New interdependent discoveries in the field of nutrition and immunology
Background of my discoveries
In 1908 the Nobel Prize Ilya Mechnikov and Paul Ehrlich shared the Nobel Prize in the field of medicine and biology for discovery in the field of immunology as a result of their researches in the theory of immunity. One of them had opened phagocytosis, and the second one discovered the existence of antibodies.
In 1930 the Nobel Prize some scientists received the Nobel Prize for their researches in the field of group of blood of the person (the Nobel Prize winners had discovered that the blood cells have some specific groups which are characteristic for those or another organisms; the autoimmune processes start up in case when these specific groups do not coincide).
In 1980 Baruh Benacerraf, Jean Dausset and George Shell shared the Nobel Prize for their discoveries concerning "genetically determined structures on the cell surface that regulate immunological reactions". George Snell had laid the foundation for our knowledge of the laws that manage the body's ability to distinguish between "self" from "non-self".
Baruj Benacerraf had demonstrated that genetic factors are intimately related to the genes that determine an individual's unique constitution of H antigens actually regulate the interaction among the various cells belonging to the immunological system and are thereby important to the strength of an immunological reaction.
The Nobel Assembly of Karolinska Institutet has in 1984 decided to award the Nobel Prize in Physiology or Medicine for 1984 jointly to Niels K. Jerne, Georges J.F. Kohler and Cesar Milstein for the theories concerning "the specificity in development and control of the immune system" and the discovery of "the principle for production of monoclonal antibodies". Their work has been devoted to functioning of antibodies at formation of the got immunity.
Susumu Tonegawa had in 1987 shared the Nobel Prize for his discovery of "the genetic principle for generation of antibody diversity. He had specified the structure of antibodies and their variability.
In 1996 Peter C Doherty and Rolf M Zinkernagel shared the Nobel prize for their discoveries concerning "the specificity of the cell to mediate an immune defence". Furthermore, regard was paid to the fundamental principles formulated by Doherty and Zinkernagel in trials with vaccination against the emergence of metastases in certain forms of cancer. In many chronic inflammatory diseases, better explanations have been provided for the associations between disease susceptibility and the histocompatibility antigen type carried by an individual. However, they did not understand the reasons of formation of many chronic inflammatory conditions such as rheumatic diseases, diabetes and multiple sclerosis. Both scientists tried to explain it through the mechanism of the acquired immunity.
Many researchers also try to find ways of treatment of many chronic diseases such as AIDS, cancer, diabetes and others by vaccination, that is through the mechanism of formation of the asquired immunity.
Formation of the concept of the first discovery in the field of nutrition
Carbohydrates should make 60 % from total of calories in food in the feed of a healthy person. Everyone knows that human blood contains 80-100 mg% of glucose. However, except for the glucose, blood of a healthy person contains also others monosugars - mannose, fucose, ribose, arabinose, xylose and others. These monosugars are present at human blood in quantity 10-15 mg%. But its role in a human body actually has not been analyzed. Within 1993-1994 we have investigated the structure of sugars of blood for 120 person by means of gas-liquid chromatographies (the objects of investigations were healthy persons as well as persons with various diseases1). We have concluded that the level of these sugars in blood of patients are various for various diseases. The least quantities of these sugars has been determinated in blood of persons with cancer or with diabetes mellitus.
Still earlier in 1984-1987 while investigating female milk from 75 mothers we have established with means of gas-liquid chromatographies that alongside with lactose the fucose and its derivatives are present in female milk at quantity 8 - 15 % from the total sum of all sugars2. We have discovered in female milk of some mothers that fucose and its derivatives were in smaller quantities, and simultaneously we have revealed the pathology of development among children who had consumed this milk.
Thus, in 1984 we have established infringements in structure of sugars of female milk, and in 1993 we have revealed similar infringements of structure of sugars in blood at of some patients.
