be recognised by a repertoire of antibodies

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Antigens vary in size and complexity
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Concept Epitopes can bind in pockets or grooves
or on extended surfaces in the binding site of
antibodies.
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Why do antibodies need an Fc region?
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Structure and function of the Fc region
Fc structure is common to all specificities of
antibody within an ISOTYPE (although there are
allotypes)
The structure acts as a receptor for complement
proteins and a ligand for cellular binding sites
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Monomeric IgM
IgM only exists as a monomer on the surface of B
cells
Monomeric IgM has a very low affinity for antigen
IgM forms pentamers and hexamers
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Multimerisation of IgM
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IgM facts and figures
Heavy chain m - Mu Half-life 5 to 10
days of Ig in serum 10 Serum level (mgml-1)
0.25 - 3.1 Complement activation by
classical pathway Interactions with cells
Phagocytes via C3b receptors Epithelial
cells via polymeric Ig receptor Transplacental
transfer No Affinity for antigen Monomeric
IgM - low affinity - valency of
2 Pentameric IgM - high avidity - valency
of 10
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IgD facts and figures
Heavy chain d - Delta Half-life 2 to 8
days of Ig in serum 0.2 Serum level (mgml-1)
0.03 - 0.4 Complement activation No Interactions
with cells T cells via lectin like IgD
receptor Transplacental transfer No
??IgD IgM ??
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IgA dimerisation and secretion
IgA is the major isotype of antibody secreted at
mucosal surfaces Exists in serum as a monomer,
but more usually as a J chain-linked dimer, that
is formed in a similar manner to IgM pentamers.
IgA exists in two subclasses IgA1 is mostly found
in serum and made by bone marrow B cells IgA2 is
found in higher concentration in mucosal
secretions, colostrum and milk and is made by
(??? )
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Secretory IgA and transcytosis
Stalk of the pIgR is degraded to release IgA
containing part of the pIgR - the secretory
component
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IgA facts and figures
Heavy chains a1 or a2 - Alpha 1 or 2 Half-life
IgA1 5 - 7 days IgA2 4 - 6 days Serum
levels (mgml-1) IgA1 1.4 - 4.2 IgA2 0.2 -
0.5 of Ig in serum IgA1 11 - 14 IgA2 1 -
4 Complement activation IgA1 - by alternative
and lectin pathway IgA2 - No Interactions
with cells Epithelial cells by
pIgR Phagocytes by IgA receptor Transplacental
transfer No
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IgE facts and figures
Heavy chain e - Epsilon Half-life 1 - 5
days Serum level (mgml-1) 0.0001 - 0.0002 of
Ig in serum 0.004 Complement activation No Inte
ractions with cells Via high affinity IgE
receptors expressed by mast cells,
eosinophils, basophils and Langerhans
cells Via low affinity IgE receptor on B
cells and monocytes Transplacental transfer
No
its role in protecting against parasitic
infections IgE is also closely linked with
allergic diseases
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IgG facts and figures
Heavy chains g 1 g 2 g3 g4 - Gamma 1 -
4 Half-life IgG1 21 - 24 days IgG2 21 -
24 days IgG3 7 - 8 days IgG4 21 -
24 days Serum level (mgml-1) IgG1 5 -
12 IgG2 2 - 6 IgG3 0.5 - 1 IgG4 0.2
- 1 of Ig in serum IgG1 45 - 53 IgG2 11 -
15 IgG3 3 - 6 IgG4 1 - 4 Complement
activation IgG1 IgG2 IgG3
IgG4 No Interactions with cells All
subclasses via IgG receptors on macrophages
and phagocytes Transplacental transfer
IgG1 IgG2 IgG3 IgG4
The neonatal Fcg receptor may be responsible!
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Fcg receptors
Receptor Cell type Effect of ligation FcgRI Mac
rophages Neutrophils, Eosinophils, Dendritic
cells Uptake, Respiratory burst FcgRIIA Macrophag
es Neutrophils, Eosinophils,
Platelets Langerhans cells Uptake, Granule
release FcgRIIB1 B cells, Mast Cells No Uptake,
Inhibition of stimulation FcgRIIB2 Macrophages
Neutrophils, Eosinophils Uptake, Inhibition
of stimulation FcgRIII NK cells,
Eosinophils, Macrophages, Neutrophils Mast
cells Induction of killing (NK cells)
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Fv
VH1
Fb
CH1
VL
CL
Fab
CH2
Elbow
Hinge
Fc
Carbohydrate
CH3
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Antibody Dependent Cell Mediated Cytotoxicity
(ADCC) Target cell is covered with antibodies,
leaving Fc portion sticking outwards. Natural
killer and other nonspecific cells that have
receptors for Fc region are stimulated to kill
targeted cells. Target organism is lysed by
substances secreted by attacking cells. Used to
destroy large organisms that cannot be
phagocytosed.
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