The Complement system functions in various ways

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In this article, I briefly explain about the various ways of functioning of the complement system.

The complement system

The complement system includes more than fifty serum proteins that assist both innate immunity and adaptive immunity to abolish pathogens, dead cells, and immune complexes from the body. Complement proteins can form complexes with antibodies and damage the membranes of antibody-attached cells. The complement system functions in diverse ways.

Liver hepatocytes synthesize most complement components, though some are produced by blood monocytes, tissue macrophages, fibroblasts, and epithelial cells of gastrointestinal and genitourinary tracts.

The complement components can be classified into seven different functional categories initiator complement components, enzymatic mediators, opsonins (phagocytosis-enhancing components), inflammatory mediators, membrane attack proteins, complement receptor proteins, and regulatory complement components.

Complement activity can be categorized into three main classes:

1) to provide innate defense against infection

2) an interface between innate and adaptive immunity

3) plays an important role in the contraction phase of the immune response

Complement attached pathogens communicate to effector cells through complement receptors

The activities of complement mainly depend upon the binding of complement fragments to host cell surface receptors. Complement receptors can be increased or decreased by the aspects of innate immunity and adaptive immunity.

When the anaphylatoxins of the complement system activate the phagocytic cells, there is an increase of tenfold in the number of complement receptors.

The different types of receptors for complement components are CR1, CD21, CR3, CRIg, G protein-coupled receptors (C5a and C3a receptors), and C1qRp. These receptors act as bridges between the complement components and the cells to which they bind.

The CR1 and CR3 receptors are especially important for inducing phagocytosis. A brief description of the CR1 receptor is given below.

Leukocytes and erythrocytes express the CR1 receptor, which binds with a high affinity with the complement component C3b. Erythrocytes clear immune complexes by binding them through CR1 receptors, and then they are carried to the liver. In the liver, phagocytes pick them up and get them cleared from the body.

Receptor-mediated phagocytosis is induced when CR1 receptors on phagocytes bind complement opsonized microbial cells, which leads to the secretion of IL-1 and prostaglandins (pro-inflammatory molecules).

On B cells, CR1 arbitrates the uptake of C3b-bound antigen, which gets degraded in the B cell lysosomal system, and simultaneously the antigenic peptides are presented to T cells.

Additionally, complement receptors on B cells transport antigens and antigenic fragments into lymph node follicles and follicles of the spleen. From follicles of lymph node and spleen, they are transported to follicular dendritic cells and macrophages for presentation to other B cells.

Functions of complement system

Complement spurs host defense to fight infection

Complement proteins opsonize harmful microbes and form membrane attack complexes (MAC). Thus, bringing an inflammatory response that helps leukocytes to reach the site of infection, and enhances the host’s defense against infection.

Cell death due to membrane attack complex (MAC)

Cell death is induced by the insertion of membrane attack complex (MAC) into cell membranes of target cells. This includes one of the primary functions of the complement system.

In earlier experiments, when erythrocytes were the target cells for MAC insertion, nearly seventeen to nineteen molecules of C9 were involved in making large holes in the cell membrane. Through these pores, small molecules and ions can pass, and these pinched erythrocyte membranes can’t make osmotic integrity. Thus, cell lysis takes place due to a huge influx of water from outer surrounding fluid.

During further research in nucleated eukaryotic cells, it is observed that a few molecules of C9 induce smaller pores in the target cell membrane. This causes cell death due to apoptosis following a calcium influx into the cytoplasm.

Some MAC-targeted cells die due to apoptosis. The statement was supported due to the observation of nuclear fragmentation in those cells, which is a marked characteristic of apoptosis.

The plasma membrane of eukaryotic cells has a number of factors, which make them resistant to face complement attack by inactivating complement proteins.

High concentrations of complement components are required to induce MAC attack on infectious microorganisms, which may lead to autoimmunity. This is because of the high number of cell fragments resulting from the lysis. In autoimmune syndromes, the complement system is targeted for therapeutic purposes.

