COMPLEMENT SYSTEM: CLASSICAL AND ALTERNATIVE PATHWAY, FUNCTIONS, DISEASES - BIOLOGY - 2025

The complement system is a group made up of more than thirty plasma proteins susceptible to heat, which increase the destructive effect of pathogenic microorganisms.

It is called "complement" since it has been shown to complement the action of antibodies in the destruction of pathogens. However, it is also capable of carrying out its functions in the absence of antibodies. Therefore, it can be considered as part of the components of the innate immune system.

Summary of the complement cascade activation pathway. By Perhelion, from Wikimedia Commons.

Its action depends on the serial activation (“cascade”) of the proteins that comprise it, in order to guarantee the rupture of pathogens through the formation of pores in their membrane, the labeling (opsonization) for their destruction by phagocytic cells and the virus neutralization.

The immune system: adaptive immunity and innate immunity

The immune system is the body's defense system to defend itself from the attack of microorganisms capable of causing disease.

It is made up of a set of cells, organs and cytokine proteins that remain alert to the arrival of pathogens. Once they detect them, they carry out the attack against them in order to guarantee their elimination. His methodology would be just like the soldiers of a barracks would do it, who come to the defense whenever situations of attack or emergency arise.

As in any defense system, the attack they carry out requires tactics, abilities, skills and cooperation of its components. All of this is enmeshed in a series of strategic steps that are collectively known as the immune response.

The immune response occurs in two large, time-separated phases: the innate immune response and the adaptive immune response.

Innate immune response

The innate immune response is the first line of defense against an infection caused by the arrival of a foreign organism.

This type of initial response implies, on the one hand, the action of containment lines (the skin and mucous membranes) that act as barriers preventing the entry of pathogens. On the other, the action of cells that remain vigilant in the innermost layers of the skin before the entry of pathogens. These microorganisms can 'creep in' as a result of a failure in the first barriers, such as a hole or cut that exists in them.

The cells that act at this level are known as phagocytes, which are responsible for recognizing invading microorganisms, phagocytizing (devouring) them and finally destroying them in their cytoplasm.

Apart from this, these cells are in charge of sending signals to the cells that participate in the second response branch in order to efficiently eliminate any pathogen that manages to overcome the first response line.

Finally, the cellular and non-cellular components that participate in this type of response are present from the birth of the organism. That is, they do not depend on the presence of antigens (foreign pathogens or toxic substances).

Adaptive immune response

This type of response, which occurs after the effector mechanisms of innate immunity have been triggered, are carried out by other cells known as lymphocytes.

Lymphocytes reinforce the defense mechanisms of innate immunity, at the same time that they make the system remember invading organisms, just in case they return.

That is, in the event of a second invasion by a foreign organism, the latter quickly recognize it, facilitating its prompt elimination. These responses are usually faster than the former precisely because of their characteristic immune memory.

Finally, it should be mentioned that adaptive immunity develops throughout the life of an organism. As it is facing different infectious agents. That is, it is acquired.

When these cells detect an organism a second time, they trigger a cell attack line and a humoral line. The second involves the release of antibodies, proteins that neutralize toxins and mark pathogens for elimination.

Antibodies, in turn, can activate a group of proteins that make up the complement system. The latter helps to quickly destroy germs and already infected cells.

Complement system

The complement system is a set of plasma proteins that are activated by the presence of pathogenic organisms.

Although this activation depends in many cases on antibodies (components of adaptive responses), it can also be activated in the absence of them. For this reason, it is considered an important component of innate responses.

There are more than 30 proteins that make up this system. They interact with each other to complement the action of antibodies and phagocytic cells in the elimination of pathogens.

These proteins have been identified with the letter "C" for complement, and are formed by combining 9 proteins (C1 to C9). All of them are proteases and are kept circulating vigilantly and inactive through the body.

Once the presence of a foreign microorganism is detected, they are activated by the action of other proteases, so that they go on the attack in defense of the organism.

Now, this activation can be carried out through three different routes: the classical route, the alternative and the lectin route. Although these differ in how activation occurs, they all coincide in the formation of an attack complex on the pathogen's membrane (MAC).