As we found out there was a lowered maintenance of these minor sugars3 in blood of the patients, we began to enter into the organism these patient absent monosugars. We have started to enter these monosugars into the nutrition of patients per 1993 as the food additive or in the form of food which contained this monosugars. We have received stunning results. The persons with the diabetes mellitus had been normalized a carbohydrate exchange, and the level of glucose in blood has been stabilized at downturn of need of an organism in exogenous insuline4. Thus also diabetic microangiopathy, a blood pressure at patients with insulin-independent diabetes was normalized, the immunity of the organism has been increased, the action of cardiovascular system came to norm and the blood pressure went down to an optimum level, some other illnesses also have been eliminated5. All these resultas had allowed us to patent in Russia the method of treatment diabetes mellitus6, and then to patent the method of normalization of the carbohydrate exchange at various others diseases with help of the minor sugars7.
Thus, in 1993 a discovery in the field of medicine and biology concerning an establishment of the role of minor sugars on management of the biochemical processes formed in the healthy human body and at many diseases has been patented.
We have opened the new group of irreplaceable components in human food of type of vitamins. We (and later - some French scientists)8 established that mannose and others minor sugar represent a new class of the irreplaceable nutrients and play the irreplaceable role in human organism. The American scientists also have started to spend comprehensive investigations from scientists of other countries about the role of mannose in at treatment of the some people diseases 9,10,11.
Thus, my researches about the role of vitaminoid sugars in the human body and their application for treatment of these or those diseases are also confirmed by scientists in many laboratories of the world. Now mannose is widely used for treatment of inflammatory diseases of a bladder.
As a result I had made the first discovery in the field of nutrition.
Formation of the concept in the field of immunology
Till now many scientists consider that both receptors of antibodies and phagocytes have stable biochemical structure which does not depend on a nutrition, stages of biochemical infringements, a level of phenotypical mutations. Really, such specific receptors located on cells of our organism as the group of blood of the person or an animal, various antibodies to those or other viruses and microorganisms have stable biochemical structure both in construction of an proteins part, and in construction of their carbohydrate part. And these immune properties do not change during human life.
At the same time we have schematically established and in the further have confirmed the new understanding in the field of immunology, in particular, the process of functioning of a high mannose receptor which carbohydrate structure is presented by type Man (9) GlcNAc (2) Fuc (1).
This high mannose receptor is present basically on phagocytes and lymphocytes, and also on other cellular and extracellular structures. At biochemical infringements in human organism this receptor can change the carbohydrate structure, and this process determines both the deficiency of immunity and the autoimmune processes.
The Basis of discovery in the field of immunology
The human immune system consists of the innate and acquired immunity. The main cellular components of innate immunity are phagocytes while the main non-cellular components are complement system, cytokines, interleukines and other proteins components.
The high mannose receptor is formed practically on all components of the acquired and congenital immunity and is responsible for reception type "self" - "non-self".
As the period of activity of the lymphocytes makes only 3 days, and the same period for the antibodies makes 2,5 - 23 days, all irregularities in in biochemical processes of the human body are starting, first of all, in the functioning to immune system. A part of lymphocyte proteins and antibodies and other components of immune system are synthesized from replaceable and irreplaceable amino acids which act with nutrition.
For synthesis of the high mannose receptor it is necessary to have enough quantity of mannose in blood of the person. Absence of it or low levels of this sugar in blood leads to glycosylation and formation abnormal antibodies with the infringement of the structure carbohydrate 15, and also to the infringement of synthesis of others glycoproteins 16,17,18,19.
The mannose level in blood of the healthy person should be supported at 20 - 50 mkmol/L20 which cannot be delivered by endocellular or metabolic processes. Therefore for synthesis of various proteoglycans including the high mannose receptor is necessarily to provide dietary mannose with food. The carbohydrate part of antibodies in the human body syntesis needs at least 80 mg of mannose or fucose in a free condition.
By means of the gas-liquid chromatography we have established for the first time, that in blood of the personas with diabetes mellitus the fucose was absent, while the mannose level was considerably lower compared with the level of healthy people 4.
We have received the patent for the method of restoration of the infringement metabolism of carbohydrates by means of minor sugars of persons suffering form diabetes 6.
