Immunology

History

" Préhistoire"

Oldest known testimonys of observations of an immunological nature go back to 430 before Jesus-Christ. At this date, during the epidemic which prevails in Athens during the Peloponnesian War, the historian Thucydide foot-note that only the people already having supported and having survived the infection were ready to deal with the patients. In the neighborhoods of 100 before Jesus-Christ, there exists in China practices of voluntary transmission of the Variole for prevention. This technique, called " variolisation" , consists in taking Pus on a patient little reached by the disease to inoculate it with a needle at a healthy subject. This process was spread as from the fifteenth century, especially in China, India and Turkey. Via the wife of the British ambassador with Constantinople, which made vaccinate his/her son in this manner, the Variolisation was made known in England towards 1722, then was propagated in the following years in all the Europe. At the same time, the country doctor Edward Jenner noted that the farm ones in regular contact, at the time of the draft, with the variola of the cow (Vaccine or Cowpox), which is inoffensive for the human ones, were saved by the epidemics of variola, then frequent, or showed only weak Symptômes. After having intensively studied the phenomenon, it took on May 14th, 1796 of the pus on a pustule of an young girl contaminated by vaccinates, and injected it with young a eight year old boy. After the boy cured minor illness induced by vaccinates, Jenner injected true variola to him. The boy also overcame this infection without serious symptoms. Compared to the variolisation, the process of Jenner offered certain major advantages: the people vaccinated by vaccinates did not present the buttons and the typical scars induced by the variolisation; there was no risk of mortality contrary to the variolisation; and the vaccinated people did not represent any risk of Contagion. The Virus of vaccinates is the origin of the names of " vaccin" and " vaccination" , and Edward Jenner is regarded today as the founder of immunology.

Turnings of the nineteenth century

Another major stage in the development of immunology is the design of a vaccine against the Rage by Louis Pasteur in 1885. July 6th, 1885, it vaccinates Joseph Meister, boy a nine year old who had been bitten two days earlier by a mad dog. Joseph Meister became the first human being then to survive the rage in the history of medicine. In one year, the vaccine was managed with 350 contaminated people, and none died of its rabic infection. Two years before, Robert Koch had discovered the person in charge of the Tuberculose, the bacillus which bears its name, and little time after, the test with the Tuberculine, which makes it possible to prove the infection by the tuberculosis, and which is based on the immunizing response. This work was used as a basis for work of Calmette and Guerin, which described the bacillus which bears their name (BCG for bacillus of Calmette and Guerin) and driving to vaccination against tuberculosis. The vaccine making it possible to fight against the infectious illness developed as from this time. Max Theiler received the Nobel Prize of medicine in 1951 for the development of a vaccine against the yellow fever.

In 1888, Red-headed Emile and Alexandre Yersin discovered the diphteric toxin . Two years later, Emil Adolf von Behring and Shibasaburo Kitasato highlight an antitoxin in the Sérum of the patients who had survived the diphteria. Emil von Behring was the first to use these anti-séra for the assumption of responsibility of the diphteric patients. For this work, it accepted in 1901 the Nobel Prize of medicine. The Belgian bacteriologist Jules Bordet discovers in 1898 that to heat the serum above 55°C blocks its capacity to stick to certain chemical substances. The capacity of the serum to kill the bacteria was also lost. It posed the following postulate: there exists in the serum a substance, sensitive to heat, necessary to the action of the serum on the bacteria, and it named this compound " Alexin". Ehrlich studied this compound in the following years, and introduced the concept of complement still used nowadays.

