![Complement pathway](https://upload.wikimedia.org/wikipedia/commons/9/98/Complement_pathway.svg)
The complement system, also known as complement cascade, is a part of the
immune system
The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinte ...
that enhances (complements) the ability of
antibodies
An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...
and
phagocytic
Phagocytosis () is the process by which a cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm), giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs phagocytosis is ...
cells to clear
microbes
A microorganism, or microbe,, ''mikros'', "small") and ''organism'' from the el, ὀργανισμός, ''organismós'', "organism"). It is usually written as a single word but is sometimes hyphenated (''micro-organism''), especially in olde ...
and damaged cells from an organism, promote
inflammation
Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
, and attack the pathogen's
cell membrane
The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...
. It is part of the
innate immune system
The innate, or nonspecific, immune system is one of the two main immunity strategies (the other being the adaptive immune system) in vertebrates. The innate immune system is an older evolutionary defense strategy, relatively speaking, and is the ...
,
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 adaptive immune system, also known as the acquired immune system, is a subsystem of the immune system that is composed of specialized, systemic cells and processes that eliminate pathogens or prevent their growth. The acquired immune system ...
.
The complement system consists of a number of small
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
s that are synthesized by the
liver
The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...
, and circulate in the blood as inactive
precursors
Precursor or Precursors may refer to:
* Precursor (religion), a forerunner, predecessor
** The Precursor, John the Baptist
Science and technology
* Precursor (bird), a hypothesized genus of fossil birds that was composed of fossilized parts of un ...
. When stimulated by one of several triggers,
protease
A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...
s in the system cleave specific proteins to release
cytokine
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
s and initiate an amplifying cascade of further cleavages. The end result of this ''complement activation'' or ''complement fixation'' cascade is stimulation of
phagocyte
Phagocytes are cells that protect the body by ingesting harmful foreign particles, bacteria, and dead or dying cells. Their name comes from the Greek ', "to eat" or "devour", and "-cyte", the suffix in biology denoting "cell", from the Greek ...
s to clear foreign and damaged material,
inflammation
Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
to attract additional phagocytes, and
activation
Activation, in chemistry and biology, is the process whereby something is prepared or excited for a subsequent reaction.
Chemistry
In chemistry, "activation" refers to the reversible transition of a molecule into a nearly identical chemical or ...
of the cell-killing
membrane attack complex
The membrane attack complex (MAC) or terminal complement complex (TCC) is a complex of proteins typically formed on the surface of pathogen cell membranes as a result of the activation of the host's complement system, and as such is an effector ...
. About 50 proteins and protein fragments make up the complement system, including
serum proteins
Serum protein electrophoresis (SPEP or SPE) is a laboratory test that examines specific Blood proteins, proteins in the blood called globulins. The most common indications for a serum protein electrophoresis test are to diagnose or monitor multip ...
, and
cell membrane receptors. They account for about 10% of the
globulin
The globulins are a family of globular proteins that have higher molecular weights than albumins and are insoluble in pure water but dissolve in dilute salt solutions. Some globulins are produced in the liver, while others are made by the immune ...
fraction of blood serum.
Three biochemical pathways activate the complement system: the
classical complement pathway
The classical complement pathway is one of three pathways which activate the complement system, which is part of the immune system. The classical complement pathway is initiated by antigen-antibody complexes with the antibody isotypes IgG and IgM ...
, the
alternative complement pathway
The alternative pathway is a type of cascade reaction of the complement system and is a component of the innate immune system, a natural defense against infections.
The alternative pathway is one of three complement pathways that opsonize and k ...
, and the
lectin pathway
The lectin pathway or lectin complement pathway is a type of cascade reaction in the complement system, similar in structure to the classical complement pathway, in that, after activation, it proceeds through the action of C4 and C2 to produce act ...
.
The alternative pathway accounts for the majority of terminal pathway activation and so therapeutic efforts in disease have revolved around its inhibition.
History
In 1888,
George Nuttall
George Henry Falkiner Nuttall FRS (5 July 1862 – 16 December 1937) was an American-British bacteriologist who contributed much to the knowledge of parasites and of insect carriers of diseases. He made significant innovative discoveries in immu ...
found that sheep blood
serum had mild killing activity against the
bacterium
Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among ...
that causes
anthrax
Anthrax is an infection caused by the bacterium ''Bacillus anthracis''. It can occur in four forms: skin, lungs, intestinal, and injection. Symptom onset occurs between one day and more than two months after the infection is contracted. The sk ...
