Download 1 TEMA 2. SISTEMA DE COMPLEMENTO

TEMA 2. SISTEMA DE COMPLEMENTO
- Historia
- Componentes
- Nomenclatura
Proteins with assigned numbers, C1, C2... Many are zymogens, i.e. proenzymes which require proteolytic cleavage to become active.
The enzymatically active form is distinguished from its precursor by a bar
drawn above.
The cleavage products of complement proteins are distinguished from
parent molecules by suffix letters, C3a, C3b, etc.
The proteins of the alternative pathway are called 'factors' and are
identified by single letters, e.g. factor B, which may be abbreviated to FB
or just 'B'.
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Tema 2. El sistema del complemento
3. Funciones del sistema del complemento
1.
Intrinsic ability to lyse the cell
membranes of many bacterial
species.
2.
Complement products released in
this reaction attract phagocytes to
the site of the reaction - chemotaxis.
3.
Complement components coat the
bacterial surface - opsonization allowing
the
phagocytes
to
recognize the bacteria and engulf
them. Intrinsic ability of the
complement system to recognize
microbial
components/antibodies
bound to the microorganism.
4.
Binding of complement to receptors
of immune cells - triggering
inflammation,
secretion
immunorregulatory molecules…
5.
4.
5. Immune clearance- removal from
immunocomplexes from circulation.
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Both classical and alternative pathways
generate a C3 convertase, which converts
C3 to C3b, the central event of the
complement pathway.
C3b in turn activates the terminal, lytic
sequence, C5-C9.
The first stage in the classical pathway is
the binding of antigen to antibody.
The alternative pathway does not require
antibody and is initiated by the covalent
binding of C3b to hydroxyl and amine
groups on the surface of various
microorganisms.
The alternative pathway provides nonspecific 'innate' immunity, whereas the
classical pathway represents a more
recently evolved link to the adaptive
immune system.
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Vía clásica
The
classical
pathway
is
activated by the cleavage of C1r
and C1s following association of
C1qr2s2 with classical pathway
activators
including
immune
complexes.
Once
activated
cleaves C4 and C2 to form the
classical pathway C3 convertase.
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C1, primer componente de la vía clásica
Electronmicrograph of a human C1q molecule
demonstrates six subunits. Each subunit
contains three polypeptide chains, giving 18 in
the whole molecule. The receptors for the Fc
regions of IgG and IgM are in the globular
heads. The connecting stalks contain regions
of triple helix and the central core region
contains collagen-like triple helix.
Model of intact C1 with two C1r and two C1s
proenzymes positioned within the ring. The
catalytic heads of C1r and C1s are closely
apposed and conformational change induced
in C1q following binding to complexed
immunoglobulin
causes
mutual
activation/cleavage of each C1r unit followed
by cleavage of the two C1s units. The cohesion
of the entire complex is dependent on Ca2+.
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Cabeza globular
Conector
triple hélice
núcleo collagen-like
Tema 2. El sistema del complemento
Unión Fc de IgG a dominio globular de C1q
Cambio conformacional C1
C1r (1) autocatálisis
C1r (2) activación
C1s (1 y 2) activación- serinesterasas
activas sobre C4 y C2
Formación C4b2a- C3 convertasa de la vía
clásica
3
Vía de las lectinas
Cleavage of C4 and C2 can
also be effected via the
lectin pathway, which is
associated with mannanbinding lectin (MBL).
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Activadores de las vías clásica y de las lectinas
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Vía alternativa
The
alternative
pathway
is
activated by the cleavage of C3 to
C3b, which associates with factor
B and is cleaved by factor D to
generate the alternative pathway
C3 convertase C3bBb.
The initial activation of C3
happens
to
some
extent
spontaneously. This step can also
be effected by classical or
alternative
pathway
C3
convertases or a number of other
serum or microbial proteases.
Activation
pathways
are
functionally analogous. C3 and C4
are homologous, as are C2 and
factor B. MASP-1 and MASP-2 are
homologous to C1r and C1s,
respectively.
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Activación del enlace tioester de C3
The α-chain of C3 contains a thioester bond formed between a cysteine and a
glutamine residue, with the elimination of ammonia.
Following cleavage of C3 into C3a and C3b*, the bond becomes unstable and
susceptible to nucleophilic attack by electrons on -OH and -NH2 groups, allowing
the C3b to form covalent bonds with proteins and carbohydrates - the active group
decays rapidly by hydrolysis, if such a bond does not form.
