Cytokines are essential agents of the immune system and, along with hormones and neurotransmitters, constitute the molecules essential for communication between cells.

The role of the immune system consists in preserving the integrity of people vis-à-vis their environment, therefore in defending themselves against infectious or parasitic agents, and also against internal disorders such as tumor cells. Permanent fights which must be strictly controlled: indeed, these must not turn against the person himself. The intensity of immune reactions must therefore be adjusted, sufficiently intense but not too intense, and specific, directed exclusively against intruders.

The reactions of the multiple partners involved must also be rigorously coordinated. And thus, the exchanges between the numerous cells of the immune system are carried out either by direct intercellular contacts, or via soluble mediators released by the cells: the cytokines.

Cytokines therefore ensure cellular communication. These low molecular weight glycoproteins are active thanks to the presence, on the surface of the target cell, of specific receptors which will transmit the message. A cytokine can be produced by different cells and, conversely, a cell can synthesize many different cytokines.

These mediators can be produced during cell activation, mainly as a result of:

• an infectious stimulus caused by infectious agents such as bacteria, viruses or parasites, or their components (such as for example DNA or RNA of a virus);
• the presence of self-components released during inflammation;
• or other cytokines.

Cytokines can be synthesized mainly by activated lymphocytes (types of white blood cells that play an important role in the immune system) and by activated macrophages (large cells capable of phagocytosing foreign particles).

Cytokines have a very short half-life of half an hour; half-life is the time taken for a substance to lose half of its physiological activity. In addition, cytokines are capable of inducing sometimes different effects on various targets, which therefore often makes their use in the clinic difficult. There are five subgroups of cytokines, which have been defined primarily by structural identities:

• the group of hematopoietins;
• the group of interferons;
• that of TNF-alpha (or growth factors);
• the IL-1 family (interleukins);
• finally chemokines or chemokines (family of small proteins sharing similar sequences of amino acids).

At rest, immune cells generally do not produce cytokines: they only produce cytokines after being activated, most often by the pathogen. Cytokines can either have an autocrine action, that is to say that they act directly on the cell which secretes them (this is for example the case of IL-2, interleukin 2), or a paracrine effect. , which means that they exert their action locally, or still act at a distance: this is then the endocrine effect, such as it exists between IL-6 and the hepatic cell, or between IL-1 and the hypothalamus. In addition, the production of cytokines and their effect can be modulated, and therefore increased or decreased, by other cytokines. Thus, these mediators sometimes act synergistically, and sometimes antagonistically.

These molecules are therefore part of an extremely complex network of communication between cells. Cytokines exert their biological activity at low concentrations, either by binding to specific high affinity receptors on the surface of cells, or by binding to soluble receptors which will themselves, secondarily, bind to a membrane receptor.

In addition, each of the cytokines can recognize one or more specific receptors, and when they bind to different receptors, they induce different effects. Concretely, these high affinity cellular receptors consist of two subunits, proteins, one of which aims to fix the cytokine, and the other to ensure the transduction of the activation signal towards the interior of the cells. cells. These receptors are located on cells of the immune system. The cytokine environment can, for example, have consequences on cancer cells, in particular. Thus, the T lymphocytes, cells which play a primordial role in the immune response, may, depending on the cytokines present, have a rather anti-tumor effect, or conversely pro-tumor effects.

On the other hand, the production of what are called pro-inflammatory cytokines will allow communication between the different cells of the immune system: these cytokines will then direct the immune response according to the nature of the signal detected. And thus, will be generated either rather an immune response of humoral type, that is to say with the production of antibodies by the B lymphocytes (response known as Th2 and responsible for a secretion of IL-4, IL-5 , IL-6, IL-10), or a cell-type immune response linked to the activation of CD 8 T lymphocytes (so-called Th1 response and characterized by secretions of IL-2, TNF-alpha and INF-gamma ). Indeed, during an immune response, all the means of defense are brought into play, however the organism predominates the most suitable response depending on the type of antigen to be eliminated.

Autoimmune diseases are pathologies that result from a dysfunction of the immune system: this will then attack the normal constituents of the cell (type 1 diabetes, multiple sclerosis or rheumatoid arthritis are examples most common autoimmune diseases). And indeed, autoimmune diseases have been shown to frequently exhibit an abnormal pattern of cytokine secretion. An example: the production of IL-12 in the absence of infection can predispose to the development of an autoimmune disease.

Another possible consequence of an abnormal cytokine secretion is cytokine storm. Inflammatory molecules, the cytokines secreted by immune cells are therefore released by the body during an attack by a pathogen. In principle, they only act locally, however sometimes the immune system “gets carried away” and produces too many cytokines. Spilled throughout the body, they create lesions in the tissues. This immune reaction is inadequate: it is possible that it causes septic shock and may prove to be fatal. It could be at play in the gravity of the pathology linked to SARS-CoV-2, COVID-19 which appeared at the end of 2019 in China and at the origin of the pandemic which is currently raging around the world.