. The killing activity disappeared when he heated the blood.
In 1891,
Hans Ernst August Buchner
Hans Ernst August Buchner (16 December 1850 – 5 April 1902) was a German bacteriologist who was born and raised in Munich. He was the older brother of Eduard Buchner (1860–1917), winner of the 1907 Nobel Prize in Chemistry.
Biography
He st ...
, noting the same property of blood in his experiments, named the killing property "alexin", which means "to ward off" in Greek.
By 1894, several laboratories had demonstrated that serum from guinea pigs that had recovered from
cholera
Cholera is an infection of the small intestine by some strains of the bacterium ''Vibrio cholerae''. Symptoms may range from none, to mild, to severe. The classic symptom is large amounts of watery diarrhea that lasts a few days. Vomiting and ...
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
Jules Jean Baptiste Vincent Bordet (; 13 June 1870 – 6 April 1961) was a Belgian immunologist and microbiologist. The bacterial genus ''Bordetella'' is named after him. The Nobel Prize in Physiology or Medicine was awarded to him in 1919 for ...
, a young
Belgian
Belgian may refer to:
* Something of, or related to, Belgium
* Belgians, people from Belgium or of Belgian descent
* Languages of Belgium, languages spoken in Belgium, such as Dutch, French, and German
*Ancient Belgian language, an extinct language ...
scientist in
Paris
Paris () is the capital and most populous city of France, with an estimated population of 2,165,423 residents in 2019 in an area of more than 105 km² (41 sq mi), making it the 30th most densely populated city in the world in 2020. S ...
at the
Pasteur Institute
The Pasteur Institute (french: Institut Pasteur) is a French non-profit private foundation dedicated to the study of biology, micro-organisms, diseases, and vaccines. It is named after Louis Pasteur, who invented pasteurization and vaccines f ...
, 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
Paul Ehrlich (; 14 March 1854 – 20 August 1915) was a Nobel Prize-winning German physician and scientist who worked in the fields of hematology, immunology, and antimicrobial chemotherapy. Among his foremost achievements were finding a cure ...
renamed the heat-sensitive component "complement."
Ehrlich introduced the term "complement" as part of his larger theory of the immune system. According to this theory, the immune system consists of cells that have specific receptors on their surface to recognize
antigens
In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...
. Upon immunization with an
antigen
In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...
, more of these receptors are formed, and they are then shed from the cells to circulate in the blood. Those
receptors
Receptor may refer to:
*Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a n ...
, which we now call "
antibodies
An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...
", 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
![Membrane Attack Complex (Terminal Complement Complex C5b-9)](https://upload.wikimedia.org/wikipedia/commons/6/60/Membrane_Attack_Complex_%28Terminal_Complement_Complex_C5b-9%29.png)
Complement triggers the following immune functions:
#
Membrane attack – by rupturing the
cell wall
A cell wall is a structural layer surrounding some types of cells, just outside the cell membrane. It can be tough, flexible, and sometimes rigid. It provides the cell with both structural support and protection, and also acts as a filtering mech ...
of
bacteria
Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among ...
. (
Classical Complement Pathway
The classical complement pathway is one of three pathways which activate the complement system, which is part of the immune system. The classical complement pathway is initiated by antigen-antibody complexes with the antibody isotypes IgG and IgM ...
)
#
Phagocytosis
Phagocytosis () is the process by which a cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm), giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs phagocytosis is ...
– by
opsonizing antigens. C3b has most important opsonizing activity. (
Alternative Complement Pathway
The alternative pathway is a type of cascade reaction of the complement system and is a component of the innate immune system, a natural defense against infections.
The alternative pathway is one of three complement pathways that opsonize and k ...
)
#
Inflammation
Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
– by attracting
macrophage
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...
s and
neutrophil
Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying in ...
s. (
Lectin pathway
The lectin pathway or lectin complement pathway is a type of cascade reaction in the complement system, similar in structure to the classical complement pathway, in that, after activation, it proceeds through the action of C4 and C2 to produce act ...
