divulgatum está dedicado a la difusión de conocimiento científico en español e inglés, mediante artículos que tratan en detalle toda clase de temas fascinantes pero poco conocidos.
divulgatum is devoted to the dissemination of scientific knowledge in Spanish and English, through articles that go into the details of all sorts of fascinating, if not
widely known, subjects.

Monday, March 14, 2016

The invisible army

An extremely sophisticated defensive system protects us against the continuous threat from a flood of microscopic invaders.

A macrophage employs its appendages, called pseudopods, to capture infectious Escherichia coli bacteria before ‘digesting’ them. (Credit: Boehringer Ingelheim International/National Geographic.)

FOR MANY millennia, disease, despite its constant and painful presence, was poorly understood by humanity. A relationship has always been evident between particular environmental factors — quality of food, temperature, even certain habits — and the development of an acute physical malaise, which in the worst cases puts the affected person at serious risk of death. However, only in the last few hundreds of years have the origin, development, symptoms, transmission routes and other particulars of almost every disease known to man, been discovered and charted. Today, we know that many of these maladies are the work of invisible microorganisms that invade our body and reproduce at our expense. The human body’s response to these infectious agents, known as pathogens, relies on a vast and tightly interconnected repertoire of cells and molecules specialised in searching, finding and eradicating these threats as effectively as possible. This invisible yet implacable microscopic army, whose branches, hierarchies and offensive techniques are the product of millions of years of evolution, is what we know as the immune system.

The human body is adapted to the great majority of external microorganisms. We constantly interact with potentially harmful microbes — as well as with many which are inoffensive — but only on very rare occasions do we become ill as a result. This is due to the perfectly orchestrated action of three defensive barriers. In the first instance, almost any pathogen must trespass numerous physical and physiological barriers, such as mucus, gastric acids, antibacterial substances and even skin itself; few organisms are able to thrive in such a desolate environment as the human body’s exterior. Whilst our physiological frontiers have evolved to hinder microbes from adhering to or crossing them, some pathogens, in turn, have specialised in trespassing this first defensive level and penetrating our body. Nevertheless, once inside, the intruders must face the furious blow of the two remaining defence levels: the innate and adaptive immune responses.

The innate immune system, so called for being present almost from birth, is responsible for deploying the first of these immune responses. This branch of the immune system is always ready, awaiting an infection. Its main mission consists of detecting this as rapidly as possible, mounting a response of a general nature, and triggering the activation of its counterpart, the adaptive immune system — so named for developing progressively as we suffer different infections throughout our life. The main features of innate immunity are a low specificity — the response does not depend on the particular pathogen it targets — an extraordinarily quick response, and the lack of immunologic memory — that is, the innate response is always the same, no matter how many times the intruder in question has been encountered in the past.

Almost immediately after penetrating the human body, most microbes are detected through certain molecules anchored to or secreted from their surface. These molecules are recognised as belonging to some kind of pathogen, thus triggering the innate immune response. The infected cells also shed chemical danger signals that alert neighbouring cells and the immune system, acting as a siren. Among the first immune cells to reach the infection site are neutrophils, which are alerted while they circulate through the surrounding blood vessels. Once activated by this ‘chemical siren’, neutrophils cross the blood vessel wall and, like bloodhounds, follow the trail of signalling particles until they gather at the infection point, where they encounter the responsible pathogen. Meanwhile, other components of the immune system, which are not cells, but molecules present in the blood, have adhered to the intruders’ surface, thereby allowing them to be phagocytosed (literally, gobbled) by neutrophils. Phagocytosed microorganisms are destroyed by means of toxic molecules present inside these cells.

Many other immune cell types rush to the infection site, among them macrophages, also in charge of phagocytosing and digesting intruders; basophils and mastocytes, responsible for generating the inflammatory response (source of the swelling, heat and redness that we can normally observe around any wound), which allows a more effective immune response; eosinophils, specialised in destroying those parasites too large to be phagocytosed; and natural killer cells (or NK cells), expert killers of infected or cancerous cells, which they inject with highly toxic substances that trigger a process of cellular ‘self-destruction’. Besides all these cells, a huge number of chemicals enable, potentiate and synchronise the immune response. Cytokines are proteins secreted by various immune cell types, whose purpose is to orchestrate and regulate the immune response, acting as communicators between the different cells involved in the fight. An example is interferon, used by virus-infected cells to make surrounding cells deploy viral defences. The sophisticated membrane attack complex, for its part, is composed of multiple proteins that self-assemble in an outstandingly specific manner, and contributes to the destruction of certain bacteria and parasites through the formation of pores in their surface, leading to its rupture, and thereby to instant death.

