Complement system

The complement system, also known as complement

cascade, is a part of the immune system that enhances
(complements) the ability of antibodies and phagocytic
cells to clear microbes and damaged cells from an
organism, promote inflammation, and attack the
pathogen's cell membrane. It is part of the innate
immune system,[1] which is not adaptable and does not
change during an individual's lifetime. The complement
system can, however, be recruited and brought into
action by antibodies generated by the adaptive immune
system.

The complement system consists of a number of small

proteins that are synthesized by the liver, and circulate
in the blood as inactive precursors. When stimulated by
one of several triggers, proteases in the system cleave
specific proteins to release cytokines and initiate an
amplifying cascade of further cleavages. The end result
of this complement activation or complement fixation
cascade is stimulation of phagocytes to clear foreign
and damaged material, inflammation to attract
Scheme of the complement system
additional phagocytes, and activation of the cell-killing
membrane attack complex. Over 30 proteins and
protein fragments make up the complement system,
including serum proteins, and cell membrane receptors. They account for about 10% of the globulin fraction of
blood serum.

Three biochemical pathways activate the complement system: the classical complement pathway, the
alternative complement pathway, and the lectin pathway.[2]

Contents
History
Functions
Overview
Classical pathway
Alternative pathway
Lectin pathway
Complement protein fragment nomenclature
Viral inhibition
Review
Activation of complements by antigen-associated antibody
Regulation
Role in disease
Complement deficiency
Deficiencies in complement regulators
Diagnostic tools
Modulation by infections
References
External links

History
In 1888, George Nuttall found that sheep blood serum had mild killing activity against the bacterium that
causes anthrax. The killing activity disappeared when he heated the blood.[3] In 1891, Hans Ernst August
Buchner, noting the same property of blood in his experiments, named the killing property "alexin", which
means "to ward off" in Greek.[4] By 1894, several laboratories had demonstrated that serum from guinea pigs
that had recovered from cholera killed the cholera bacterium in vitro. Heating the serum destroyed its killing
activity. Nevertheless, the heat-inactivated serum, when injected into guinea pigs exposed to the cholera
bacteria, maintained its ability to protect the animals from illness. Jules Bordet, a young Belgian scientist in
Paris at the Pasteur Institute, concluded that this principle has two components, one that maintained a
"sensitizing" effect after being heated and one (alexin) whose toxic effect was lost after being heated. The
heat-stable component was responsible for immunity against specific microorganisms, whereas the heat-
sensitive component was responsible for the non-specific antimicrobial activity conferred by all normal sera. In
1899, Paul Ehrlich renamed the heat-sensitive component "complement."[3]

Ehrlich introduced the term "complement" as part of his larger theory of the immune system[5]. According to
this theory, the immune system consists of cells that have specific receptors on their surface to recognize
antigens. Upon immunization with an antigen, more of these receptors are formed, and they are then shed from
the cells to circulate in the blood. Those receptors, which we now call "antibodies", were called by Ehrlich
"amboceptors" to emphasise their bifunctional binding capacity: They recognise and bind to a specific antigen,
but they also recognise and bind to the heat-labile antimicrobial component of fresh serum. Ehrlich, therefore,
named this heat-labile component "complement", because it is something in the blood that "complements" the
cells of the immune system. Ehrlich believed that each antigen-specific amboceptor has its own specific
complement, whereas Bordet believed that there is only one type of complement. In the early 20th century, this
controversy was resolved when it became understood that complement can act in combination with specific
antibodies, or on its own in a non-specific way.

Functions
Complement triggers the following immune functions:[6]

1. Phagocytosis – by opsonizing antigens. C3b has most important opsonizing activity

2. Inflammation – by attracting macrophages and neutrophils
3. Membrane attack – by rupturing cell wall of bacteria

Overview
Most of the proteins and glycoproteins that constitute the complement system are synthesized by hepatocytes.
But significant amounts are also produced by tissue macrophages, blood monocytes, and epithelial cells of the
genitourinary system and gastrointestinal tract. The three pathways of activation all generate homologous
variants of the protease C3-convertase. The classical complement
pathway typically requires antigen-antibody complexes for activation
(specific immune response), whereas the alternative pathway can be
activated by spontaneous complement component 3 (C3) hydrolysis,
foreign material, pathogens, or damaged cells. The mannose-binding
lectin pathway can be activated by C3 hydrolysis or antigens without
the presence of antibodies (non-specific immune response). In all
three pathways, C3-convertase cleaves and activates component C3,
creating C3a and C3b, and causes a cascade of further cleavage and
activation events. C3b binds to the surface of pathogens, leading to
greater internalization by phagocytic cells by opsonization.