)
Overview
Most of the
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
s and
glycoprotein
Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycos ...
s that constitute the complement system are synthesized by
hepatocytes
A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass.
These cells are involved in:
* Protein synthesis
* Protein storage
* Transformation of carbohydrates
* Synthesis of cholesterol, b ...
. But significant amounts are also produced by tissue
macrophage
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...
s, blood
monocyte
Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also inf ...
s, and
epithelial cells
Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellula ...
of the
genitourinary system
The genitourinary system, or urogenital system, are the organs of the reproductive system and the urinary system. These are grouped together because of their proximity to each other, their common embryological origin and the use of common pathwa ...
and
gastrointestinal tract
The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organ (biology), organs of the digestive syste ...
. The three pathways of activation all generate homologous variants of the
protease
A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...
C3-convertase
C3 convertase (''C4bC2b'', formerly ''C4b2a'') belongs to family of serine proteases and is necessary in innate immunity as a part of the complement system which eventuate in opsonisation of particles, release of inflammatory peptides, C5 conve ...
. The classical complement pathway typically requires
antigen-antibody complex
An immune complex, sometimes called an antigen-antibody complex or antigen-bound antibody, is a molecule formed from the binding of multiple antigens to antibodies. The bound antigen and antibody act as a unitary object, effectively an antigen o ...
es for activation (specific immune response), whereas the alternative pathway can be activated by spontaneous
complement component 3
Complement component 3, often simply called C3, is a protein of the immune system. It plays a central role in the complement system and contributes to innate immunity. In humans it is encoded on chromosome 19 by a gene called ''C3''.
Function
C ...
(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
Phagocytes are cells that protect the body by ingesting harmful foreign particles, bacteria, and dead or dying cells. Their name comes from the Greek ', "to eat" or "devour", and "-cyte", the suffix in biology denoting "cell", from the Greek '' ...
by
opsonization
Opsonins are extracellular proteins that, when bound to substances or cells, induce phagocytes to phagocytose the substances or cells with the opsonins bound. Thus, opsonins act as tags to label things in the body that should be phagocytosed (i.e. ...
.
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
C5 convertase is an enzyme belonging to a family of serine proteases that play key role in the innate immunity. It participates in the complement system ending with cell death.
There are four different C5 convertases able to specifically conv ...
is also formed by the classical pathway when C3b binds C4b and C2b.
C5a is an important
chemotactic protein, helping recruit inflammatory cells. C3a is the precursor of an important
cytokine
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
(adipokine) named
ASP (although this is not universally accepted
) and is usually rapidly cleaved by
carboxypeptidase B
Carboxypeptidase B (, ''protaminase'', ''pancreatic carboxypeptidase B'', ''tissue carboxypeptidase B'', ''peptidyl-L-lysine -arginineydrolase'') is a carboxypeptidase that preferentially acts upon basic amino acids, such as arginine and lysine ...
. Both C3a and C5a have
anaphylatoxin
Anaphylatoxins, or complement peptides, are fragments ( C3a, C4a and C5a) that are produced as part of the activation of the complement system. Complement components C3, C4 and C5 are large glycoproteins that have important functions in the imm ...
activity, directly triggering
degranulation
Degranulation is a cellular process that releases antimicrobial cytotoxic or other molecules from secretory vesicles called granules found inside some cells. It is used by several different cells involved in the immune system, including granulo ...
of
mast cell
A mast cell (also known as a mastocyte or a labrocyte) is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem cell that is a par ...
s as well as increasing vascular permeability and
smooth muscle
Smooth muscle is an involuntary non-striated muscle, so-called because it has no sarcomeres and therefore no striations (''bands'' or ''stripes''). It is divided into two subgroups, single-unit and multiunit smooth muscle. Within single-unit mus ...
contraction.
C5b initiates the
membrane attack pathway, which results in the
membrane attack complex
The membrane attack complex (MAC) or terminal complement complex (TCC) is a complex of proteins typically formed on the surface of pathogen cell membranes as a result of the activation of the host's complement system, and as such is an effector ...
(MAC), consisting of C5b,
C6,
C7,
C8, and polymeric
C9.