Beginning of the twentieth century

At the beginning of the twentieth century, research in immunology takes two distinct directions. The immunology humorale, whose principal figures were Paul Ehrlich and Emil Adolf von Behring, left the principle that the base of defense against the infections was to be in a substance contained in the serum, like the antitoxins. This theory prevailed about the years 1900 and during several tens of years. In parallel, and as from years 1883/1884, the point of view of the cellular immunity developed, which is based on work of George Nuttall like Ilja Iljitsch Metschnikov. Metschnikov could prove the implication and the importance of the action of the cells of the body in the fight against the pathogenic ones by studying the action of the white globules on bacteria. Its work on the Phagocytose was worth to him the Nobel Prize of medicine in 1908, jointly with Paul Ehrlich. As it will be shown later, these two types of phenomena are the two facets of the action of the immune system and the immunizing response. It must however be waited the years 1940 so that the assumption of cellular immunity is generally recognized, and that the assumption according to which the Anticorps would be the main actors of the immunizing response are abandoned.

In 1901, Karl Landsteiner highlighted the existence of the blood groups and by this discovery allowed to cross a new big step in the comprehension of the immune system. It accepted in 1930 the Nobel Prize of medicine. In 1906, Clemens Peter Freiherr von Pirquet observed that the patients with whom it managed serum of horse had a strong reaction to the second injection. It named this reaction of over-sensitiveness " Allergy ". The phenomenon of Anaphylaxie was discovered by Charles Robert Richet, which accepted for that the Nobel Prize of medicine in 1913. Emil von Dungern and Ludwik Hirszfeld publishes in 1910 their research on the transmission of the blood groups, and thus the first results on the genetics of part of the immune system. In this work, they propose the nomenclature “ABO”, which will become an international standard in 1928. In 1917, Karl Landsteiner describes the concept of Haptène S, which after being itself combined with a protein is able to induce an immunizing response with production of specific Anticorps. Lloyd Felton makes a success of in 1928 the purification of the Anticorps starting from the serum. Of 1934 with 1938, John Marrack developed the theory of the specific recognition of a Antigène by an antibody.

By studying the rejection of Clerc's Offices, Peter Gorer discovered the antigen H2 of the mouse, and thus, without the knowledge, the first antigen of what one will call then the major Complexe of histocompatibility (MHC for English major histocompatibility complex). Always by the study of the rejection of Clerc's Office, Peter Medawar and Thomas Gibson discovered important functions of the immunizing cells. It is by this work that the general acceptance of cellular immunity was done. In 1948, Astrid Fagraeus discovered that the antibodies are produced in the blood plasma by the lymphocytes B. The following year, Frank Macfarlane Burnet and Frank Fenner published their assumption of the immunological tolerance, which was validated a few years later by Jacques Miller, which discovered the elimination of the lymphocytes T car-reagents in the thymus. Burnet and Fenner accepted the Nobel Prize of medicine in 1960 for their work on the tolerance. In 1957, Frank Macfarlane Burnet described the basic principle of adaptive immunity as being the Sélection clonale.

The English Alick Isaacs and Switzerland Jean Lindemann, by studying the infection of cellular cultures by viruses, discovered into 1957 that the cells, during the infection by a virus, were mainly resistant to another infection by a second virus. They insulated starting from the infected cells a protein which they named Interféron. At the end of the years 1960 and the beginning of the year 1970, John David and Barry Bloom discovered the factor of inhibition of the migration of the Macrophage S (MIF) as well as many other substances secreted by the lymphocytes. Dudley Dumonde proposed for these substances the name of " lymphokine". Stanley Cohen, which accepted in 1986 the Nobel Prize of medicine for its discovery of growth factors NGF and EGF, started, with the beginning of the year 1970, to work with Takeshi Yoshida on the functions of the lymphokines. They reflect in obviousness that these substances, produced many types different of cells, were capable of remote action, like Hormones. Following the many discoveries in this field, Stanley Cohen proposed in 1974 the " term; cytokine" who asserted himself quickly. Meanwhile, more than one hundred cytokines different were identified, and their structures and activities studied in detail.

