This is a great discussion! I would like to suggest two interesting theoretical papers by a Brazilian immunologist, prof Nelson Vaz, who is cited in many references of prof Alfred Tauber.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2270771/

http://archive.org/details/VisitingImmunology

May I interpret "custodial" in this way? The top priority of the immune system is to keep the homeostasis, in another word, is prone to anti-inflammatory vs. inflammatory, as well as somehow provides nurture at the setting of injury. An example is the macrophages, most of time the tissue macrophages is in the phenotype of M2.

Well, the immune system is like water, if you put then in a model, it will fit. The immune system's first and primordial function is to regulate cells in the body, the endocrine system and homeostasis. But when the immune system sees cells that it thinks aren't from your body or anomalies, it starts to move...

It is different for each disease. The pathways, the transcriptions, the cells are the same, and show differences in different places. The Lynphocyte T Helper 1, can be a T regulatory, if the cytokines in the environment is predominantly IL-10 and TGF-Beta. When you study the immune system you can say that you see something in a specific timeframe, not necessarily active all the time. That's why it is correct to say that the immune system is not static, but malleable!

I hope this was helpful.

The short answer is immune system is both custodial and defense

In the female reproductive system, it is clear that the immune system is not primarily a defense system but rather a modulating system that can be considered custodial, but even more, it actually acts to promote the overall reproductive success of the woman.

Nice post. I've generally thought that the main function of immune system was defense while the custodial role was secondary. After reading this post, I am not so sure.

Thanks colleagues. The question, I think, is a big one - at least in the larger culture, a "game changer" with all sorts of important consequences - practical, theoretical, futuristic.

Immunology is a field in which the "trees" are fascinating - and absorbing. There is so much to learn,,,,,,,,But so, I think, is the "forest" (the big questions). Scientists tend to explore the "trees" while philosophers examine "the forest.." Each have their own methods and approaches, often disrespected and poorly understood on the other side. The one is certainly not the other. Few straddle this fence.

But every once in a while game changing big ideas come along with ... down the road if they sufficiently explored and well digested..........major consequences. I think that this idea - that the immune system is a custodial system, a "home improvement " system if you prefer, with homeostatic and primary health promoting functions as well as defensive functions -- is such an idea -- and merits a spot light....

Agree or disagree?

I completely agree, Michael. The paradigm on my “tree” (reproductive immunology) from 1953 until about 5-10 years ago, was clearly one of immune suppression or quiescence (and Th2 dominance) during pregnancy. Those ideas are quickly being replaced by this idea of immunomodulation. Innate immune processes are necessary and involved in reproduction from the time of ovulation through parturition. TLR’s on uterine decidual cells and on trophoblasts seem to initiate the inflammatory processes of implantation and placentation and I suspect are also involved in the initiation of labor. Uterine NK cells are not actually cytotoxic at all; they are busy producing cytokines and chemokines! And the list goes on….It is indeed an absorbing and exciting time to be studying these processes.

see

http://www.hindawi.com/journals/cdi/2012/258391

Chen, S.-J., Liu, Y.-L., & Sytwu, H.-K. (2012). Immunologic Regulation in Pregnancy: From Mechanism to Therapeutic Strategy for Immunomodulation. Clinical and Developmental Immunology, 2012. doi:10.1155/2012/258391

or

Koga, K., & Mor, G. (2010). REVIEW ARTICLE: Toll-Like Receptors at the Maternal–Fetal Interface in Normal Pregnancy and Pregnancy Disorders. American Journal of Reproductive Immunology, 63(6), 587–600. doi:10.1111/j.1600-0897.2010.00848.x

Gret comment Donna! To bad we missed the meeting below. Could't be more pertainent!

The human being - a bacteria controlled superorganism

Rather than just being a single organism, the human body is host to trillions of bacterial organisms that interact and influence our development and function from the moment we are born. This new perspective of the human animal is the theme of a forthcoming conference at Karolinska Institutet.

Reporters are welcome to attend the conference "Who controls who? A Systems Biology View of Host - Microbiome Interactions".

Date: Friday 31 August - Saturday 1 September 2012

Venue: The Rolf Luft Auditorium, Karolinska University Hospital, Solna

http://ki.se/ki/jsp/polopoly.jsp?d=130&a=148608&l=en&newsdep=130

Yes sir it is the major defence mechanism of human body against many infections. besides fitting virus,bacterial, other ingestion processes it protect human from number of ailment . it is already proved & proceeding further understanding

This is a great discussion! I would like to suggest two interesting theoretical papers by a Brazilian immunologist, prof Nelson Vaz, who is cited in many references of prof Alfred Tauber.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2270771/

http://archive.org/details/VisitingImmunology

No It is not a custodial system but defence system. The potency of defence depends on titer levels of immunity.However it takes care of body from unknown viral attack & many more infection to body.