MAC is the cytolytic endproduct of the complement cascade; it forms a transmembrane channel, which causes
osmotic
Osmosis (, ) is the spontaneous net movement or diffusion of solvent molecules through a selectively-permeable membrane from a region of high water potential (region of lower solute concentration) to a region of low water potential (region of ...
lysis of the target cell.
Kupffer cells
Kupffer cells, also known as stellate macrophages and Kupffer–Browicz cells, are specialized cells localized in the liver within the lumen of the liver sinusoids and are adhesive to their endothelial cells which make up the blood vessel walls. Ku ...
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
Protostomia () is the clade of animals once thought to be characterized by the formation of the organism's mouth before its anus during embryonic development. This nature has since been discovered to be extremely variable among Protostomia's memb ...
horseshoe crab
Horseshoe crabs are marine and brackish water arthropods of the family Limulidae and the only living members of the order Xiphosura. Despite their name, they are not true crabs or crustaceans: they are chelicerates, most closely related to arachn ...
species, putting the origins of the system back further than was previously thought.
Classical pathway
![Complement-pathways](https://upload.wikimedia.org/wikipedia/commons/b/b0/Complement-pathways.png)
The
classical pathway
Classical may refer to:
European antiquity
*Classical antiquity, a period of history from roughly the 7th or 8th century B.C.E. to the 5th century C.E. centered on the Mediterranean Sea
*Classical architecture, architecture derived from Greek and ...
is triggered by activation of the C1-complex. The C1-complex is composed of 1 molecule of
C1q
The complement component 1q (or simply C1q) is a protein complex involved in the complement system, which is part of the innate immune system. C1q together with C1r and C1s form the C1 complex.
Antibodies of the adaptive immune system can bind ...
, 2 molecules of C1r and 2 molecules of C1s, or ''C1qr
2s
2''. This occurs when C1q binds to
IgM
Immunoglobulin M (IgM) is one of several isotypes of antibody (also known as immunoglobulin) that are produced by vertebrates. IgM is the largest antibody, and it is the first antibody to appear in the response to initial exposure to an antig ...
or
IgG
Immunoglobulin G (Ig G) is a type of antibody. Representing approximately 75% of serum antibodies in humans, IgG is the most common type of antibody found in blood circulation. IgG molecules are created and released by plasma B cells. Each IgG ...
complexed with
antigen
In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...
s. A single pentameric IgM can initiate the pathway, while several, ideally six, IgGs are needed. This also occurs when
C1q
The complement component 1q (or simply C1q) is a protein complex involved in the complement system, which is part of the innate immune system. C1q together with C1r and C1s form the C1 complex.
Antibodies of the adaptive immune system can bind ...
binds directly to the surface of the pathogen. Such binding leads to conformational changes in the C1q molecule, which leads to the activation of two
C1r
Complement C1r subcomponent (, ''activated complement C1r'', ''C overbar 1r esterase'', ''C1r'') is a protein involved in the complement system of the innate immune system. In humans, C1r is encoded by the ''C1R'' gene.
C1r along with C1q and C1 ...
molecules. C1r is a serine protease. They then cleave
C1s
Complement component 1s (, '' C1 esterase'', ''activated complement C1s'', ''complement C overbar 1r'', ''C1s'') is a protein involved in the complement system. C1s is part of the C1 complex. In humans, it is encoded by the ''C1S'' gene.
C1s cle ...
(another serine protease). The C1r
2s
2 component now splits
C4 and then
C2, producing C4a, C4b, C2a, and C2b (historically, the larger fragment of C2 was called C2a but is now referred to as C2b). C4b and C2b bind to form the classical pathway C3-convertase (C4b2b complex), which promotes cleavage of C3 into C3a and C3b. C3b later joins with C4b2b to make C5 convertase (C4b2b3b complex).
Alternative pathway
The
alternative pathway
The alternative pathway is a type of cascade reaction of the complement system and is a component of the innate immune system, a natural defense against infections.
The alternative pathway is one of three complement pathways that opsonize and ...
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.
C3b that is generated from C3 by a C3 convertase enzyme complex in the fluid phase is rapidly inactivated by
factor H
Factor H is a member of the regulators of complement activation family and is a complement control protein. It is a large (155 kilodaltons), soluble glycoprotein that circulates in human plasma (at typical concentrations of 200–300 micrograms ...
