Transcript Immunoglobulins and the Complement System

Dental Microbiology #211
IMMUNOLOGY
Lecture 4
The Antibodies and the Complement
System
Topics
• The structure of Immunoglobulins
• Classes of Immunoglobulins
• Biological properties of Immunoglobulins
• The Complement system and its function
The Antibodies
Antibodies are synthesized by B lymphocytes in 2
forms: soluble and cell bound.
The cell-bound form is the BCR.
The soluble form is released into the circulation
as antibodies
Each B produces Ab of a single specificity and
expresses on the cell surface only one BCR
specificity
The specificity of the Ab produced by a B cell is
the same as of its BCR
The Antibodies Fig 1
Antibodies are also called
Immunoglobulins
Immunoglobulins (Ig) are divided into 5
classes:
IgG
IgM
IgA
IgD
IgE
Ig are glycoproteins
They differ in size, amount of CHO and biologic
functions
Ig structure Fig 2
S-S
The prototypic Ig molecule is IgG.
It is made up of 4 polypeptide chains held
together by disulfide bonds
Two Light (L) and two Heavy (H) chains form
the letter Y in which the two arms and the
stem are linked by a Hinge region
L chain 212-213 amino acids long
H chain 440 amino acids
The chains are held together by disulfide
bonds
Variable and Constant regions Fig 3
VH
CH
VL
CL
CH
The first 110 amino acids in
each chain are variable (V
regions) (red).
The remaining 110 aa in the L
chain and the remaining 330 aa
in the H chain are constant (C
regions) (blue)
The V regions contact the
antigen. The C regions are
involved in biological functions
Ig Domains
Each segment of about 110 amino acids is tightly
packed and forms a domain.
Each Ab molecule has therefore 4 V domains (one
in each H and one in each L chain), one C domain
in each L chain and either 3 or 4 C domains in each
H chain. Each IgG H chain has 3 C domains but
IgM and IgE H chains each has 4 C domains.
Ig Fragments Fig 4
The IgG molecule can be
dissected by proteolytic
enzymes:
Papain 2 Fab and 1 Fc
fragment.
Pepsin 1 large F(ab)2 and
several small fragments from
the Fc segment
The function of the Ig segments
The distinct Ig segments are involved in
different functions:
The Fab binds Ag
The Fc is involved in:
Transplacental passage of Ab
Enhanced phagocytosis by macrophages and
PMN (opsonization)
Activation of Complement:
Kills foreign cells, triggers inflammatory
reactions. Enhances phagocytosis
Ag-binding function Fig 5
Antibodies bind Ag in
pockets or grooves defined
by the V regions of the H
and L chains.
Ig classes and their functions
All Ig classes bind Ag in the same way via their
Fab segments. This leads to Ag neutralization
Distinct classes have different Fc segments and
thus perform distinct biologic functions:
IgG:
Neutralizes toxins and prevents viral entry into
cells
Crosses the placenta from mother to fetus.
Activates the Complement cascade.
Enhances phagocytosis (opsonization)
IgM:
Neutralizes toxins and viruses
Activates the Complement cascade
IgA: Attention Dentists!!!
Crosses secretory epithelia.
Neutralizes toxins and viruses
Clears pathogens in secretions: saliva, nasal,
bronchial secretions, seminal fluid, etc.
IgE:
Releases pharmacologic mediators from basophils
and mast cells and triggers allergic reactions (Hay
fever)
IgD: Function unknown
Ig Biologic functions (Fig 6.)
Polymeric Ig (Fig. 7)
All immunoglobulins are
constructed from a
basic unit of two H and
two L chains, but IgM
and IgA form polymers
In order to form the
polymers, both IgM and
IgA have an additional
polypeptide chain, called
the J chain, that helps to
hold the subunits
together
The Complement System
The complement system (Abbr. C):
• A group of proteins present in the plasma of all
individuals. Part of the innate immune system.
• A major biological effector system of both the
innate and the adaptive immune responses.
• The C components are present in the plasma in
an inactive state.
• Upon activation most C components become
proteolytic enzymes and act in sequence to cleave
the next C component into active fragments.
There are 9 complement proteins (C1 to C9)
The C facilitates and amplifies inflammatory
responses in several ways:
1. Increases vascular permeability
2. Destroys cell membranes of pathogens and
thus induce cell death through lysis
3. Increases recognition of pathogens by
phagocytic cells and enhances phagocytosis
(opsonization).
The three C activation pathways Fig 8
Adaptive
Innate
Innate
In the adaptive immune response, the classical C
pathway becomes activated when either IgM or
IgG Ab binds to specific Ag.
The binding of Ab to Ag exposes a site on the Fc
segment of the Ig H chain which in turn binds to
and triggers the activation of the first C
component (C1).
Activation of the C cascade Fig 9
Activation of the C cascade. Fig 10
The Membrane Attack Complex
The activation of the first C component called C1 starts
the sequential enzymatic activity that becomes
progressively amplified (C cascade).
Each component splits the next one into a large and a small
fragment.
The large fragments become attached to the target cell
membrane and end up by forming the Membrane Attack
Complex (MAC).
MAC Fig 11
The MAC terminates with
multiple copies of the last
C component called C9
which generate pores in
the target cell membrane
thus inducing cell lysis
Role of the small C fragments Fig 12
The small fragments called
anaphylatoxins induce
powerful inflammatory
reactions, by increasing
vascular permeability and
thus allowing passage of
inflammatory cells from
the blood vessels into the
surrounding tissue
(diapedesis).
Humoral and Cellular Immunity
The Antibodies and Complement constitute the
Humoral arm of the immune response
The T cells and the Antigen-Presenting Cells
constitute the Cellular arm of the immune
response
END