In the alternative pathway, C3b binds to Factor B. Factor D releases

Factor Ba from Factor B bound to C3b. The complex of C3b(2)Bb is
a protease which cleaves C5 into C5b and C5a. C5 convertase is also Membrane Attack Complex (Terminal
formed by the classical pathway when C3b binds C4b and C2b. C5a Complement Complex C5b-9)
is an important chemotactic protein, helping recruit inflammatory
cells. C3a is the precursor of an important cytokine (adipokine) named
ASP (although this is not universally accepted [7]) and is usually rapidly cleaved by carboxypeptidase B. Both
C3a and C5a have anaphylatoxin activity, directly triggering degranulation of mast cells as well as increasing
vascular permeability and smooth muscle contraction.[7] C5b initiates the membrane attack pathway, which
results in the membrane attack complex (MAC), consisting of C5b, C6, C7, C8, and polymeric C9.[8] MAC is
the cytolytic endproduct of the complement cascade; it forms a transmembrane channel, which causes osmotic
lysis of the target cell. Kupffer cells and other macrophage cell types help clear complement-coated pathogens.
As part of the innate immune system, elements of the complement cascade can be found in species earlier than
vertebrates; most recently in the protostome horseshoe crab species, putting the origins of the system back
further than was previously thought.

Classical pathway

The classical pathway is triggered by activation of the C1-complex.

The C1-complex is composed of 1 molecule of C1q, 2 molecules of
C1r and 2 molecules of C1s, or C1qr2 s2 . This occurs when C1q
binds to IgM or IgG complexed with antigens. A single pentameric
IgM can initiate the pathway, while several, ideally six, IgGs are
needed. This also occurs when C1q binds directly to the surface of the
pathogen. Such binding leads to conformational changes in the C1q Reaction Cascade of the
molecule, which leads to the activation of two C1r molecules. C1r is a Complement System: Classical,
serine protease. They then cleave C1s (another serine protease). The Alternative and Lectin Pathway,
C1r2 s2 component now splits C4 and then C2, producing C4a, C4b, Amplification Loop, Terminal
C2a, and C2b (historically, the larger fragment of C2 was called C2a Pathway, and Membrane Attack
Complex.
but is now referred to as C2b). C4b and C2a bind to form the classical
pathway C3-convertase (C4b2a complex), which promotes cleavage
of C3 into C3a and C3b. C3b later joins with C4b2a to make C5
convertase (C4b2a3b complex).[9]

Alternative pathway

The alternative pathway is continuously activated at a low level, analogous to a car engine at idle, as a result of
spontaneous C3 hydrolysis due to the breakdown of the internal thioester bond (C3 is mildly unstable in
aqueous environment). The alternative pathway does not rely on pathogen-binding antibodies like the other
pathways.[2] C3b that is generated from C3 by a
C3 convertase enzyme complex in the fluid
phase is rapidly inactivated by factor H and
factor I, as is the C3b-like C3 that is the product
of spontaneous cleavage of the internal thioester.
In contrast, when the internal thioester of C3
reacts with a hydroxyl or amino group of a
molecule on the surface of a cell or pathogen, the
C3b that is now covalently bound to the surface
is protected from factor H-mediated inactivation.
The surface-bound C3b may now bind factor B
to form C3bB. This complex in the presence of
factor D will be cleaved into Ba and Bb. Bb will
remain associated with C3b to form C3bBb,
which is the alternative pathway C3 convertase.