C4 also contains a thioester bond which becomes activated similarly when C4 is
split into C4a and C4b.
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Activación / asa de amplificación
/ regulación de la vía alternativa
Alternative pathway activation depends on the
presence of protected surfaces.
Amplification: 'Protected' means that bound
C3b is protected from proteolytic degradation.
C3b bound to an activator surface binds
factor B, which is cleaved by factor D to
produce
the
alternative
pathway
C3
convertase , which drives the amplification
loop, by cleaving more C3- higher C3
deposition
Inhibition: On self surfaces the binding of
factor
H
is
favoured
and
C3b
is
inactivated/catabolised by factor I.
The binding of factor B or factor H controls
the development of the alternative pathway
reactions.
CR1 and DAF limit complement activation on
self cell membranes - cofactors of factor I in
dissociation of C3bBb convertase.
Protected surfaces: bacterial
immunoglobuline aggregates.
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membranes,
Tema 2. El sistema del complemento
Inactivación de C3
Factor I cleaves C3b in three places to release C3c, leaving C3dg, a fragment
of the α-chain, still bound to the substrate.
The first two cleavages are promoted by factor H, MCP or CR1 and produce an
intermediate iC3b.
The third cleavage is promoted by CR1.
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Activadores de la vía alternativa
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Vía lítica
Classical (C4b2a) or alternative
(C3bBb) pathway C3 convertases
associate with C3b bound on a
cell
surface
to
form
C5
convertases
(C4b2a3b
/
C3bBb3b), which split C5.
The
larger
fragment,
C5b
associates with C6 and C7, which
can then bind to plasma
membranes.
The complex of C5b67 assembles
C8 and a number of molecules of
C9 to form a membrane attack
complex (MAC), C5b-9.
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Vía lítica
Assembly of the C5b-9 membrane attack complex (MAC). Recruitment of a further C3b into the
C3bBb enzymic complex generates a C5 convertase which cleaves C5a from C5 and leaves the
remaining C5b attached to the membrane. Once C5b is membrane bound, C6 and C7 attach
themselves to form the stable complex, C5b67, which interacts with C8 to yield C5b678.
This unit has some effect in disrupting the membrane, but primarily causes the polymerization of
C9 to form tubules traversing the membrane. The resulting tubule is referred to as a MAC.
Disruption of the membrane by this structure permits the free exchange of solutes, which is
primarily responsible for cell lysis
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Reguladores de la activación del complemento
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Las funciones del sistema del complemento
The complement system has an
intrinsic ability to lyse the cell
membranes of many bacterial species.
(2) Complement products released in
this reaction attract phagocytes to the
site of the reaction - chemotaxis. (3)
Complement components coat the
bacterial surface - opsonization allowing the phagocytes to recognize
the bacteria and engulf them. These
reactions may be triggered by the
intrinsic ability of the complement
system to recognize microbial
components or by antibodies bound to
the microorganism.
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Opsonización
Upper panel: A bacterium is sensitized
by the covalent binding of C3b, iC3b
and C4b, which allow it to be
recognized by complement receptors
(CR) on neutrophils and mononuclear
phagocytes. This promotes
phagocytosis and activation of the
phagocyte. In primates, erythrocytes
also express CR1, which allows them
to bind opsonized bacteria and
immune complexes. In the lower panel
fluoresceinated bacteria which have
been opsonized with antibody and
complement are seen adhering to
human erythrocytes.
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Receptores del complemento
The complement receptors CR1 and CR2 are formed from
numerous repeated complement control protein (CCP) domains.
CR3 and CR4 are integrins which share a common β chain (CD18).
CR1, CR3 and CR4 are expressed on macrophages and other
phagocytic cells, while CR2 is confined to B cells and follicular
dendritic cells, where it has a function in the maturation of the
antibody response
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Quimiotaxis
C5a and C3a both act on mast
cells to cause degranulation
and release of vasoactive
amines, including histamine
and 5-hydroxytryptamine,
which enhance vascular
permeability and local blood
flow. The secondary release of
chemokines from mast cells
causes cellular accumulation
and C5a itself acts directly on
receptors on monocytes and
neutrophils to induce their
migration to sites of acute
inflammation and subsequent
activation.
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The table lists major
inflammatory
mediators, which
control blood
supply and vascular
permeability or
modulate cell
movement. The
main sources are
given (centre
block).
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