In our further researches we have shown infringement of the carbohydrate metabolism at patients with adiposity, cancer, AIDS, some cardiovascular diseases, a cataract and many other diseases 12,35. We have shown also that deviations in structure of the proteoglycan carbohydrate part result not only in formation of one disease, diabetes mellitus, but also in a lot of others diseases. It allows us to confirm that absence (or lack) of minor sugars in blood leads to infringement of synthesis of many proteoglycans, including the high mannose receptor. Therefore minor sugar are vital elements of the nutrition, as vitamins and they are necessary such for synthesis of the high mannose receptor.
At restoration of carbohydrates metabolism infringements among the persons suffering diabetes mellitus by means of minor sugars we have reached also the normalization of innate immunity at these patients. Therefore we had continued researches in both theoretical and practical fields with a purpose to understand the role the high mannose receptor in formation of the acquired and innate immunity, including autoimmune processes.
What basic carbohydrate structure has the high mannose receptor on cellular and soluble components of immune system?
On the surface of cells (lymphocytes, phagocytes), soluble structures (antibodies, cytokines, interleukines, etc.) there is a high mannose receptor with the following carbohydrate structure - Man(9)GlcNAc(2)Fuc(1 )22,23. The similar structure we can find on enzymes24, vesicular-integral membrane protein 25 and others glycoproteins and glycolipids receptors.
If there will be no such a receptor on the surface of the cell and other high-molecular components, they will be recognized as "non-self" and will be destroyed by immune system. Thus, our organism is protected to survive in the environment of other organisms.
What is the main difference of the high mannose receptor from others?
The basic difference of it the high mannose receptor consists in its constant indetermination. Thus, the receptor of group of blood is constant and, consequently, the group of blood does not change during human life. The antibody's receptor on the surface of lymphocytes or an antibody is constant and during all human life these antibodies created by the organism during various vaccination, counteract the occurrence of ilnesses.
But the structure of the high mannose receptor can change strongly within several months and even weeks depending on dietary of mannose in organism of the person that results in changes in the immune system.
How can this receptor change during infringement of dietary mannose in blood of a person?
During an infringement of dietary mannose together with food or infringement of the condition of microflora in a gastroenteric tract (abnormal microflora) 26 the decrease of the level of mannose in blood 27 starts and the carbohydrate structures with smaller quantity of mannose molecules begin to be synthesized.
Thus are formed four new structures - eight mannose molecules - Man(8)GlcNAc(2)Fuc(1)28, seven 24, five 29, three 30. This decrease in quantity of mannose molecules in the molecules of proteoglycans forms infringement of reception system aside its simplifications (see Figures.1-6).
Figure 1. Healthy cell having normal high mannose system of the reception . This system consists of one molecule fucose, two molecules N-acetylglucosamine and 9 molecules of the mannose {Man(9)GlcNAc(2)Fuc(1)}. The cell receptor has big dimension for the best comprehension of incipient infringements.
Figure 2. Cell having infringement in system reception because of lack of blood mannose. One molecule of the mannose is not synthesized in carbohydrate structure of the high mannose receptor {Man(8)GlcNAc(2)Fuc(1)}.
Figure 3. Cell having infringement in system reception because of long-time lack of blood mannose. Two molecules of the mannose are not synthesized in carbohydrate structure of the high mannose receptor {Man (7) GlcNAc (2) Fuc (1)}.
Figure 4. Cell having infringement in system reception because of long-lived lack of blood mannose. Four molecules of the mannose are not synthesized in carbohydrate structure of the high mannose receptor {Man(5)GlcNAc(2)Fuc(1)}.
Figure 5. The cell having fatal infringements in system reception at very low maintenance of the level of mannose in blood. Already 6 molecules of mannose are absent in structure of the high mannose receptor {Man (3) GlcNAc (2) Fuc (1)}.
Figure 6. A cell at sick of AIDS at last stages of development of disease. The high mannose receptor practically does not exist {GlcNAc (2) Fuc (1)}.
If there are less mannose molecules in the high mannose receptor, than the immune system receptor is forming easier, and a lot of various microorganisms and other antigenes are not distinguished by this receptor.