Modern immunology

The Sixties are in general regarded as the beginning of the modern time of immunology. Rodney To carry and Gerald Edelman succeeded in elucidating the structure of the antibodies between 1959 and 1961, and were prizes winner of the Nobel Prize of medicine in 1972. At the same time, Jean Dausset, Baruj Benacerraf and Georges Snell discovered the major Complexe histocompatibility, also called system HLA (of English Human Leukocyt Antigen) at the human being, discovered which enabled them to receive the Nobel Prize of medicine in 1980. In 1959, Joseph Murray carries out the first allogreffe by transplanting a kidney. With Donnal Thomas, he studies the artificial immunosuppression which allows the tolerance of the patients opposite their Clerc's Office; They accepted the Nobel Prize of medicine in 1990 for these studies. About 1960 also, the scientific community discovered, thanks to work of Jacques Miller, other fundamental characteristics of the immunizing cells, in particular the description of the functions and differentiation of the lymphocytes B and T. After this opening, the theory according to which immunity is divided into a cellular part and another humorale was essential, and the two theories were not put any more in competition. In the following decades, the various sub-types (called isotypic) of antibody were identified and their studied respective functions. In 1975, Georges Köhler, the Nile Jerne and César Milstein describe the method of production of the monoclonal antibodies. This discovery had an major impact on the basic research, like for the diagnosis and the treatment of diseases, and they accepted in 1984 the Nobel Prize of medicine. Others major discoveries were done in the following years: In 1973, Ralph Steinman and Zanzil Cohn discover the dendritic cells; In 1974, Rolf Zinkernagel and Peter Doherty discover the restriction of the presentation of the antigen by the molecules of the MHC, discovered which been worth to him the Nobel Prize of medicine in 1996; In 1985, Susumu Tonegawa identifies genes of immunoglobulins, and receives for that in 1987 the Nobel Prize; the same year, Leroy Hood makes in the same way for genes of the receiving of the cells T.

Another concept emerges in 1986: that of the orientation of the immunizing response. Based on the role of the lymphocytes T CD4+, this concept, developed by Robert Coffman and Tim Mosmann, the dichotomy between a " presents; Th1" , answer directed against of the cells on the one hand, which will produce specific cytotoxic lymphocytes, like in the case of cancer or of an intracellular infection; and an answer " Th2" against a soluble agent, which will produce specific antibodies, like in the case of an extracellular bacterium or of a toxin. The Th1/Th2 balance is always an intense research field.

The concept of tolerance induced by lymphocytes was for the first time evoked in 1969 by Nishizuka and Sokakura. They had their results concerning a subpopulation of lymphocytes T suppressors able to prevent a reaction of naive lymphocytes. Very discussed, these results will be forgotten until the redécouverte phenomenon by Sakaguchi in 1982 under the name of T regulating, subject actively studied currently.

Since the years 1950, the theory which dominates in immunology is that of the recognition of the " soi" and of the " non-soi" by the adaptive immune system. However, this model does not make it possible to explain satisfactorily the phenomena of Tolérance, of Rejet of Clerc's Office, nor the need for the presentation of the antigen, and in 1989, Charles Janeway proposes a model according to which it would be the innate immunity which would be the true guardian of the keys of the release of an immunizing response. The decision to react or not vis-a-vis a foreign agent would rest on the recognition of reasons by putative receivers which it names the PRR (for English Pattern Recognition Receptor). This model is thorough starting from 1994 by Polly Matzinger, which develops the Théorie of the danger. According to Matzinger, the release of the immunizing response would be done on the basis of molecular reason associated with the pathogenic organizations (PAMP, of English Pathogen-associated molecular pattern) by the PRR. This model was validated in experiments since by the identification of receivers of signals of dangers and some of their ligand S.

Nowadays, the multiplication of the cytokines, chimiokines, sub-types and markers cellular makes difficult to have an overall picture of the field.

