Complement refers to a set of serum proteins that cooperates with both the
innate and the adaptive immune systems to eliminate pathogens. These proteins
work in a cascade-like manner to eliminate pathogens and promote inflammation.
Three main pathways activate the complement system: the classical pathway, the
lectin pathway, and the alternative pathway.
The classical pathway is triggered by the binding of antibodies to antigens on the
surface of pathogens. This binding initiates a series of protein cleavages, leading
to the formation of a membrane attack complex (MAC) that punctures the
pathogen's cell membrane, causing cell lysis. The lectin pathway is activated by
the binding of mannose-binding lectin (MBL) to mannose residues on the surface
of pathogens. This binding also leads to the formation of a MAC. The alternative
pathway is continuously active at a low level and is triggered by the spontaneous
hydrolysis of C3, a complement protein. This pathway provides a rapid response to
invading pathogens, even in the absence of antibodies.
The complement system consists of serum and cell surface 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. Complement proteins are plasma proteins that are normally inactive;
they are activated only under particular conditions to generate products that
mediate various effector functions of complement.
Properties of Complement
Complement shows the following properties:
1. It is present in sera of all mammals including humans and in lower animals
including birds.
2. These are heat-labile substances that are inactivated by heating serum at
56°C for 30 minutes.
3. These are glycoproteins and are synthesized primarily by liver cells and to a
very less extent by macrophages and many other cell types.
4. The complement usually does not bind to the antigen or antibody but only
to antigen–antibody complex.
5. The importance of the complement lies in the fact that it contributes to
both the acquired and innate immunity of an individual.
There are four main effects of complement:
1. It causes lysis of cells (such as bacteria, viruses, allografts, and tumor cells).
2. It generates mediators that participate in triggering specific cell functions,
inflammation, and secretion of immunoregulatory molecules.
3. It facilitates opsonization, the process by which bacteria are more readily
and more efficiently engulfed by phagocytes.
4. It causes immune clearance, in which immune complexes from the
circulation are removed and are transported to spleen and liver.
Nomenclature of Complement: Complement components are designated by
numerals, viz., C1–9. These components circulate in plasma in the form of
proenzymes that are functionally inactive. Activation involves cleavage by
proteolysis into peptide fragments. The fragments are designated with lowercase
suffixes—for example, C3 is cleaved into two fragments, C3a and C3b.
Complement activation takes place through any of the following three pathways:
1. The classical pathway
2. The alternative pathway
3. The lectin pathway
Classical pathway: It is activated by certain isotypes of antibodies bound to
antigens; the alternative pathway, which is activated on microbial cell surfaces
in the absence of antibody; and the lectin pathway, which is activated by a
plasma lectin that binds to mannose residues on microbes. All of these
pathways activation results in the generation of enzyme complexes that are
able to cleave the complement protein, C3.
The classical pathway uses a plasma protein called C1q to detect antibodies
bound to the surface of a microbe or other structure. Once C1q binds to the Fc
portion of the antibodies, two associated serine proteases, called C1r and C1s,
become active and initiate a proteolytic cascade involving other complement
proteins. The classical pathway is one of the major effector mechanisms of the
humoral arm of adaptive immune responses.
The alternative pathway: is triggered when a complement protein called C3
directly recognizes certain microbial surface structures, such as bacterial LPS.
C3 is also constitutively activated in solution at a low level and binds to cell
surfaces, but it is then inhibited by regulatory molecules present on
mammalian cells. Because microbes lack these regulatory proteins, the
spontaneous activation can be amplified on microbial surfaces. Thus, this
pathway can distinguish normal self from foreign microbes on the basis of the
presence or absence of the regulatory proteins.
The lectin pathway: It is triggered by a plasma protein called mannose-binding
lectin (MBL), which recognizes terminal mannose residues on microbial
glycoproteins and glycolipids. After MBL binds to microbes, two zymogens
called MASP1 (mannose-associated serine protease 1, or mannan-binding
lectin-associated serine protease) and MASP2, with similar functions to C1r
and C1s, associate with MBL and initiate downstream proteolytic steps
identical to the classical pathway.
The central event in complement activation is proteolysis of the complement
protein C3 to generate biologically active products and the subsequent
covalent attachment of a product of C3, called C3b, to microbial cell surfaces or
to antibody bound to antigen.
Complement activation depends on the generation of two proteolytic
complexes: the C3 convertase, which cleaves C3 into two proteolytic fragments
called C3a and C3b; and the C5 convertase, which cleaves C5 into C5a and C5b.