An eukaryotic cell can recuperate from a MAC attack by shedding MAC-containing membrane vesicles into the extracellular fluid. It can also internalize and degrade the vesicles in intracellular lysosomes. Contrary to this, according to recent work, an insufficient number of MAC complexes on the eukaryotic cell surface can lead to the progression of the cell cycle rather than apoptosis.

Microorganisms show different susceptibility to complement-mediated lysis

Microorganisms differ in their susceptibility to complement-mediated cell lysis. Enveloped viruses, e.g., herpes viruses, orthomyxoviruses, paramyxoviruses, influenza viruses, and retroviruses, show their susceptibility to complement-induced cell lysis. Both antibodies and complement play vital roles in defending viruses and giving protection from reinfection.

Among bacteria, gram-positive bacteria show good resistance to complement lysis because complement proteins can’t penetrate the cell wall. Whereas, in gram-negative bacteria, the membrane attack complex is placed between the inner and outer cell membranes. It breaks both membranes simultaneously.

Neisseria meningitidis, causing the disease meningitis, is a gram-negative bacteria and shows susceptibility to MAC-mediated cell lysis. The people who show susceptibility to the fatal disease meningitis are deficient in some complement components.

Complement promoting opsonization

Opsonization is a process, in which opsonins such as antibodies and complement components coat harmful pathogens that can be recognized by receptors on phagocytic cells, leading to phagocytosis. When complement-coated antigen binds to phagocytic cells, the destruction of antigen takes place by the process of complement receptor-induced phagocytosis.

Both complement and antibody can give protection against viruses by building a thick protein coat around a virus. This protein coat helps to neutralize the viral infection by preventing virus attachment with host cell receptors. Then phagocytosis is promoted by activated macrophages through complement and Fc receptors, followed by intracellular destruction.

Complement promoting inflammation

Complement also promotes inflammation along with opsonization. The smaller fragments of complement factor C3 and C5 cleavage, C3a, and C5a act as anaphylatoxins, thus inducing inflammation.

When produced in a large amount, these fragments produce a shock-like syndrome similar to a systemic allergic reaction, including IgE antibodies. Such type of reaction is known as anaphylactic shock, and these small complement fragments are known as anaphylatoxins.

The structurally similar proteins C3a and C5a bind G-protein coupled receptors (GPCRs) on granulocytes, monocytes, mast cells, macrophages, endothelial cells, and some dendritic cells. This helps in creating a signaling cascade that leads to the secretion of cytokines IL-6 and TNF-α, the soluble proinflammatory mediators.

These cytokines help to increase the vascular permeability that aids in leukocyte migration into the infection site with a collateral rise in the motility of smooth muscle. This helps push the released fluid to the damaged site.

Additionally, the binding of C3a and C5a to the GPCRs spurs phagocytosis of pathogens by the anaphylatoxin-signaled localized degranulation of neutrophils, basophils, and eosinophils (granulocytes). This localized degranulation causes the release of the inflammatory mediators histamines and prostaglandins.

The movement of lymphocytes is accelerated by the inflammatory mediators towards the neighboring lymph nodes, where they undergo activation by the pathogen.

Complement- a functional bridge between innate immunity and adaptive immunity

The complement system acts at the junction of innate and adaptive immunity and provides an integrated host defense against harmful pathogens. It acts as one of the major effector mechanisms of innate immunity. However, the complement functions in host defense extend transcending innate immunity. It also well modulates the adaptive immune system through multiple mechanisms.

Complement and its interaction with antigen-presenting cells

The binding of complement components to antigen-presenting cells not only enhances their phagocytic ability but also modulates the secretion of cytokines. Antigen-presenting cells like dendritic cells and macrophages express many complement receptors.

The complement components like C1q, C3b, MBL, and C4b, when binding to antigens, can engage their receptor with antigen-presenting cells during antigen recognition. Then, through the receptor, it gives a signal and helps in antigen uptake.

When signaling happens through the anaphylatoxin receptor C5aR, it can modulate the antigen-presenting cell to produce cytokines like IL-12.

Complement and humoral immunity

The humoral arm of immunity produces effector and memory B cells. The B cells produce antibodies that help in opsonizing and neutralizing harmful pathogens and keep immunological memory against reinfection.

