Immunology

Immunology is a branch of biology that deals with the immune system, studying aspects of the host’s defenses against infection and the adverse consequences of immune responses. Thus, immunology deals with the physiological functions of the immune system (and its components) both during an illness and in a healthy condition, as well as malfunctions of the immune system itself (autoimmune diseases, hypersensitivity, and transplantation).

Immunology therefore has close ties with many other biological and medical disciplines. It can be divided into:

  • immunobiology, which studies the biological factors and properties related to the functions of the immune system in its various functional articulations;
  • immunochemistry, which applies the principles of chemical reaction to the study of immune phenomena, with particular regard to the structure of antigens and the antibody molecule (immunocytochemistry is the laboratory technique that uses the principles of immunochemistry in the study of cellular functions and properties);
  • immunohistochemistry, which studies tissue antigens using antibodies or antigen-antibody systems conjugated with fluorescent compounds, enzymes, radioactive isotopes, ferritin, etc.

Immunology is a rather recent science, and its birth coincides with Edward Jenner, who discovered, in 1796, that the pathogen causing cowpox could protect against human smallpox, an often fatal disease, and inoculated that pathogen taken from the pustules of cowpox patients directly into healthy individuals, thus protecting them from the infection of the more serious human smallpox.

Immunity is the state of specific resistance, congenital or induced, of an organism to infectious diseases or toxic substances, by the formation of humoral antibodies or the development of cellular immunity. The life of every organism is threatened by other organisms, and evolution has selected a range of defenses to deal with these threats; in particular, Vertebrates have developed an elaborate set of procedures against microorganisms that constitute the immune system. This defensive process allows organisms not to fall back into the same infection, as it is capable of recognizing an enemy, destroying it and remembering it to eliminate it in a second attack.

The basic steps of this process are based on the recognition of the enemy and the very precise discrimination between the invader and the structures that are part of the organism. If this distinction is not precise, the immune system can attack its own organism and generate those diseases defined as auto-immune. The first activity is the recognition of precise targets and the second is the destructive response that allows the system to eliminate the enemy. The recognition is carried out by lymphocytes, while the destruction is carried out both by lymphocytes and other cells such as macrophages and neutrophil cells. A very important and little known aspect is the role that the immune system plays in controlling the growth of cells in the body that for some reason become cancerous, in fact in immunocompromised individuals is higher the probability of developing different forms of cancer.

Specialized branches

Immunodermatology is the specialized branch of dermatology that uses diagnostic methods based on the principles of immunology to study and describe skin diseases. Its practical implications are considerable and concern different pathological forms such as pemphigus or autoimmune syndromes with cutaneous extrinsicity.

Immunohaematology is the branch of medicine that deals with the study of haematological problems using immunological techniques and guidelines. It has had a flourishing development, especially as a consequence of the improved possibilities to demonstrate the presence of incomplete antibodies. The knowledge in the field of post-transfusion isoimmunization phenomena and maternal-fetal Rh factor incompatibility (isoimmunization) has been increased and, above all, those concerning the morbid forms sustained by the appearance of autoantibodies, that is of specific incomplete antibodies elaborated by the organism against its own blood cells (immunohaemopathies, immunoerythropathies, immunopancitopenias, immunoplasmopathies).

Immunoparasitology applies immunological principles to the study of phenomena involved in the interaction between parasite and host organism.

Immunopathology is the medical discipline that studies morbid conditions related to alterations or abnormal reactions of the immune system.

Veterinary immunology is a branch of immunology dedicated to improving animal health. Like humans, animals also suffer from diseases caused either when organisms try to invade their body, or when their immune system does not function properly. Wild, domestic, and farm animals are commonly exposed to a whole range of dangerous bacteria, viruses and parasites, which threaten their welfare. Animal infections can have widespread effects on human working sectors, like food and agriculture. Moreover, many animal infections can be naturally transmitted across the species barrier to infect humans and vice-versa, a process termed zoonosis. For example, well-studied infections including swine and avian influenza, as well as, malaria and Lyme disease are due to transmission from animals and insects to humans. It is therefore extremely important that these types of diseases are effectively controlled. These measures not only prevent any further transmission to other animals and humans, but also reduce any potentially devastating social and economic consequences.