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
Complement factor B is a protein that in humans is encoded by the ''CFB'' gene.
Function
This gene encodes complement factor B, a component of the alternative pathway of complement activation. Factor B circulates in the blood as a single chai ...
to form C3bB. This complex in the presence of
factor D
Factor D (, ''C3 proactivator convertase'', ''properdin factor D esterase'', ''factor D (complement)'', ''complement factor D'', ''CFD'', ''adipsin'') is a protein which in humans is encoded by the ''CFD'' gene. Factor D is involved in the alterna ...
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
CD46 complement regulatory protein also known as CD46 (cluster of differentiation 46) and Membrane Cofactor Protein is a protein which in humans is encoded by the ''CD46'' gene. CD46 is an inhibitory complement receptor.
Gene
This gene is foun ...
,
CD55
Complement decay-accelerating factor, also known as CD55 or DAF, is a protein that, in humans, is encoded by the ''CD55'' gene.
DAF regulates the complement system on the cell surface. It recognizes C4b and C3b fragments that are created during a ...
and
CD59
CD59 glycoprotein, also known as MAC-inhibitory protein (MAC-IP), membrane inhibitor of reactive lysis (MIRL), or protectin, is a protein that in humans is encoded by the ''CD59'' gene. It is an LU domain and belongs to the LY6/uPAR/ alpha-ne ...
, 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
The innate, or nonspecific, immune system is one of the two main immunity strategies (the other being the adaptive immune system) in vertebrates. The innate immune system is an older evolutionary defense strategy, relatively speaking, and is the ...
.
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
Anaphylatoxins, or complement peptides, are fragments ( C3a, C4a and C5a) that are produced as part of the activation of the complement system. Complement components C3, C4 and C5 are large glycoproteins that have important functions in the imm ...
, and C5b. The C5b then recruits and assembles C6, C7, C8 and multiple C9 molecules to assemble the
membrane attack complex
The membrane attack complex (MAC) or terminal complement complex (TCC) is a complex of proteins typically formed on the surface of pathogen cell membranes as a result of the activation of the host's complement system, and as such is an effector ...
. This creates a hole or pore in the membrane that can kill or damage the pathogen or cell.
Lectin pathway
The
lectin
Lectins are carbohydrate-binding proteins that are highly specific for sugar groups that are part of other molecules, so cause agglutination of particular cells or precipitation of glycoconjugates and polysaccharides. Lectins have a role in rec ...
pathway is homologous to the classical pathway, but with the opsonin,
mannose-binding lectin (MBL), and
ficolin
Ficolins are pattern recognition receptors that bind to acetyl groups present in the carbohydrates of bacterial surfaces and mediate activation of the lectin pathway of the complement cascade.
Structure
Ficolins (Fi+Col+Lin) are a group of oligo ...
s, 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. 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.
However, this was amplified in their 1999 4th edition, to say that:
"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."
This nomenclature is used in another literature:
The assignment is mixed in the latter literature, though.
Some sources designate the larger and smaller fragments as C2a and C2b respectively
while other sources apply the converse.
[Doan T, Melvold R, Viselli S, Waltenbaugh C (2007). ''Lippincott's Illustrated Reviews: Immunology,'' 320p. Lippincott Williams & Wilkins] 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
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.
Review
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.
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
Pathogen-associated molecular patterns (PAMPs) are small molecular motifs conserved within a class of microbes. They are recognized by toll-like receptors (TLRs) and other pattern recognition receptors (PRRs) in both plants and animals. A vast arra ...
(PAMPs),
however, utilizing specificity of the antibody, complements can detect non-self targets much more specifically.
Some components have a variety of binding sites. In the classical pathway, C4 binds to Ig-associated C1q and C1r
2s
2 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 protein Complement control protein are proteins that interact with components of the complement system.
The complement system is tightly regulated by a network of proteins known as "regulators of complement activation (RCA)" that help distinguish target ...
s, which are present at blood plasma and host cell membrane. Some complement control proteins are present on the membranes of self-cells preventing them from being targeted by complement. One example is
CD59
CD59 glycoprotein, also known as MAC-inhibitory protein (MAC-IP), membrane inhibitor of reactive lysis (MIRL), or protectin, is a protein that in humans is encoded by the ''CD59'' gene. It is an LU domain and belongs to the LY6/uPAR/ alpha-ne ...
