Download lect 4& immun 2011

Second line defense
Complement system consists of 30 proteins exist in blood
serum and tissue in an inactive form.
-The final product of the activation is a complex membrane
attack complex (MAC) that produces trans-membrane
channels in gram negative bacteria and lyses of foreign cells.
-These protein initially act as opsonins and
chemotactic factors, and trigger inflammation and
fever.
The Functions of Complement
1. Lysis of cells, bacteria, and viruses – the major effector
of the humoral branch of the immune system
2. Opsonization, which promotes phagocytosis of
particulate Ags
3. Anaphylatoxin, C3a, C4a, c5a can produce degradation of
mast cells and basophile with release of mediators,
leading to increase vascular permeability and smooth
muscle contraction.
4. Immune clearance, which removes immune complexes
from the circulation and deposits them in the spleen
and liver
Complement Activation
1. Classical Pathway : begins with the formation of Ag-Ab
complex
2. Alternative Pathway : is initiated by bacterial cell wall
polysaccharides
– Ab-independent
3. Lectin Pathway : is activated by the binding of mannosebinding lectin (MBL) to mannose
residues on glycoproteins or
carbohydrates on the surface of
microorganisms
– Ab-independent
- Antigens are molecules that react with
antibodies and sensitized lymphocytes.
-Whereas immunogens are any foreign
substances which when introduced into
an animal, stimulate the specific
immune response.
- Antigen must posses these characters:
• High molecular weight: manosaccharides
and a`a` are not antigen , while proteins
and polysaccharides are antigens.
• Chemical nature: proteins and some
polysaccharides are good immunogens .
Lipids alone are not immunogens unless
they are combined with proteins as L.P.S
• Foreigness: for a substance to be
antigenic it must be foreign to the animal in
which it is introduced.
Epitope: ( antigen determinant)
The body recognizes antigens by threedimension shapes of regions called
antigenic determinants, which are
known as epitopes.
IgG antibody
Fab ( Ag- binding fragment).
The actual portions of an AB
molecules that have a shape
corresponding to that of an
epitope of an antigen
Binding of epitopes to
the
corresponding
molecules of sIg on
the surface of Blymphocytes
Hapten:
- Small molecules less 5000 Daltons, make poor
antigens by themselves because they evade
detection. Such small molecules called hapten.
- Hapten can become antigenic when bound to
larger, carrier molecules ( protein).
e.g: proteins in blood bind to penicillin which by itself
is too small to trigger a specific immune response.
Bound to a carrier, penicillin can become antigenic
and trigger an allergic response in some patients.
Categories
of
antigens
based
on
1.Exogenous antigens
their relationship to the body:
The source of antigen is from outside the
host.
e.g pollens, drugs, pollutants and microbes
outside the cells of body, bear exogenous
antigens.
Exogenous antigens include toxins and
other secretions and components of
microbial cell walls, membrane, flagella,
and pili.
2 – Endogenous antigens
Microbes reproduce inside a body`s
cells produce endogenous antigens .
3- Autoantigens: it is self antigen
Are antigenic molecules found on an
individual's normal cells.
The body components are always
recognized as (self) and so are non
immunogenic under ordinary conditions
Groups of antigens
The Classic Pathway
• Complement cascade requires presence
of cations, both calcium and magnesium.
• Activation of the classic pathway almost
always initiated by immunoglobulin.
– Requires only 1 molecule of IgM.
– Requires 2 molecules of IgG.
Classical Pathway Begins with Ag-Ab Binding
Two IgG, One IgM
 The classical pathway:
1- C1 becomes an active enzyme when it
binds to antibody-antigen complex.
Fab of IgG or IgM bind to epitopes on an
antigen , constant regions of IgG contain
a binding site for C1q.
Binding of C1q activates C1r and C1s
forming C1( the first enzyme)
2- Activated C1 cleaves several molecules of C4
to C4a , C4b
And C2 to C2a, C2b fragments of C2a and C4b
combine forming C4b2a ( C3 convertase)
3- C4b2a cuts C3 to C3b( opsonin ) and C3a
( anaphylaoxin)
Some C3b binds to C4b2a forming C4b2a3b ( C5
convertase)
C5 convertase initiate MAC
inflammatory
responses
inflammatory
responses
The membrane attack complex (MAC)
Cleavage of C5 by a C5 convertase, produces:
- C5a: -is a potent anaphyllatoxin (like C3a)
is a chemotactic attractant for neutrophils
- C5b: which serves as the anchor for the assembly
of a single molecule of C6,C7and C8 the resultant
complex C5b678 guides the polymerization of as
many as 18 molecules of C9 into a tube inserted into
the lipid bilayer of the plasma membrane .
