Download Immunology: 2nd lecture/ 3rd Class /Microbio.Deprt.Vet.Med.2015

Immunology: 2nd lecture/ 3rd Class /Microbio.Deprt.Vet.Med.2015-2016
Assist. Prof.Dr.Ikram Abbas Aboud Al-Samarraae
The Complement System:The complement system consists of several plasma proteins that interact
with one another and with other molecules of the immune system in a highly
regulated manner to generate products that function to eliminate microbes.
The name of complement system is derived from experiments performed
by Jules Bordet (1890) shortly after the discovery of antibodies .He
demonstrated that if fresh serum containing antibacterial antibodies was
added to the bacteria at physiologic temperature (37C).The bacteria were
lyses. However, the serum was heated to 56c or more, lost its lytic capacity.
Bordet concluded that the serum must contain another heat – labile
component that assists or complement, the lytic function of antibodies.
The complement system proteins, that function in both adaptive and
innate host defense system .These proteins are highly regulated and interact
via a series of proteolytic cascades. The term “Complement “refers to ability
of these proteins to complement (augment) the effects of these components
of the immune system (e.g .Antibodies).
-Complement system has several main effects:1- Lyses of cells (e.g. Bacteria and tumor cells).
2- Production of mediators that participate in inflammation & attract
phagocytes.
3- Opsonization
phagocytosis, and
of
organisms
&immune
complexes
for
cleanse
4- Enhancement of antibody – mediated immune response.
The complement system synthesized mainly by the liver and phagocytic
cells.
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-The Complement Activation:The several complement components are proenzyme which must be
cleaved to form active enzymes. The complement components of the
classical pathway are numbered from C1 to C9, and the reaction sequence is
C1-C2-C3-C4-C5-C6-C7-C8-C9. UptoC5 activation involves proteolysis
cleavages, liberating smaller fragments from C2 through C5. The smaller
fragments are by convention denoted by the letter a (e.g.C4a) and larger
fragments b (e.g.C5b). Activation of the complement system can be initiated
either by antigen – antibody complexes or by a variety of non immunologic
molecules .sequential activation of complement components occurs via two
main pathways.
A-The Classical Pathway:Only IgM & IgG activate or fix complement via the classical path way
of the IgG, only IgG subclasses 1,2&3 fix complement , IgG4 don’t fixed .
C1 which is bound to a site in the Fc region is composed of three proteins.
C1q, C1r & C1s . C1q is an aggregate of polypeptides that bind to the Fc
portion of IgG & IgM .The antibody – antigen immune complex bound to
C1 activates C1s which cleaves C4 C4 & C2 to form C4b2b. The latter is an
active C3 convertase which cleaves C3molecules into two fragments C3a &
C3b. C3a an anaphylatoxin. C3b forms a complex with C4b2b producing
anew enzyme, C5 convertase which cleaves C5 to form C5a &C5b. C5a is
anaphylatoxin & chemotactic factor .C5b binds to C6 & C7 to form a
complex that inserts into the membrane bilayer. C8 then bind to the C5b,C6
,C7 complex ,followed by the polymerization of up to sixteen C9 molecules
to produce the membrane attack complex (MAC) that generates a channel or
pore in the membrane and causes cytolysis by allowing free passage of water
across the cell membrane .
B-Alternative pathway:Many unrelated substances, from complex chemical (e.g. endotoxin) to
infectious agents (e.g. Parasites) , activate a different pathway .C3 is cleaved
, and aC3 convertase is generated via the action of factors B, D & properdin
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. The alternative C3 convertase (C3bBb) generates more C3b. The
additionalC3b binds to the C3 convertase to form C3bBb, which is the
alternative pathway C5convertase that generates C5b, leading to production
of the membrane attack complex.
-Major Biologic Effects Complement:A-Opsonization:Cells, antigen – antibody complexes, and other particles are phagocytosed
much more efficiently in the presence of C3b because of the presence of C3b
receptors on the surface of many phagocytes.
B- Chemotaxis:C5a stimulates movement of neutrophils & monocytes toward sites of
antigen deposition.
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C-Anaphylatoxins:C3a &C5a can produce increased vascular permeability and smooth
muscle contraction. C3a & C5a also stimulate mast cell to release histamine.
D- Cytolysis:
Insertion of the C5b6789 complex into the cell surface leads to killing or
lyses of many types of cells, including erythrocytes, bacteria & tumor cells.
-Clinical Consequences of Complement Deficiencies:Many genetic deficiencies of complement proteins have been described
& these generally lead to enhanced susceptibility to infectious diseases ( e.g.
C2 deficiency frequently lead to serious pyogenic bacterial infections).
Deficiency in components of the membrane attack complex greatly
enhances susceptibility to Neisserial infections.
Deficiency in component of alternative pathway with greater
susceptibility to meningococcal disease.
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