Concepts in Immunology

Because of complexity of the studied phenomena and their close friend overlap, the immunologists are often reduced to use more or less abstract concepts to interpret information available. With the wire of time, more and more of new concepts, recutting itself more or less, are done day in the scientific community, most of the time by opposing two opposite concepts. The list below cannot be exhaustive, but gives an outline of some of these great concepts. It takes again naturally certain points already seen in the history, but develops them under a simplified and more pragmatic aspect.

Antigen

Innate or adaptive

Important concept, that of the system " inné" and of the adaptive system (or acquired, although this term is less and less used). It is a question here of opposing phenomena " non-spécifiques" with events " spécifiques" , insinuations " antigène".

In the first case, it is about a reaction according to the introduction of a new element, whatever he is, and which rests on a total reaction of a cellular type. All the wounded cells, whatever is the cause, have similar reactions, and the cells of the immune system react in also stereotyped ways. This innate answer is fast, without memory and independent of the antigen. A multitude of situation (wound, viral or bacterial infection, etc) lead to similar innate reactions.

The adaptive answer relates to phenomena related to the antigens, and consists of the selection of clones of lymphocytes, able to target what is perceived like a threat. This adaptive answer is slow, strictly dependant on the antigens, and has an immunizing memory. Each different situation will lead to the selection of some clones lymphocytaires which will deal with the danger.

Cellular or humoral

Th1 or Th2

Oneself or not-oneself

The cellular answer was regarded for a long time as resulting from a direct recognition by the immunizing cells of the foreign cells. Otherwise how to explain that substances produce a strong reaction at an organization and none at another? The introduction of a foreign element (infection or Clerc's Office) must be followed by an acceptance or a rejection by the immune system. At the time of a Clerc's Office of skin for example, the skin taken on the donor was well accepted by the immune system of the donor. However, after the Clerc's Office, the immune system of the receiver can decide to regard the new skin well as foreign, and to reject it, whereas it does not constitute of anything a danger. This concept remains very current, although its mechanisms were mainly elucidated by the study of the interactions between TCR and the molecules of CMH.

Immunogenic or tolerogene

Another question can arise: how it is made that certain bodies " étrangers" are not recognized? The first concept is that of " tolerance centrale" , which stipulates that no organization owes, at the base, to produce lymphocytes car-reagents, i.e. lymphocytes reacting against the antigens of the " soi". The second concept is that of tolerance peripheral. It rests on lymphocytes which inhibit the answers of the other immunizing cells, and whose action is very plastic. The problem here is thus of knowing under which conditions the introduction of a foreign element, an antigen, goes or to induce an immunizing response, in which case the antigen is immunogenic, or to produce a tolerance for this antigen. One speaks in this case about substance tolerogene.

Dangerous or without danger

The theory of the danger rests on a simple report: in certain situations, the same antigen can be perceived as without danger (tolerogene), dangerous (immunogenic), and if it is immunogenic, to develop very different answers, cellular answers or various answers antibody, going until the Allergie. The theory of the danger stipulates that it is the conditions under which the antigen is perceived which determines the type of immunizing response which will be developed. These particular conditions imply signals of danger in more or less great number and more or less great quantity, and which accompany the antigen. The combination of the signals of danger (or their absence) directs the immunizing response.

Bodies of immunity

The whole of the bodies of the immune system is called the lymphoid system.

Primary or central lymphoid bodies

the osseous Marrow : they is there that the cells of the Immune system are produced, by a process called Hématopoïèse. It is also the place of the acquisition of the Immunocompétence of the lymphocytes B.
the thymus : it is there that place has the maturation and the selection of the lymphocytes T.