This tube forms a channel allowing the passage of
ions and small molecules. Water enters the cell by
osmosis and the cell lysis.
Formation of C5b6789,
Membrane-attack Complex
Inflammatory Response:
Cytokines Signal Initiation
Membrane attack complex
The Alternative Pathway Is
Ab-independent
- The activation of alternative pathway doesn’tneed Ab; thus, it is a component of the innate
immune system.
- It is initiated by cell-surface constituents thatare foreign to the host, e.g., bacterial cell wall.
- C1, C4 and C2 are not involved in the alternativepathway.
- Four serum proteins, C3, factor B, factor D, andproperdin, are involved in this pathway.
-The alternative pathway C3-convertase
consists of the activated B and D factors,
forming an unstable compound that can
become stable after binding properdin, a
serum protein ( C3bBb).
-After the creation of C3 convertase, the
complement system follows the same path
regardless of the means of activation split
hundreds of molecules of C3 to C3a and C3b.
-
- Binding of another C3b-fragment to the C3convertase of the alternative pathway
creates a C5-convertase analogous to the
MBL or classical pathway.
- The C5-convertase of the alternative
pathway consists of C3bBbC3b that can
enzymatically split hundreds of molecules of
C5 into C5a and C5b.
The Lectin Pathway Originates with Host
Proteins Binding Microbial Surfaces
Lectin: proteins that bind to a carbohydrate
MBL (mannose-binding lectin):
- a protein which binds to
mannose
residues on glycoproteins or carbohydrates on the
surface of microorganisms (structurally similar to
C1q)
MASP-1 & MASP-II: MBL-associated serine
protease (structurally similar to C1r and C1s)
-When the carbohydrate-recognizing heads of
MBL bind to specifically arranged mannose
residues on the phospholipid bilayer of a
pathogen,
-MASP-I and MASP-II are activated to cleave
complement components C4 and C2 into C4a,
C4b, C2a, and C2b.
- C4b and C2a combine on the surface of the
pathogen to form C3 convertase (C4b 2a),
while C4a and C2b act as chemo-attractants.
Q2: Why doesn’t mannose-binding lectin
(MBL) bind to host carbohydrates?
A2:
Mammalian cells normally have sialic
acid residues covering the sugar groups
recognized by MBL and are not a target for
binding.
Biological Effects Mediated by Complement
1. Cell lysis
The membrane-attack complex can lyse a broad
spectrum of cells:
G(-) bacteria
parasites
viruses
erythrocyte
nucleated cells (tumor cells)
Because the activation of alternative and lectin pathways is
Ab-independent, these pathways serve as important innate
immune defenses against infectious microorganisms.
2. Inflammatory response
- Various
peptides generated during activation of
complement play a role in the development
of an effective inflammatory response.
- C3a, C4a, C5a (called anaphylatoxin) bind to
complement receptors on mast cells and basophils
and induce degranulation with release of histamine
and other mediators.
- The anaphylatoxins also induce smooth-muscle
contraction, increased vascular permeability,
extravasation, and chemoattraction (induced by
C5a, C3a, and C5b67)
3. Opsonization
- C3b is the major opsonin of the complement
system, although C4b also have opsonizing activity.
binds to the surface of microbes
Opsonization by Ab and
complement
4. Viral neutralization
- Formation of larger viral aggregates reduces the
net number of infectious viral particles.
- The deposits of Ab and complement on viral
particle neutralizes viral infectivity by blocking
attachment to susceptible host cells and
facilitates binding of the viral particle to cells
possessing CR1.
5. Clearance of
immune complexes
Innate Immunity: Complement
Comparison of 3 Pathways
Determinants of innate
immunity
Innate immunity is genetically controlled and
varies widely with species, race and to less
extent between individuals.
a)Species and race:
-Man and guinea pigs are highly susceptible to
diphtheria while rats are not.
-Man is susceptible to common cold while dogs
are not.
-American Indian and Negro are more susceptible
to tuberculosis than white races.
B) Individual differences:
Age: the very young and aged are particular
liable to infection.
Nutrition: Malnutrition and starvation
predispose to infection by decreasing the total
white cell count and phagocytosis.
Hormones: Some endocrine diseases cause a
decrease in resistance to infection such as
diabetes mellitus, hypothroidism and adrenal
dysfunction.