This complex is formed by the association of many proteins on the outer face of the pathogen's membrane that culminates in the formation of pores or holes in it.

How does the activation of the complement system occur?

Activation occurs at the sites where infection occurs and is caused by the presence of invading microorganisms.

During it, all initially inactive complement proteins are activated in a chain reaction. That is, once one has been activated, the latter activates the next and so on.

Active proteases are generated by cleavage of the precursor protein or zymogen (inactive form). The latter cuts the next one in two by activating it.

Thus, the activation of a small group of proteins at the beginning of the cascade causes a huge increase in the activation of successive zymogens (amplification).

This amplification helps the pathogen's membrane attack complex to form rapidly. This promotes the opening of pores that will eventually break down parasites, bacteria and other organisms capable of causing infection.

The complement can be activated in three independent ways

Although the ultimate goal with complement activation is always the formation of the pathogen membrane attack complex, there are three ways in which this can be accomplished. The beginning of each of them depends on the action of different molecules.

However, they all converge on the activation of C3 convertase, a protein that cleaves the C3 protein into C3a and C3b. The latter binds to the pathogen's membrane and fractures C5 into C5a and C5b. C5b also binds to the membrane and recruits the rest of the proteins that will assemble to give rise to the pore (C6, C7, C8 and C9).

Classic way

It receives this name for being the first way to be described. It constitutes a point of connection between the mechanisms of innate and adaptive responses as it is activated by antibody complexes that have previously bound to the surface of the pathogen.

This begins with the binding of C1q (the first protein of the complement cascade) to the membrane of the invading microorganism. This union can take place in three different ways:

- Directly with protein and non-protein components on the surface of bacteria, such as lipoteichoic acid present in gram-positive bacteria.

- C-reactive protein, a plasma protein that binds to phosphocholine residues present in bacterial surface polysaccharides.

- To immune complexes, made up of two or more antibodies of the IgG or IgM isotypes that have previously bound to the pathogen.

Lectin pathway

Activation by this pathway depends on the recognition of specific carbohydrates exposed on the surface of the pathogen by proteins called lectins.

Lectins are proteins that only interact with carbohydrates. Some examples of these are: the MLB protein that specifically binds to polysaccharides that contain the sugar mannose present on the surface of viruses and bacteria, and those that recognize only N-acetylglucosamine residues present in the bacterial wall.

Alternative route

This pathway is activated directly by the binding of the C3 protein (which generates C3b) already active on the surface of the pathogen.

It is important to know that in the absence of infections C3b occurs through this route in very low values. These limited amounts of C3b are kept inactive by the action of a protein known as factor H.

Only when there is infection and C3 binds to the pathogen, the regulatory effect of factor H is evaded and this binds to a second factor known as factor B. The latter is cleaved by the action of factor D and the products bind to C3 already present in the membrane forming the C3 convertase.

From here, the activation steps common to the three pathways are followed.

Features

It allows the rapid destruction of pathogenic cells through the formation of pores that rapidly destroy their membrane.

By binding activated complement proteins, it marks pathogens to be recognized and ingested by phagocytic cells for destruction. This process is known as opsonization.

The small fragments that are produced from the breakdown of zymogens act as chemoattractants that recruit more phagocytes to the site of infection.

It allows to neutralize invading viruses. That is, it inactivates them so that they are later phagocytosed and eliminated.

Related diseases

Foot x-ray with rheumatoid arthritis, a disease caused by deficiencies in the complement system. By Lariob, from Wikimedia Commons.

Deficiencies in the synthesis of complement proteins as well as factors that produce an unregulated activation of these proteins can lead to numerous diseases.

The deficiencies are generally caused by genetic errors that lead to erroneous activation events. This results in failure in an increased susceptibility to infections, rheumatic diseases and angioedema (edema of the skin and mucosa).

The absence of regulation, such as the absence of Factor H, can cause an excess of activation. This ends in uncontrolled inflammation, produced by the lysis of own cells.

References

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