Secondary or peripheral lymphoid bodies

On the level of the blood system, there are protein escapes. These proteins find in the interstitial Liquide and must turn over in blood in order to control its Osmolarité. The lymphatic capillaries recover these Protéine S and collect also the disease-causing agents, cells of the immune system and remains of dead cells. The lymphatic system involves the lymph on the level of an integrating center which corresponds to the lymphatic ganglia. After the passage of the lymph in the ganglion, the lymph is purified. The Lymphe circulates towards the heart with one way. It joined the Blood circulation on the level of the heart by the thoracic Canal and is thrown in the left vein subclavian.
the lymphatic ganglia have a more or less globulous structure. They break up into several zones.

a sine capsulaire which allows the arrival of the related lymphatic vessels. The lymph crosses the sine enters the ganglion via spans.
the cortex of the ganglion is occupied by the lymphocytes B. The cells B are gathered in cluster. These are the follicules which grow bigger in the event of infection.
the paracortex shelters the lymphocytes T and the dendritic cells.
In the center, one has an output area with as many lymphocytes B than of lymphocytes T. It is the hile by which leave the efferent lymphatic vessels.

the secondary appendices (aggregate lymphoid formations) have particular zones of purification. They are the Anneau of Waldeyer to the aérodigestif crossroads (amygdala S and adenoids), the appendix and the Plaques of Peyer.
the Rate also forms part of the immune system because it purifies blood with respect to the pathogenic ones which could be there.

Tertiary lymphoid bodies

The tertiary lymphoid bodies include/understand all fabrics and bodies where the immunizing response takes place. They contain few lymphoid cells under the normal physiological conditions but can import of it a great quantity at the time of the presence of pathogenic. They include/understand:

the Skin
the Respiratory system
the digestive Tract -- to see GALT
the genital tract -- to see MALT
… the remainder of the body.

It is necessary to note the existence of immunizing sanctuaries. They are fabrics where the immunizing cells do not penetrate; it is of the Testicule S and the former room of the eye. The naive lymphocytes cannot cross the hemato-encephalic Barrière.

Various types of immune reactions

Immunity humorale

They are the mechanisms of defense implying of the soluble factors. It is of two type: innate defense and adaptive defense.

Innate immunity humorale

Innate defenses correspond to molecules present spontaneously in the organization and which preexist to the threat. It is of the natural antibodieses, the défensines, the system of the complement. The attacked fabrics also produce molecules of the ignition, such as the tissue Facteur and the derivatives of the arachidonic Acide: Leucotriène S and Prostaglandin S

Adaptive immunity humorale

It is supported by the presence of circulating Anticorps. The antibodies are produced by the plasmocytes, resulting from the final differentiation of a clone of Lymphocyte B. It is of the molecules of the type Immunoglobuline of various types:

the IgM which are the first products during an infection. They are décavalents and their greed for the antigens is very large. They have an important role in the formation of complexes immunes.
the IgG of high affinity, having a crucial role in the cytotoxicity related to the antibodies.
the IgE supports of the immediate Allergy (standard reaction of over-sensitiveness 1).
the IgA secreted on the level of the mucous membranes, play an important role in the neutralization of the pathogenic present on the épithélia (Bronche S, digestive Tract).

In a general way, the Anticorps act in two different ways: either by the activation of the complement, or by fixing of the complex immune on an immunizing cell having a receiver for the constant fragment of the antibodies (such as the Macrophage S, the Lymphocytes NK for example)

Cellular immunity

The immunizing phenomena with cellular mediation imply various types of cell, gathered in two concepts: cells of the innate Immunity and those of the adaptive Immunity.

Cells of innate immunity

In fact cells are able to react to a phenomenon without preliminary education. They react to stimuli present on a variety of pathogenic, and independently of the Antigène S. It acts:

of the Lymphocytes NK;
of the Granulocyte S, in the past called Polynuclear;
of the Macrophage S;
of the dendritic cells, which are best the cells presenters of antigen S.

