Transcript The complement system

The complement system,
antigens
Martin Liška
The complement system
• A complex consisting of at least 20 serum proteins, which,
once activated, acts like a part of the innate immune
defense
• The complement components are present in serum in
inactive form
• The complement is activated in a cascading manner (=
each protein activates that following) and it has widespread
physiologic and pathophysiologic effects
• Complement proteins are synthesized mainly in the liver,
but tissue macrophages and fibroblasts can synthesize
some complement proteins as well
The complement system
nomenclature
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C1q, C1r, C1s, C2-9
Factor B, Factor D
Properdin
Regulatory proteins (C1-inhibitor, Factor I,
C4bBP, Factor H, S protein, anaphylatoxin
inactivator)
The classical pathway of
complement activation
• The pathway is activated through antigenantibody complexes: initially, C1 component
binds to a site on the Fc fragment of Ig (IgG (but
not IgG4) or IgM); however, native Ig molecules
do not interact with C1
• C1 component – contains three polypeptides (C1q,
C1r, C1s); C1q attaches first to Ig (for initiation of
complement activation, C1q has to interact with
two or more Ig monomers) → C1q activates
proenzyme C1r → C1r cleaves proenzyme C1s →
C1s is able to cleave C4 component
The classical pathway of
complement activation
• Activated C1s cleaves C4 to C4a (an
anaphylatoxin) + C4b → C4b binds to cell
membranes → the next component becomes
susceptible to enzymatic attack by activated C1
• C4b + C2 + C1s → removal of C2a →
enzymatically active molecular complex C4b2b (=
C3 convertase of the classical pathway)
• Formation of C3 convertase represents the nodal
point for all pathways of complement system
activation
The alternative pathway of
complement activation
• The alternative pathway is considered to be a
primitive „bypass“ mechanism, that does not
require C1, C2 and C4
• The pathway is activated through reaction of
the complement system and some substances of
microbial origin (polysaccharides – e.g.
lipopolysaccharides of G negative bacteria,
teichoic acid of G positive bacteria, zymosan from
yeast cell walls, surface components of some
animal parasites) or other foreign materials
The alternative pathway of
complement activation
• C3 cleaves into C3a + C3b spontaneously;
however, these are inactive under standard
conditions
• In this case, C3b binds to microbial surface
→ it reacts with factor B → removal of Ba
(it is chemotactic for neutrophils) →
C3bBb (= C3 convertase of the alternative
pathway) – it is stabilized by properdin (P)
The lectin pathway of complement
activation
• The pathway is activated through
binding of MBL (mannose-binding lectin)
to microbial surface → C4 → C4a is
released + C4b → C4b reacts with C2 →
C2b is released → C4b2a complex (= C3
convertase)
Further events of complement
activation process
C3 convertase causes generation of:
a/ C3a, C4a, C5a fragments
- they act as peptide mediators of inflammation
- they are chemotactic for phagocytes
b/ C3b
- it binds to complement receptors and causes
opsonization of microbes and immunocomplexes
Further events of complement
activation process
c/ MAC (membrane attack complex)
- formed from terminal complement
components (C5b, C6, C7, C8, C9); it
attacks membrane of cells (e.g.microbes),
causing their osmolysis
Complement receptors
• Fragments of complement components can bind to
complement receptors, which are expressed on the
surface of different cells.