, also known as protectin, which inhibits C9 polymerization during the formation of the
membrane attack complex
The membrane attack complex (MAC) or terminal complement complex (TCC) is a complex of proteins typically formed on the surface of pathogen cell membranes as a result of the activation of the host's complement system, and as such is an effector ...
. The classical pathway is inhibited by
C1-inhibitor
C1-inhibitor (C1-inh, C1 esterase inhibitor) is a protease inhibitor belonging to the serpin superfamily. Its main function is the inhibition of the complement system to prevent spontaneous activation but also as the major regulator of the cont ...
, which binds to C1 to prevent its activation.
C3-convertase can be inhibited by
decay accelerating factor
Complement decay-accelerating factor, also known as CD55 or DAF, is a protein that, in humans, is encoded by the ''CD55'' gene.
DAF regulates the complement system on the cell surface. It recognizes C4b and C3b fragments that are created during ...
(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
Barraquer–Simons syndrome is a rare form of lipodystrophy,
which usually first affects the head, and then spreads to the thorax. It is named for Luis Barraquer Roviralta (1855–1928), a Spanish physician, and Arthur Simons (1879–1942), a Germ ...
,
asthma
Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, cou ...
,
lupus erythematosus
Lupus erythematosus is a collection of autoimmune diseases in which the human immune system becomes hyperactive and attacks healthy tissues. Symptoms of these diseases can affect many different body systems, including joints, skin, kidneys, blo ...
,
glomerulonephritis
Glomerulonephritis (GN) is a term used to refer to several kidney diseases (usually affecting both kidneys). Many of the diseases are characterised by inflammation either of the glomeruli or of the small blood vessels in the kidneys, hence the ...
, various forms of
arthritis
Arthritis is a term often used to mean any disorder that affects joints. Symptoms generally include joint pain and stiffness. Other symptoms may include redness, warmth, swelling, and decreased range of motion of the affected joints. In som ...
,
autoimmune heart disease,
multiple sclerosis
Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This d ...
,
inflammatory bowel disease
Inflammatory bowel disease (IBD) is a group of inflammation, inflammatory conditions of the colon (anatomy), colon and small intestine, Crohn's disease and ulcerative colitis being the principal types. Crohn's disease affects the small intestine a ...
,
paroxysmal nocturnal hemoglobinuria
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, life-threatening disease of the blood characterized by destruction of red blood cells by the complement system, a part of the body's innate immune system. This destructive process occu ...
,
atypical hemolytic uremic syndrome
Atypical hemolytic uremic syndrome (aHUS) is an extremely rare, life-threatening, progressive disease that frequently has a genetic component. In most cases it can be effectively controlled by interruption of the complement cascade. Particular mo ...
and ischemia-reperfusion injuries,
and rejection of transplanted organs.
The complement system is also becoming increasingly implicated in diseases of the central nervous system such as
Alzheimer's disease
Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
and other neurodegenerative conditions such as spinal cord injuries.
Deficiencies of the terminal pathway predispose to both
autoimmune disease
An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. At least 80 types of autoimmune diseases have been identified, with some evidence suggesting that there may be more than 100 types. Nearly a ...
and
infection
An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable dise ...
s (particularly
Neisseria meningitidis
''Neisseria meningitidis'', often referred to as meningococcus, is a Gram-negative bacterium that can cause meningitis and other forms of meningococcal disease such as meningococcemia, a life-threatening sepsis. The bacterium is referred to as a ...
, due to the role that the
membrane attack complex
The membrane attack complex (MAC) or terminal complement complex (TCC) is a complex of proteins typically formed on the surface of pathogen cell membranes as a result of the activation of the host's complement system, and as such is an effector ...
("MAC") plays in attacking
Gram-negative
Gram-negative bacteria are bacteria that do not retain the crystal violet stain used in the Gram staining method of bacterial differentiation. They are characterized by their cell envelopes, which are composed of a thin peptidoglycan cell wall ...
bacteria).