The components of complements increase the binding affinity between a B cell and a complement-bound antigen. The complement enhances B cell immunity principally through the CD35 (CR1) and CD21(CR2) receptors expressed on B lymphocytes and follicular dendritic cells.

Complement works with T-cell mediated immunity

The T cells mature in the thymus. During the process of maturity, sialic acid residues in their cell surface carbohydrates tend to increase. The immature T cells are coated with negatively charged sialic acid residues, which protect them from binding with natural IgM antibodies and from complement-mediated lysis.

A transcriptional repressor NKAP regulates the density of cell surface sialic acid. In the absence of the repressor, the T cells leave the thymus at the usual rate but are unable to survive till the completion of maturity.

These T cells are not protected from IgM antibodies and complement-mediated lysis. Defective T cells can not bind to soluble inhibitors of complement activation. It is due to a lack of sufficient sialic acid in their cell surface carbohydrates.

The complement takes part in quality control analysis to make sure about the T cell’s maturity, which is ready to leave the thymus. The T cell, when activated through its antigen receptor, secretes the complement factors C3a and C3b.

The T cell survives upon the production of complement factor C3a. The factor C3a, an anaphylatoxin, attaches to the receptors on the T-cell membrane. This attachment induces the T cell to generate proinflammatory cytokines that support a T-helper cell response (TH1). The interaction of the C3b fragments with the cell surface molecule CD46 also helps in the survival of TH1 cells.

The complement factor C5a binds to receptors in antigen-presenting cells and stimulates them to produce the cytokine IL-12. In this way, it facilitates their growth and survival. So, it can be said that the T cell-induced adaptive immune response is positively influenced by signals coming from complement components.

Role of complement in the contraction phase of the immune system

When the adaptive immune response is at its last phase, most of the lymphocytes undergo apoptosis. This phase is also known as the contraction phase of the immune system, where only a few antigen-specific cells are left behind to render an immunological memory.

This stage is also marked by the presence of soluble antigen-antibody complexes in the bloodstream and organs of the immune system. To avoid the onset of autoimmunity, these lymphocytes and immune complexes are disposed of safely to turn down inflammation. Complement components play a vital role in carrying out these processes.

Disposal of apoptotic cells and immune complexes

Apoptotic cells on the outer surface of their plasma membranes express the phospholipid phosphatidylserine, which is restricted to the cytoplasmic side of the plasma membrane in healthy cells. In apoptotic cells, this exposed phosphatidylserine is bound by the serum protein annexin A5, which is caught by the complement factor C1q.

The complement component C1q recognizes the presence of cell surface DNA and proteins on the extracellular membranes of apoptotic cells. Thus, it induces apoptosis through C1q receptors. If the complement component C1q is absent, apoptotic bodies are released from the dying cells. These can act as antigens and start autoimmune responses.

Antigen-antibody complexes are coated with C3b, which facilitates their binding with CR1 receptors on erythrocytes. There are about a thousand erythrocytes per every white blood cell. Though the erythrocytes, express low levels of CR1 receptors, still, they account for nearly 90% of the CR1 receptors in blood.

Erythrocytes play a vital role in clearing C3b opsonized immune complexes from the circulation by sending them to the liver and spleen. In the liver and spleen, immune complexes are confiscated from the RBCs and phagocytosed.

Conclusion

The complement activity has three major classes. It induces innate defense against infection and acts as an interface between innate and adaptive immunity. It also plays a vital role in the contraction phase of the immune system.

The complement system functions in various ways. Cell death is one of the primary functions of the complement system. It is induced by the insertion of membrane attack complex (MAC) into cell membranes of target cells. It also enhances host defense against infection. Complement promotes opsonization and inflammation.

The components of the complement bind to the antigen-presenting cells. This binding not only enhances their phagocytic ability but also modulates the secretion of cytokines. These components increase the binding affinity between a B cell and a complement-bound antigen.

The complement component C1q induces apoptosis through its receptors. In the absence of the complement component C1q, apoptotic bodies are released from the dying cells. These can act as antigens and start autoimmune responses.

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