As stated by researchers at Yale University, who took 253 blood samples at several different times over a two-month period from patients with COVID-19, and which they compared to 108 healthy people serving of witnesses, “patients with a severe form of COVID-19 have, for the most part, high levels of most of the cytokines associated with the hyperstimulation of the immune system, called the cytokine storm: the massive release of these inflammatory molecules by immune cells“, The newspaper said Le Monde dated August 4, 2020. Ultimately, it would therefore appear that the interleukin molecules: IL-1 alpha, IL-1 beta, IL-6, IL-10, IL-18 as well as TNF-alpha, a key player in the inflammation, in particular are excreted massively during severe forms of COVID-19.

However, some research also tends to show that the severe or even fatal forms of COVID-19, observed particularly in the elderly, may be more linked to a “deeply suppressed” immune response. It therefore seems that the cytokine shock following an infection with Sars-CoV-2 (the viral agent responsible for COVID-19) mainly affects adults in the prime of life: thus, children, including the immune system is still immature, and older people, whose immunity is weakened, would rather be spared from this type of immune surge.

Finally, the cytokines which seem to have the most deleterious effects, via an exacerbation of inflammation, in the context of SARS-CoV-2 infection are interleukin-6 and GM-CSF. Indeed, this explosion of inflammation would lead, in particular, to arterial hypertension, a decrease in the quantity of oxygen distributed to tissues by the blood, as well as to pulmonary lesions. The resulting acute respiratory distress syndrome can lead to multi-organ failure and death.

In terms of treatment, cytokines can be either therapeutic agents or targets.

There are thus drugs which make it possible, in particular, to counteract the massive explosion of cytokine production as it occurs during a cytokine storm. Among them, the most famous molecules are:

• tocilizumab;
• sarilumab.

These two molecules are monoclonal antibodies which target the IL-6 receptor, as indicated by the French Society of Pharmacology and Therapeutics.

• In addition, a third molecule, called anakinra, acts by blocking the interleukin-1 (IL-1) receptor.

These drugs are used in particular to treat several inflammatory diseases, such as rheumatoid arthritis.

Research is still ongoing to determine which treatments would be useful in the treatment of COVID-19, in particular depending on the immune reaction it induces.

Cytokine storm, an excessive, self-sustaining cytokine production, is also called “cytokine release syndrome” and is characterized by over-stimulation of molecules and cells of the immune system. At the biological level, the diagnosis could be made by evaluating the abnormalities that frequently appear in people with such a syndrome, namely:

• marked lymphopenia (decrease in the number of lymphocytes circulating in the blood);
• an increase in muscle enzymes (creatinine phospho kinase or CPK);
• increased liver enzymes;
• disturbed coagulation parameters;
• a high level of C reactive protein in the blood.

Healthcare professionals need to be vigilant about the diagnosis, as the distinction between sepsis and cytokine release syndrome is sometimes difficult.

“It is not certain that the medical applications of a scientific discovery appear immediately as obvious to the researcher who is the author”, indicated the immunologist Didier Fradelizi in an article devoted to cytokines. And the scientist cites as an example the story of the discovery of Interleukin-2, or IL-2, by laboratory technician Doris Morgan. Thus, this signed the first paper, published in 1976 in the journal Science, “demonstrating that lymphocytes stimulated in vitro secrete a factor capable of causing human or murine T lymphocytes to proliferate continuously in culture”.

A few years later, this factor was baptized Interleukin-2, and the discovery of this molecule was to found a new discipline of biology: the study of cytokines, or soluble messengers which ensure communications between cells, which are also molecules with very promising therapeutic potential. The term cytokine was coined in 1974 by Stanley Cohen, and indeed, more than a new word, it is a new concept that this American biologist proposed at that time. Some people sometimes consider that the first cytokine was identified as early as 1957 with interferon, or even as early as 1948 with pyrogen, a factor emitted during infection to induce fever.

First used as a research tool in cell biology, in particular thanks to its power to grow a cell line, T lymphocytes, Interleukin-2 notably enabled Luc Montanier and Françoise Barré to identify HIV, the virus responsible AIDS, in the ganglion lymphocytes of patients suffering from a then unknown condition which associated immunodeficiency and lymphadenopathy.

Then, little by little, it appeared that these new molecules were not only interesting tools for cultivating cells: they were, too, the physiological mediators of intercellular communications. And soon, the set of cytokines was seen to be a complex interactive network. Then, the first clinical applications were born, first in the context of anti-tumor immunotherapy, then in immunostimulation for vaccination against hepatitis B in immunocompromised chronic renal failure patients. And PSubsequently, multiple fields of application of cytokines developed, both in the field of oncology and hematology, immunology, autoimmune diseases, rheumatology, or even… infectiology. Very often, large pharmaceutical groups have now acquired smaller biotechnology companies which had already made significant progress in terms of research and development on these possible therapeutic applications, current and future, of cytokines.