Another kind of cell, different to the ones already mentioned, plays a key role in the immune response: dendritic cells, on which falls the crucial mission of acting as intermediaries between the innate and adaptive immune systems. When dendritic cells, which patrol the body examining the molecules present on the surface of surrounding cells, detect a molecular pattern that is characteristic of a pathogen — such as a bacterium or a virus — they immediately awake. Taking with them the tell-tale molecule, called antigen, they travel to the nearest lymph node, where they present the antigen to cells belonging to the adaptive immune system: T lymphocytes, also known as T cells. Antigen presentation constitutes the link between the innate and adaptive immune responses, and it is essential for complete and successful eradication of the infectious agent; without the help of the adaptive response, the innate immune system is generally only capable of keeping the infection under control, not of putting an end to it.

An ongoing battle: a group of lymphocytes (centre, stained purple) fights against cancer cells. (Credit: Transmissible Cancer Group.)

The cells of the adaptive immune system, B and T lymphocytes (or simply B cells and T cells), are characterised by a high specificity — that is, each antigen is recognised by a specific group of lymphocytes, specialised in combating it — and immunologic memory, thanks to which, upon future encounters with the same pathogen, the lymphocytes qualified to fight it will be immediately deployed to neutralise the infection with much greater efficiency. B lymphocytes, which are capable of recognising an antigen directly — with no need for it to be ‘presented’ to them by other cells — have the important function of producing antibodies, also called immunoglobulins. Following activation, B cells rapidly multiply and flood the infected area with antibodies; these adhere to the pathogens’ surface, flagging them for destruction by the many other cells immersed in the battle. By coating the pathogens, antibodies also contribute to preventing them from entering and infecting new cells.

T cells, for their part, mainly divide into three types: helper T cells do not attack infectious organisms directly, but play different support roles aimed at maximising the immune response — for instance, partaking in the activation of B cells, or secreting cytokines that modulate the activity of other cells; cytotoxic T cells, in contrast, are involved in the destruction of infected or cancerous cells, by using proteins destined to cause the rupture or self-destruction of such cells; lastly, regulatory T cells are in charge of limiting and suppressing the immune response, to ensure that it remains under control and does not become excessively harmful for the body itself.

In order to develop affinity for a specific antigen (even for antigens to which the body has not been, and perhaps will never be, exposed), lymphocytes must go through a process of pure Darwinian selection. During said ‘training’, those cells incapable of recognizing a given antigen with great precision — or even worse, prone to attacking the body — are chemically killed, so only the cells that are perfectly adapted to the role that they are to perform are selected and allowed to multiply. In the case of T lymphocytes, approximately one in thirty cells survives this ruthless selection process. Each of these elite guardians recognises a different and unique antigen; on the whole, there are receptors for around one quadrillion antigens. In other words, virtually any microorganism that ventures into our body will present a collection of particles that will be recognised by some lymphocyte group.

However, the lymphocytes’ greatest weapon is not their affinity for a particular antigen, but their ability to ‘recall’ this antigen after the first exposure to it. Upon resolution of the infection, most lymphocytes die, and their remains — together with those of all the cells that have succumbed during the attack — are processed by macrophages. Nevertheless, a small number of lymphocytes is preserved with the aim of conserving the ‘memory’ of the antigens associated to the defeated pathogen. This allows the adaptive immune response to be much more rapid and efficient in the event that the same pathogen is encountered again. The phenomenon of immunologic memory is the basis of what is undoubtedly the greatest medical advance in history: vaccination. Vaccines exert their protective action by causing a deliberate exposure to an innocuous (dead or inactive) version of a microorganism, aimed at stimulating an immune response and generating a ‘memory’ of the infectious agent, while sparing the body from the effects of the infection itself. Therefore, should a pathogenic version of the same microorganism be found in the future, the immune system will recognise it instantly, as if it had confronted it before, and an immediate and effective immune response will thwart the establishment of the infection — and, thereby, the development and spread of the disease.

Even with these extensive defensive resources (many of which have not been mentioned here), the immune system reveals itself inadequate against the best adapted, most virulent pathogens, as proved by the many infectious diseases that afflict humanity. The ability of certain microorganisms to evolve with extreme rapidness often puts our immunologic memory in check, rendering it ineffective. The best example is the influenza virus, capable of mutating with such ease that even the combination of previous exposures and vaccination cannot stop it from spreading. On the other hand, a defect in any of the components of the immune system can generate abnormalities in the immune response, which are the cause of disorders as common as hypersensitivity reactions, among which figure allergies and asthma; autoimmune diseases, like rheumatoid arthritis and multiple sclerosis; and immunodeficiencies, whose most notable example is the acquired immunodeficiency syndrome, or AIDS.

To conquer further victories against the pathogens that keep sowing mankind with disease, as well as against the conditions caused by a defective immune system, our hope resides in achieving as deep an understanding as possible, capable of providing medicine with new methods to potentiate, modify and dominate this incredibly powerful weapon that evolution has granted us.

Special thanks are due to Isobelle Bolton for her invaluable help with translation.

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Delves, P.J., Roitt, I.M. The Immune System. First of Two Parts. The New England Journal of Medicine (2000).
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Kono, H., Rock, K.L. How dying cells alert the immune system to danger. Nature Reviews Immunology (2008).