The C3bBb complex is stabilized by binding

oligomers of factor P (properdin). The stabilized
C3 convertase, C3bBbP, then acts enzymatically
to cleave much more C3, some of which
becomes covalently attached to the same surface
as C3b. This newly bound C3b recruits more B,
D and P activity and greatly amplifies the
complement activation. When complement is
activated on a cell surface, the activation is
limited by endogenous complement regulatory
proteins, which include CD35, CD46, CD55 and The classical and alternative complement pathways
CD59, depending on the cell. Pathogens, in
general, don't have complement regulatory
proteins (there are many exceptions, which reflect adaptation of microbial pathogens to vertebrate immune
defenses). Thus, the alternative complement pathway is able to distinguish self from non-self on the basis of
the surface expression of complement regulatory proteins. Host cells don't accumulate cell surface C3b (and
the proteolytic fragment of C3b called iC3b) because this is prevented by the complement regulatory proteins,
while foreign cells, pathogens and abnormal surfaces may be heavily decorated with C3b and iC3b.
Accordingly, the alternative complement pathway is one element of innate immunity.

Once the alternative C3 convertase enzyme is formed on a pathogen or cell surface, it may bind covalently
another C3b, to form C3bBbC3bP, the C5 convertase. This enzyme then cleaves C5 to C5a, a potent
anaphylatoxin, and C5b. The C5b then recruits and assembles C6, C7, C8 and multiple C9 molecules to
assemble the membrane attack complex. This creates a hole or pore in the membrane that can kill or damage
the pathogen or cell.

Lectin pathway

The lectin pathway is homologous to the classical pathway, but with the opsonin, mannose-binding lectin
(MBL), and ficolins, instead of C1q. This pathway is activated by binding of MBL to mannose residues on the
pathogen surface, which activates the MBL-associated serine proteases, MASP-1, and MASP-2 (very similar
to C1r and C1s, respectively), which can then split C4 into C4a and C4b and C2 into C2a and C2b. C4b and
C2b then bind together to form the classical C3-convertase, as in the classical pathway. Ficolins are
homologous to MBL and function via MASP in a similar way. Several single-nucleotide polymorphisms have
been described in M-ficolin in humans, with effect on ligand-binding ability and serum levels. Historically, the
larger fragment of C2 was named C2a, but it is now referred to as C2b.[10] In invertebrates without an
adaptive immune system, ficolins are expanded and their binding specificities diversified to compensate for the
lack of pathogen-specific recognition molecules.

Complement protein fragment nomenclature

Immunology textbooks have used different naming assignments for the smaller and larger fragments of C2 as
C2a and C2b. The preferred assignment appears to be that the smaller fragment be designated as C2a: as early
as 1994, a well known textbook recommended that the larger fragment of C2 should be designated C2b.[11]
However, this was amplified in their 1999 4th edition, to say that:[12] "It is also useful to be aware that the
larger active fragment of C2 was originally designated C2a, and is still called that in some texts and research
papers. Here, for consistency, we shall call all large fragments of complement b, so the larger fragment of C2
will be designated C2b. In the classical and lectin pathways the C3 convertase enzyme is formed from
membrane-bound C4b with C2b."[12]

This nomenclature is used in another literature:[13] "(Note that, in older texts, the smaller fragment is often
called C2b, and the larger one is called C2a for historical reason.)"[14] The assignment is mixed in the latter
literature, though. Some sources designate the larger and smaller fragments as C2a and C2b
respectively[15][16][17][18][19][20][21][22][23] while other sources apply the converse.[11][12][24][25][26]
However, due to the widely established convention, C2b here is the larger fragment, which, in the classical
pathway, forms C4b2b (classically C4b2a). It may be noteworthy that, in a series of editions of Janeway's
book, 1st to 7th, in the latest edition[22] they withdraw the stance to indicate the larger fragment of C2 as C2b.