• CR1 – erythrocytes, granulocytes,
monocytes and B cells
- important for IC clearance
• CR2 – B cells and follicular dendritic cells
- immunoregulation
• CR3, CR4 – phagocytes
- opsonization
Regulatory mechanisms of the
complement system
• Some serum proteins enzymatically attack
complement components, thereby inactivating
them (factor I inactivates C3b; anaphylatoxin
inactivator inactivates anaphylatoxins (C3a, C4a,
C5a))
• Some serum proteins bind to, and thus inhibit,
complement components (C1-INH inhibits C1; C1INH deficiency → HAE = recurrent episodes of
local edema; factor H acts with factor I the inhibition
of C3b; S protein binds to C5b67 → prevention of
MAC binding to cell membrane)
Regulatory mechanisms of the
complement system
• Regulatory proteins in cell membranes
(DAF (decay-accelerating factor) – it has
the same function as factor H → the
inactivation of C3b and C4b; membrane
cofactor protein – it serves as a cofactor for
inactivation of C4b and C3b)
Functions of the complement
system
• C3a, C5a – anaphylatoxins (= they cause release of
histamine and other vasoactive compounds from
basophils and mast cells, increasing capillary
permeability)
• C3b, C4b – opsonization (they bind IC to
macrophages and neutrophils, enhancing
phagocytosis; also binds complexes to erythrocytes,
facilitating removal by the liver and spleen)
• C5a – chemotaxis (attracts phagocytic cells to sites of
inflammation and increases their overall activity)
Functions of the complement
system
• C8, C9 – components of MAC
• Ba – neutrophil chemotaxis
• Bb – macrophage activation
Functions of the complement
system - overview
• Inflammation (mast cell degranulation, chemotaxis,
increases vascular permeability, margination and
diapedesis of polymorphonuclears, smooth muscle
contraction, activation of polymorphonuclears, NK cells
and macrophages)
• Clearance of immune complexes
• Cell lysis (G negative bacteria, Protozoa, some viruses)
• Viral neutralization
• Opsonization
The complement system overview
• The alternative and lectin pathways are clear
components of innate immune system, whereas
the classical pathway depends on addaptive
immune response (it is triggered through antigenantibody reaction)
• Three functions of the complement system:
1/ C3b coats microbes and promotes the binding of
these microbes to phagocytes (by receptors for
C3b)
The complement system overview
2/some breakdown products of complement proteins
are chemoattractants for neutrophils and
monocytes and promote inflammation at the site
of complement activation
3/ complement activation results to the formation of
a polymeric protein complex (MAC), causing
osmolysis or apoptosis of microbes
Antigen
• A substance, which is recognized by
immune system and induces the immune
response
• It comes from environment (exoantigen), or
from individual’s own structures
(autoantigen)
• Usually proteins or polysaccharides (lipids
and nucleic acids can act as antigens when
combined with proteins or polysaccharides)
Haptens
• Small and well-defined chemical structures, which
are not immunogenic themselves, but can add a
new epitope when combined to an existing antigen
• The antibody directed against the new epitope will
react with the free hapten as well as the haptenepitope site in the altered antigen
• Typically drugs (e.g.penicillin ATB, hydralazine)
Epitope
• The portion of antigen, which is recognized by the
immune system (lymphocytes, Ig)
• Epitopes may be linear (amino acid sequence
important), conformational (space conformation
important)
• Some epitopes are on the antigen’s surface, others
are internal
• Cross-reactive antigens – share one or more
identical or similar epitopes
Antigen-antibody reaction
• Binding sites of antibodies (paratope)
interract with the corresponding sites of the
antigen (epitope)
• The bonds that hold the antigen-antibody
complex are non-covalent (hydrogen,
electrostatic and hydrophobic bonds, Van
der Waals forces)
• Antigen-antibody complex is reversible
T cell dependent and independent
antigens
1/ T cell dependent antigens
- more common, typically contain protein
component
- a help from T helper cells is necessary for
specific humoral immune response
generating, otherwise the response is not so
effective
- the help comes in form of cytokines
secreted by the T cell
T cell dependent and independent
antigens
2/ T cell independent antigens
- in some antigens, antibody production can
be induced directly, without help from T
cells
- bacterial lipopolysaccharides and polymeric
forms of proteins (e.g. Haemophilus,
Str.pneumoniae)
Superantigens
• Antigenic structures, capable to induce
response of T cells by external binding to
MHC molecules (i.e. outside of the usual
binding site)
• The stimulation is polyclonal and extensive
• Some bacterial toxins (Staph.aureus,
Str.pyogenes, Pseud.aeruginosa)
Sequestered antigens
• The antigens, which are normally hidden
from the immune system at privileged sites,
and thus the immune system cannot identify
them (e.g. lens, testes)
• However, if these allergens are released
(injury), the immune system could response
to them (the potential mechanism of
autoimmunity development)
Immunologically privileged tissue
• In allogeneic transplantation, some tissues are
rejected less frequently (e.g. CNS, cornea,
gonades).
• The mechanisms of protection from the immune
system: separation from the immune system
(haematoencephalic barrier); the preference of
Th2- and suppression of Th1-reactions; active
protection from effector T cells
• The privileged status is not absolute (see MS)
Molecular size of antigens
• Molecules < 5 kDa are not able to induce
immune response, the optimal molecular
size for immune response induction is
approximately 40 kDa
Degree of foreignness
• An antigen must be foreign or alien to the
host
• The greater the phylogenetic difference, the
more foreign something becomes; based on
this fact, we can distinguish the following
types of antigens:
Degree of foreignness
• Autologous – are found within the same individual (e.g. a
skin graft from an individual’s thigh to his chest); that is,
they are not foreign
• Syngeneic – are found in genetically identical individuals
(e.g. identical twins); that is, they are not foreign
• Allogeneic (alloantigens) – are found in genetically
dissimilar members of the same species (e.g. a kidney
transplant from mother to daughter); it is foreign
• Xenogeneic (heterogeneic) – are found in different
species (e.g. a transplant of monkey kidneys to human); it
is foreign