Immunology applications

Immunology has various applications in different fields of science and is usually divided into:

  • Classical immunology: this branch of immunology is closely related to epidemiology and medicine and deals with the relationship between the body, pathogens and immunity. The earliest example of a description of this phenomenon was given by Thucydides during a plague epidemic in ancient Athens in 430 BC, where he noted how people who had already been infected (and survived) once did not get sick again despite being in close contact with other plague victims. The basis of classical immunology (and all immunology) is the study of the interaction between antigen and antibody and the various components of the immune system, including their functions and the interactions they establish.
  • Clinical immunology: deals with the study of diseases of the immune system or caused by a functional alteration of the immune system. Among the diseases that affect the immune system there are those caused by certain lentiviruses (slow viruses) such as HTLV and the best known HIV. The latter virus, through complex mechanisms of receptor interaction, is able to infect cells, in particular T lymphocytes and their subpopulations and macrophages, which have on their surface a protein called CD4. The progressive alteration of these cells, fundamental for the defense against infections, leads to AIDS, acronym that stands for Acquired Immunodeficiency Syndrome, in which the infected individual is no longer able to defend himself against infections. With regard to diseases caused by alterations of the immune system, we should remember: primitive immunodeficiencies, i.e. induced by genetic defects, in which a part of the immune system is unable to generate an adequate response to the attack of a pathogenic agent, and autoimmune diseases, where the immune system attacks components of its own organism no longer recognizing them as part of itself (eg rheumatoid arthritis). Other diseases of the immune system include hypersensitivities, where the system responds inappropriately to harmless compounds (e.g., asthma, allergies). This branch of immunology also deals with rejection following transplantation, where the immune system recognizes as foreign and attacks organs or other components that are transplanted from another living being, either from another of the same species (allografts) or from different species (xenografts). The goal of these studies is to find a way to prevent such rejection, currently based on anti-rejection drugs, which weaken the immune system.
  • Immunotherapy: refers to the use of components of the immune system to treat a disease or disorder, for example in the treatment of cancer along with chemotherapy and radiation therapy. Immunotherapy is also used in patients who are immunosuppressed (e.g., AIDS patients) or suffering from other immunodeficiencies or autoimmune diseases.
  • Diagnostic Immunology: the discoveries made in immunology (especially that of the specificity of the binding between an antibody and its antigen) have served to invent various diagnostic techniques for the detection of various molecules (as long as they are immunogenic) for both research and actual diagnosis. Antibodies specific for a given molecule, are used as “tracers”, ie antibodies made detectable and / or measurable, through a radioactive marking (usually Iodine-131) or with a fluorescent compound or an enzyme (usually HRP) can if placed in contact with appropriate substrate, to develop a coloration in a manner proportional to the amount of tracer bound to the molecule to detect / measure. Among the various applications are the immunoblot, the ELISA test as well as tests for the detection of drugs, microbes or to distinguish the various blood groups. These tests are carried out in analytical laboratories. Serological reactions belong to these techniques.
  • Evolutionary immunology: the study of the immune system in living and extinct species can help to understand the evolution of species and the development of their immune system, which started from a simple phagocytic protection of the cell, and evolved to be able to protect multicellular organisms, such as antimicrobial compounds in insects to lymphatic organs in vertebrates.

Humoral, cellular and specific immunity

There are three types of immunity: humoral immunity, cellular immunity and specific immunity, the one carried out by proteins that have a stimulus function, called lymphokines.

Humoral immunity is made up of molecules in solution, these are called immunoglobulins or antibodies and constitute 20% of blood proteins; part of humoral immune defense is also the complement that is represented by a series of proteins that help antibodies to kill bacteria and acts in a non-specific way.

Cellular immunity is represented by that carried out by whole cells, such as phagocytes that are able to ingest and destroy foreign material; neutrophils and macrophages are part of this family. One of the fundamental roles of antibodies is to help phagocytes to recognize foreign substances; there is also a type of cell that has on its surface proteins that have the same characteristics of antibodies and, moreover, another type of cell that secretes lymphokines that help to heal from infection. The first immune response of the body is for a short time non-specific, phagocytes are activated when they encounter a bacterium and cells that are infected by a virus produce molecules called interferons, which interact with receptors exposed by other cells and make them less vulnerable to viral infection.

Specific immunity, on the other hand, is carried out by lymphocytes, which are activated both by direct contact with the pathogenic substance and indirectly by proteins or fragments of them that are digested and presented on the surface by macrophages. This event causes these responses to be recognized as foreign and the lymphocyte begins the production of antibodies. The antibody recognizes a part of the foreign structure called an epitope, and each protein has the potential to have many epitopes that can be recognized by antibodies. The main characteristic of antibodies is their specificity, in fact our organism is able to produce a very high number of different antibodies able to recognize as many different structures.

Each antibody molecule consists of two classes of protein chains called light and heavy, and each antibody consists of two identical pairs of the heavy chain and two pairs of the light chain. In this four-chain structure, the two equal ends, which represent the N-terminal part of the protein, contain specificity for the antigen and, therefore, each antibody can bind to two antigen molecules at a time and this binding is highly specific.