Viral inhibition

Fixation of the MBL protein on viral surfaces has also been shown to enhance neutralization of viral
pathogens.[27]

Review

Activation pathway Classic Alternative Lectin

Activator Ag–Ab Complex spontaneous hydrolysis of C3 MBL-Mannose Complex
C3-convertase C4b2a C3bBb C4b2a
C5-convertase C4b2a3b C3bC3bBb C4b2a3b
MAC development C5b+C6+C7+C8+C9

Activation of complements by antigen-associated antibody

In the classical pathway, C1 binds with its C1q subunits to Fc fragments (made of CH2 region) of IgG or IgM,
which has formed a complex with antigens. C4b and C3b are also able to bind to antigen-associated IgG or
IgM, to its Fc portion.[13][19][22]

Such immunoglobulin-mediated binding of the complement may be interpreted as that the complement uses
the ability of the immunoglobulin to detect and bind to non-self antigens as its guiding stick. The complement
itself can bind non-self pathogens after detecting their pathogen-associated molecular patterns (PAMPs),[22]
however, utilizing specificity of the antibody, complements can detect non-self enemies much more
specifically.
Some components have a variety of binding sites. In the classical pathway, C4 binds to Ig-associated C1q and
C1r2 s2 enzyme cleaves C4 to C4b and 4a. C4b binds to C1q, antigen-associated Ig (specifically to its Fc
portion), and even to the microbe surface. C3b binds to antigen-associated Ig and to the microbe surface.
Ability of C3b to bind to antigen-associated Ig would work effectively against antigen-antibody complexes to
make them soluble.

Regulation
The complement system has the potential to be extremely damaging to host tissues, meaning its activation must
be tightly regulated. The complement system is regulated by complement control proteins, which are present at
a higher concentration in the blood plasma than the complement proteins themselves. Some complement
control proteins are present on the membranes of self-cells preventing them from being targeted by
complement. One example is CD59, also known as protectin, which inhibits C9 polymerisation during the
formation of the membrane attack complex. The classical pathway is inhibited by C1-inhibitor, which binds to
C1 to prevent its activation.

C3-convertase can be inhibited by Decay accelerating factor (DAF), which is bound to erythrocyte plasma
membranes via a GPI anchor.

Role in disease

Complement deficiency

It is thought that the complement system might play a role in many diseases with an immune component, such
as Barraquer–Simons Syndrome, asthma, lupus erythematosus, glomerulonephritis, various forms of arthritis,
autoimmune heart disease, multiple sclerosis, inflammatory bowel disease, paroxysmal nocturnal
hemoglobinuria, atypical hemolytic uremic syndrome and ischemia-reperfusion injuries,[28][29] and rejection of
transplanted organs.[30]

The complement system is also becoming increasingly implicated in diseases of the central nervous system
such as Alzheimer's disease and other neurodegenerative conditions such as spinal cord injuries.[31][32][33]

Deficiencies of the terminal pathway predispose to both autoimmune disease and infections (particularly
Neisseria meningitidis, due to the role that the membrane attack complex ("MAC") plays in attacking Gram-
negative bacteria).[34]

Infections with N. meningitidis and N. gonorrhoeae are the only conditions known to be associated with
deficiencies in the MAC components of complement.[35] 40–50% of those with MAC deficiencies experience
recurrent infections with N. meningitidis.[36]

Deficiencies in complement regulators

Mutations in the complement regulators factor H and membrane cofactor protein have been associated with
atypical hemolytic uremic syndrome.[37][38] Moreover, a common single nucleotide polymorphism in factor H
(Y402H) has been associated with the common eye disease age-related macular degeneration.[39]
Polymorphisms of complement component 3, complement factor B, and complement factor I, as well as
deletion of complement factor H-related 3 and complement factor H-related 1 also affect a person's risk of
developing age-related macular degeneration.[40] Both of these disorders are currently thought to be due to
aberrant complement activation on the surface of host cells.
Mutations in the C1 inhibitor gene can cause hereditary angioedema, a genetic condition resulting from
reduced regulation of bradykinin by C1-INH.

Paroxysmal nocturnal hemoglobinuria is caused by complement breakdown of RBCs due to an inability to

make GPI. Thus the RBCs are not protected by GPI anchored proteins such as DAF.[41]

Diagnostic tools

Diagnostic tools to measure complement activity include the total complement activity test.[42]

The presence or absence of complement fixation upon a challenge can indicate whether particular antigens or
antibodies are present in the blood. This is the principle of the complement fixation test.

Modulation by infections
Recent research has suggested that the complement system is manipulated during HIV/AIDS, in a way that
further damages the body.[43]

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