Cells of adaptive immunity

They are reactions which bring into play cells of the type Lymphocyte T. Their maturation depends on an antigenic stimulus and an education by a Cellule presenter of antigen. Their activation vis-a-vis a target depends on the presentation of the antigen by the target cell. The lymphocytes T are thus able to recognize only transformed cells (i.e. infected by pathogenic intracellular, or a tumoral cell). There are two principal types of lymphocytes T:

the lymphocytes CD8 + recognize an antigen carried by a molecule of CMH of the type I. They generally are different in cytotoxic lymphocytes and produce relatively few Cytokine S;
the lymphocytes CD4 + recognize an antigen carried by a molecule of CMH of the type II. Their principal action is the secretion of cytokines, which directs and amplifies the immunizing response, it is what one names the " help" (in French: helps), from where the nickname of " helper" given to these lymphocytes T. the current Paradigme is to differentiate two types of CD4+: the lymphocytes helpers which direct towards a cytotoxic answer (" Th1 ") and those which direct towards an answer more humorale (" Th2 ").

Diseases of immunity

Immunizing deficits

See immunizing Deficit.

Congenital

With prevalence humorale, concerning the antibodies.
With cellular prevalence.
Combined.

Iatrogenic (Chemotherapy of cancer, treatment Immunosuppresseur)
Viral (HIV AIDS)
Related to a severe pathology (Leukemia, evolved/moved cancer, etc).

Unfavourable immune reactions

various types of Allergy or over-sensitiveness.

Of the type 1, known as " immédiate": Médiée by IgE, rapid even striking down.
Of the type 2, also called " disease sérique": Direct Cytotoxicity of immunoglobulins.
Of the type 3: Complexes circulating immunes.
Of the type 4 known as " retardée": Delayed allergy of cellular immunity.

the autoimmune Diseases.
reactions to the blood Transfusion.
the rejection of Clerc's Office of body.

Immunology in practice

Immunology in the laboratories of diagnosis and research

The knowledge of the immunological mechanisms allowed the development of many techniques of quantitative analyzes as well as qualitative.

Techniques

The principal techniques are the reactions of precipitation, the reactions of agglutination and the reactions of neutralization.

The majority of these techniques use the properties of the monoclonal Anticorps. Their Affinity and them Spécificité of connection to their target makes them tools impossible to circumvent for detection. They make it possible to determine the presence of a particular épitope in a sample, thus allowing in the techniques like the Western blot or ELISA to detect Protéines, Isoforme S of proteins, or particular protein modifications (Phosphorylation, Acétylation, etc).

The capacity to form complex immunes makes it possible to cause the agglutination and the precipitation of the target with the antibodies: it is the principle of the Immunoprécipitation, used seeks some to detect interactions between two proteins or to purify a compound in a solution.

Another property of the antibodies used in animal private clinic and for a few years in human private clinic has been the faculty of some Isotype S of antibody to bind the complement, and thus to lyse the cells on the surface of which they are fixed. In practice, that makes it possible to destroy the cells having a antigenic marker particular.

Applications

The diagnosis of the infection by HIV is based on detections of antibodies circulating in the serum of the patients, just as the diagnosis of the infection by the virus of hepatitis B. the proportioning of some Hormone S (thyroid hormones in particular) in the serum is also made by Turbidimétrie or Néphélométrie: the automats detect the opacification of a solution, related to the precipitation of the complexes antigen-antibody.

In addition, the determination of the lymphocytary formula calls upon the Cytométrie in flow, using monoclonal anticoprs coupled to fluorescent Molécule S

Immunology in practice medical

The use of all kinds of Vaccine S.A. allowed triumph of medicine against many infectious illness. Thus, the Variole is éradiquée, and other diseases are candidates with the eradication by vaccination: the Measles, the Hepatitis B for example. They are diseases caused by Virus whose human being is only the tank. The vaccination of most of the population would allow of the éradiquer. They are objectives laid down by the the World Health Organization.

In addition, there exists since 2006 vaccines intended to decrease the risk of Cancer S of the Cervix. This vaccine is directed against a virus responsible for the transformation of the epithelial cells of the collar into tumoral cells. To vaccinate the young girls before their first sexual contacts would make it possible to decrease by 80% the cases of cancer of the coll.

See too

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