Infections with ''N. meningitidis'' and ''
N. gonorrhoeae
''Neisseria gonorrhoeae'', also known as ''gonococcus'' (singular), or ''gonococci'' (plural), is a species of Gram-negative diplococci bacteria isolated by Albert Neisser in 1879. It causes the sexually transmitted genitourinary infection gon ...
'' are the only conditions known to be associated with deficiencies in the MAC components of complement.
40–50% of those with MAC deficiencies experience recurrent infections with ''N. meningitidis''.
Deficiencies in complement regulators
Mutations in the genes of complement regulators, especially
factor H
Factor H is a member of the regulators of complement activation family and is a complement control protein. It is a large (155 kilodaltons), soluble glycoprotein that circulates in human plasma (at typical concentrations of 200–300 micrograms ...
, have been associated with atypical
hemolytic uremic syndrome
Hemolysis or haemolysis (), also known by several other names, is the rupturing ( lysis) of red blood cells (erythrocytes) and the release of their contents (cytoplasm) into surrounding fluid (e.g. blood plasma). Hemolysis may occur in vivo ...
,
and C3 glomerulopathy.
Both of these disorders are currently thought to be due to complement overactivation either on the surface of host cells or in plasma, with the molecular location of genetic variation in complement proteins providing clues into the underlying disease processes.
Moreover, several
single nucleotide polymorphism
In genetics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a sufficiently larg ...
s and mutations in the complement factor H gene (the most common of which results in the protein change p.Y402H) have been associated with the common eye disease
age-related macular degeneration
Macular degeneration, also known as age-related macular degeneration (AMD or ARMD), is a medical condition which may result in blurred or no vision in the center of the visual field. Early on there are often no symptoms. Over time, however, som ...
.
Polymorphisms of
complement component 3
Complement component 3, often simply called C3, is a protein of the immune system. It plays a central role in the complement system and contributes to innate immunity. In humans it is encoded on chromosome 19 by a gene called ''C3''.
Function
C ...
,
complement factor B
Complement factor B is a protein that in humans is encoded by the ''CFB'' gene.
Function
This gene encodes complement factor B, a component of the alternative pathway of complement activation. Factor B circulates in the blood as a single chai ...
, and
complement factor I
Complement factor I, also known as C3b/C4b inactivator, is a protein that in humans is encoded by the ''CFI'' gene. Complement factor I (factor I) is a protein of the complement system, first isolated in 1966 in guinea pig blood plasma, serum, t ...
, 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
Macular degeneration, also known as age-related macular degeneration (AMD or ARMD), is a medical condition which may result in blurred or no vision in the center of the visual field. Early on there are often no symptoms. Over time, however, som ...
.
Mutations in the C1 inhibitor gene can cause
hereditary angioedema
Hereditary angioedema (HAE) is a disorder that results in recurrent attacks of severe swelling. The swelling most commonly affects the arms, legs, face, intestinal tract, and airway. If the intestinal tract is affected, abdominal pain and vomitin ...
, a genetic condition resulting from reduced regulation of
bradykinin
Bradykinin (BK) (Greek brady-, slow; -kinin, kīn(eîn) to move) is a peptide that promotes inflammation. It causes arterioles to dilate (enlarge) via the release of prostacyclin, nitric oxide, and endothelium-derived hyperpolarizing factor and ...
by C1-INH.
Paroxysmal nocturnal hemoglobinuria
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, life-threatening disease of the blood characterized by destruction of red blood cells by the complement system, a part of the body's innate immune system. This destructive process occu ...
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.
Diagnostic tools
Diagnostic tools to measure complement activity include the
total complement activity test.
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
The complement fixation test is an immunological medical test that can be used to detect the presence of either specific antibody or specific antigen in a patient's serum, based on whether complement fixation occurs. It was widely used to diagnos ...
.
Modulation by infections
Research has suggested that the complement system is manipulated during
HIV
The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune ...
/
AIDS
Human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV), a retrovirus. Following initial infection an individual m ...
, in a way that further damages the body.
Role in the brain
Research from over the last decade has shown that complement proteins of the classical complement pathway have an important role in
synaptic pruning
Synaptic pruning, a phase in the development of the nervous system, is the process of synapse elimination that occurs between early childhood and the onset of puberty in many mammals, including humans. Pruning starts near the time of birth and con ...
in the brain during early development.
References
External links
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{{Authority control
Immune system