There are various types of antibodies that have been classified as IgM, IgD, IgG, IgE and IgA: their difference lies in the heavy chain. Antibodies are produced by B lymphocytes, which originate in the bone marrow; the letter B represents the initial of an organ called Fabrizio’s bursa, which is the place where these cells are produced in birds where they were studied for the first time.

The immune system has an extraordinary versatility: in fact, it can produce antibodies against almost any substance that is new to the cell; this characteristic has raised enormous questions about the limits and potentialities of this system and about the mechanisms of production of these different structures. For years immunologists have debated the genetic mechanisms that contributed to such great diversity, but the selective theory, which holds that the antigens themselves select the appropriate antibody from a pre-existing set of antibodies, is probably the most correct.

Antibody selection

It was Niels Kaj Jerne to formulate the theory of antibody selection, known as the theory of clonal selection, which assumes that there is a continuous production of lymphocytes, which present on their surface immunoglobulin molecules, that the molecules on the surface of a single B cell have the same specificity and that for each antigenic determinant there is only a small part of the set of B cells able to bind to the antigen. When an antigen is circulating in the body binds only to those B cells that have the appropriate specificity and this induces the B cell that has interacted, to produce daughter cells that synthesize and secrete this specific antibody, the antigen then selected from a pre-existing group of cells, those that have the appropriate specificity and these cells are now clones derived from the original cell.

The theory of clonal selection resembles the Darwinian theory of natural selection in that the antigen selects cells that will multiply from a diverse group of cells that originated independently of the selective pressure, somewhat like random mutation causes the genetic variability necessary for adaptation. In an initial, defined antigen-independent phase, the bone marrow produces large numbers of B lymphocytes, each with an ability to bind to a different antigen. When a B cell encounters an antigen that binds to the exposed antibody, the phase called “antigen-dependent” begins on its surface where this cell is activated to grow, divide, produce and secrete that particular antibody.

So there must be a mechanism responsible for the production of antibody diversity and to produce, in the absence of selection, a huge number of variable regions of the antibodies and this variability is originated by a recombination at the DNA level of the genes coding for immunoglobulins. This mechanism is able to produce an enormous number of different antibodies from a limited number of genes. A human being has about 100,000 genes but the 10 trillion B lymphocytes of an individual can produce 100 million different antibodies.

The information for this enormous production must also be maintained throughout the life of the individual and then the DNA of each lymphocyte once recombined to produce that particular antibody will remain stable throughout the life of the cell. This discovery made by Susumu Tonegawa showed that the genes for immunoglobulins are present in our chromosomes as detached and scattered segments in different regions of the genome and rearrange to form a particular antibody during lymphocyte development.

The recombination of these DNA fragments creates the diversity of antibodies: in fact, as we said, the antibody is formed by two heavy chains and two light chains joined together to form a Y structure, where the light chains are located next to the heavy ones on the two upper branches and each lymphocyte produces only one type of heavy chain and one type of light chain, thus creating an antibody different from the others.

If considering a thousand different chains the recombination and combination of these can produce millions of different antibodies, so it is possible to imagine an almost infinite potential for the production of antibodies. It has been said that B lymphocytes have on their surface the specific antibody and they are activated by the contact with the antigen to produce this immunoglobulin, but there are in our immune system lymphocytes called T lymphocytes (they are produced by the thymus gland) that have on their surface molecules able to bind to the antigen, but they participate in the immune defense with a different mechanism from the production of antibodies.

There are two types of T lymphocytes: those defined as cytotoxic or killer T cells, which are responsible for the control of cell growth in many tissues and participate in the process of apoptosis, and helper lymphocytes or helper T cells, which recognize antigens present in the body and produce protein factors (lymphokines) that stimulate B lymphocytes to produce antibodies. T cells present on their surface a recognition molecule that is able to discriminate as precise as those of the antibody called T cell receptor, which exists only on the surface of these cells and all T cell activities are related to the presence of this molecule. T cell receptor diversity is similar to that of antibodies and is also encoded by different genes that recombine to form very large numbers of different receptors.

Their specificity is very high and also, very importantly, this molecule is able to recognize antigens that come from its own body. The antigen is presented to the T receptor in the form of very short protein molecules (peptides) on the surface of a cell in a complex with a very important cellular protein called MHC (major histocompatibility complex). This molecule is very important for the recognition by each organism of what are the characteristics that define its immune identity; its importance was first discovered in transplantation experiments in which the characteristics of tolerance between different individuals is due to the similarity of this protein complex.

References

  1. J. Daguet, Eléments d’immunologie médicale, Paris, 1967
  2. M. Landy, W. Braun, Immunological Tolerance, New York, 1969
  3. B. Amos, Progress in Immunology, New York, 1972;