Complement system

The complement system helps or “complements”, the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime. However, it can be recruited and brought into action by the adaptive immune system.

The complement system consists of a number of small proteins found in the blood, generally synthesized by the liver, and normally circulating as inactive precursors (pro-proteins). 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 activation cascade is massive amplification of the response and activation of the cell-killing membrane attack complex. Over 25 proteins and protein fragments make up the complement system, including serum proteins, serosal proteins, and cell membrane receptors. They account for about 5% of the globulin fraction of blood serum.

Three biochemical pathways activate the complement system: the classical complement pathway, the alternative complement pathway, and the mannose-binding lectin pathway.

History

In the late 19th century, Hans Ernst August Buchner found that blood serum contained a "factor" or "principle" capable of killing bacteria. In 1896, Jules Bordet, a young Belgian scientist in Paris at the Pasteur Institute, demonstrated that this principle had two components: one that maintained this effect after being heated, and one that lost this effect after being heated. The heat-stable component was responsible for the immunity against specific microorganisms, whereas the heat-sensitive (heat-labile) component was responsible for the non-specific antimicrobial activity conferred by all normal serum. This heat-labile component is what we now call "complement."

The term "complement" was introduced by Paul Ehrlich in the late 1890s, 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. Upon immunization with an antigen, more of these receptors are formed, and they are then shed from the cells to circulate in the blood. These receptors, which we now call "antibodies," were called by Ehrlich "amboceptors" to emphasize their bifunctional binding capacity: They recognize and bind to a specific antigen, but they also recognize 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. In the early half of the 1930s, a team led by the renowned Irish researcher, Jackie Stanley, stumbled upon the all-important opsonization-mediated effect of C3b. Building off Ehrlich's work, Stanley's team proved the role of complement in both the innate as well as the cell-mediated immune response.

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 of the Complement

causing cell lysis.]] The following are the basic functions of the complement
# Opsonization - enhancing phagocytosis of antigens # Chemotaxis - attracting macrophages and neutrophils # Lysis - rupturing membranes of foreign cells # Clumping of antigen-bearing agents # Altering the molecular structure of viruses

Overview

The proteins and glycoproteins that constitute the complement system are synthesized by the liver hepatocytes. But significant amounts are also produced by tissue macrophages, blood monocytes, and epithelial cells of the genitourinal tract 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 and mannose-binding lectin pathways can be activated by C3 hydrolysis or antigens without the presence of antibodies (non-specific immune response). In all three pathways, a C3-convertase cleaves and activates component C3, creating C3a and C3b, and causing a cascade of further cleavage and activation events. C3b binds to the surface of pathogens, leading to greater internalization by phagocytic cells by opsonization. C5a is an important chemotactic protein, helping recruit inflammatory cells. Both C3a and C5a have anaphylatoxin activity, directly triggering degranulation of mast cells as well as increasing vascular permeability and smooth muscle contraction. C5b initiates the membrane attack pathway, which results in the membrane attack complex (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 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

{|style="width:25%;float:left" class="wikitable" |+ |- !!! C2 fragment nomenclature |- ! |Different assignment for the fragments C2a and C2b, as to which is larger or smaller, is found below in several current text books in immunology; however, we might safely make assignment that the former is smaller. In a literature below, in the publishing year of as early as 1994, they commented that the larger fragment of C2 should be designated C2b. In the 4th edition of their book, they 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 MBLectin pathways the C3 converatase enzyme is formed from membrane-bound C4b with C2b" (p. 341).

This nomenclature is used in another literature:

"(Note that, in older texts, the smaller fragment is often called C2b, and the larger one is called C2a for historical reason.)" (p. 332).

The assignment is mixed in the latter literature, though. |- ! | Literature can be found where the larger and smaller fragments are assigned to be C2a and C2b, respectively, and literature can be found where the opposite assignment is made. However, due to the widely established convention, C2a here is the larger fragment, which, in the classical pathway, forms C4b2a. It may be noteworthy that, in a series of editions of Janeway's book, 1st to 7th, in the latest edition 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 and other neurodegenerative conditions such as spinal cord injuries.

Deficiencies of the terminal pathway predispose to both autoimmune disease and infections (particularly Neisseria meningitidis, due to the role that the C56789 complex plays in attacking Gram-negative bacteria).

Mutations in the complement regulators factor H and membrane cofactor protein have been associated with atypical haemolytic uraemic syndrome. Moreover, a common single nucleotide polymorphism in factor H (Y402H) has been associated with the common eye disease age-related macular degeneration. 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, an autoimmune condition resulting from reduced regulation of the complement pathway.

Mutations in the MAC components of complement, especially C8, are often implicated in recurrent Neisserial infection.

Modulation by infections

Recent research has suggested that the complement system is manipulated during HIV/AIDS to further damage the body.

References

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