How quickly can these infringements in our organism be formed? A reduction of quantity of mannose molecules in high mannose receptor does not lead to immediate change of reception system of the cells, as the term of the life of various cells of our organism is various. First of all, there are infringements in antibodies, lymphocytes, hepatocytes which term of the life is between 2 and 120 days. Therefore, the decrease in the level of mannose in blood forms infringement of the reception of high mannose receptor, first of all, in the system of immunity of the person.
Protective functions of the human body from penetration of pathogenic microorganisms are weakened; and more frequent diseases by cold and a flu occur as a result formations of immune system cells with infringement of reception. The further decrease in the mannose level in human blood results in formation of infringement in the carbohydrate part of reception structure and in other cells (beta cells, muscular, a connecting tissue and others). Decrease in the mannose level in blood of the person for the long time (10 - 50 years) causes the formation of AIDS and cancer. In the organism of patients with AIDS the system of cellular reception it so infringed because of high protein diets and long reception of the antibiotics recommended by doctors, that the receprion system actually does not work because of absence of the mannose in high mannose receptor 31.
What infringements can be caused by long decrease of mannose in blood and, consequently, what kind of infringements of synthesis of various receptors can be observed?
Decrease in quantity of mannose molecules in structure of the glycoproteins and glycolipids receptors results in infringements in many biochemical processes. Now these infringements are revealed actually at all diseases. Adiposity is connected with deterioration of reception of insulin muscular and hepatocytes. The diabetes mellitus is connected with infringement of vesicle carbohydrate structure for a evacuation of insulin from beta cells at insulin-dependent diabetes and deterioration of reception of insulin in cells of the liver at insulin-independent diabetes 32,33.
Decrease in quantity of mannose molecules in structure of the glycoproteins and glycolipids receptors results to infringements in many biochemical processes. Now these infringements are revealed actually at all diseases. Adiposity is connected with deterioration by reception of insulin muscular and hepatocytes. The diabetes mellitus is connected with infringement of vesicle carbohydrate structure for a conclusion of insulin from beta cells at insulin-dependent diabetes and deterioration of reception of insulin in cells of the liver at insulin-independent diabetes 32,33.
It is impossible. The increase of the level of mannose in blood, first of all, leads to the synthesis ofhigh mannose receptors with the raised quantity of mannose molecules in carbohydrate structure of immune cells and soluble components. They start to destroy all cells which have receptors with smaller quantity of mannose molecules. In this case the autoimmune processes in human organism start. The immune cells of the body begin to destroy cells of own organism with smaller quantity of mannose molecules defining them as "non-self".
If during infringements of biochemical processes the small amount of such cells was generated in organism of the patient as a result of autoimmune processes, the temperature of body does nor rise. As the number of cells revealed by newly constructed high mannose receptors as "non-self" rises, than the intensity of the autoimmune processes of destruction of organism's own cells becomes more and more fast. There are also processes which start to destroy various microorganisms and viruses which had created their colonies in human organism because of decreasing immune control. In this case the temperature of the human body can rise essentially till become critical one.
Therefore, to cure patients with AIDS it is necessary to control the autoimmune processes. It is necessary to rise slowly the level of mannose in blood, stage by stage, without overloads during several years 35.
Thus, for a synthesis of normal receptors in the human body including high mannose, it is necessary to support the level of vitaminoid sugars in blood either by means of food, or by means of food additives and to not suppose decrease in the level of mannose in blood during long time.
Thus, the double and interdependent discovery in the field of biology and medicine allows to form essentially new approaches in consideration of the reasons of formation of biochemical processes in human organism while there is a lack of minor sugars in the nutrition, while there is a decrease of functions of the innate and acquired immunity; at last, allows to find out the reasons of occurrence of autoimmune processes in the organism of patients, including those during the change of donor bodies or those bodies from stem cells in the future from stem cells 34.
These discoveries in the field of immunology and nutrition open new opportunities in theoretical judgement and practical use the received new approaches in these fields of knowledge and open new opportunities in treatment of the cancer, the diabetes mellitus, AIDS and many other diseases, and also to manage of autoimmune processes at change of bodies and chronic diseases.
References cited
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