We must go back to Charles Darwin when he sees adaptation to environmental facts.

I like the discussio because of the antagonisms: autoimmunity_autoagression or else: immunesurveillance_immunedefense and tolerance_rejection, which ends up in allo-_auto_immune and HLA-controlled reactions. I will read the suggested references and thank your for kindling my interest.

Urs E. Nydegger, M.D. www.immune-complex.ch

Dear MIchel

I would say that immune system is custodial and defense systems and that the second role emerges from the first one. Donna mention the changes on her tree. If you follow system biology ideas, the idea is to connect the trees actually called branches ( or sub-trees) . Things are changing rapidly in infectious diseases also. With the amount of data available it becomes clear that a holistic view is necessary. The biological Reduccionism adopted for centuries is not anymore supported, questions should be answer taking into account the body, the influences of environment, but mainly the mechanisms that garantee its robustness to misfunction and the survival of the bunch of cells mentioned. Dynamical aspects, interactions, should be understood...If we will succeed to understand everything I do not know..but the system biology approach is changing the way of thinking and doing research, is changing the way the questions are raised...interdisciplinary and transdisciplinary work is necessary....the systemic science view is necessary...we are connecting branches there also...

So much to say, so much to lear we are only seeing the top of the iceberg.

"Those ideas are quickly being replaced by this idea of immunomodulation. Innate immune processes are necessary and involved in reproduction from the time of ovulation through parturition".

The effects of exercise on muscles, inflammation and immune function is another good example of the orchestration of those processes not as part of a defense mechanism.

Can we consider immunity (immune response) inflammatory response (inflammation)?

The immunity - this is the inflammation?

Why definition of immunity is very different in the Russian and English textbooks? In Russian literature is called innate immunity prior immune biological protection of the body from infection (RM Khaitov) or non-specific resistance (RV Petrov).

This is correct? R.M.Haitov and RV Peter are an active members of Russian Academy of Sciences.

Re Dr. Zabrodskii questions: the definitions are not different. Immunity (understood as protection from potentially noxious pathogens by their elimination) is divided into innate (which, roughly, operates via phagocytic cells and their abiulities to kill [mostly bacteria and parasites] with enzymes and ROS) and adoptive, which acts via lymphoocytes and their secretions (mostly B cell antibodies and T-cell-derived interleukins). I do not kow where from Michal found the definition linking the innate immune processes with pre-partum period only. True enough, this is the 'more primitive' (eveolutionarily older) part of the immune system which activates early in fetal life, but stays and works for the body until death.

Can we consider immunity (immune response) inflammatory response (inflammation)?

The immunity - this is the inflammation?

In Russian literature is called а prior immune biological protection of the body from infection (RM Khaitov) or non-specific resistance (RV Petrov). The term "innate immunity" is not used.

This is correct?

Dr. Jacek Witkowski ! It was clear to me (your answer).

Dr. Ahed Khatib! Despite the assertions of our academics, I think that the immune response - one of the elements of inflammation. The immune response can be without inflammation (do not cite examples.)

Dr. Ahed Khatib! Thank you.

Dr Zabrodskii: IMHO, you are right; first - immunity (both innate and adaptive) is a part of inflammatory process; second - innate immunity (phagocytosis and killing of bacteria) STARTS inflammation (some forms of it), while adoptive (lymphocyte-dependent) immunity IS STARTED within the inflammatory process; third - immunity (at least adoptive) is possible without (much) inflammation, however it is more difficult to have inflammation without immunity (at least the innate. A propos, Khaitow's and Petrov's terms are correct, just more descriptive. Although, the term 'non-specific' for innate immunity is a bit misleading, as it seems to be triggered by interactions between the toll-like receptors (TLRs) on phagocytes and bacterial molecules, which are at least somewhat specific (the PAMPs (pathogen-associated molecular paterns)).

Dr. Jacek Witkowski! Thank you.

This is good question !

The word "immunity" needs to be investigated ! As a word, Immunity describes a state of ACQUIRED OR CONFERRED state of resistance. For the host to survive UNDER ITS NATURAL CONDITIONS, it or SOME FUNCTIONAL VERSION of it must pre-exist (more on this later). As in world affairs, immunity is an acquired or conferred state of freedom from outside interference (in simple terms). Is it in this sense the word must be seen and this organ is best described ?

Here is a beautiful definition of custodial: responsible for or providing protective supervision and guardianship rather than seeking to improve or cure.

But superimposed on this is the hand of evolution. The immune system has been directed by evolution to work towards (as one of the organs) the SURVIVAL of the host. Evolution's arrow points towards protection leading to survival. This clearly involves the ACTIVE protective role in cases where it is obvious survival is at stake, but UNDER IDEAL CONDITIONS would be in a such a way that its actions itself do not kill the host !!

Clearly, the influenza epidemic of 1918 claimed more lives due to the over-zealous ACTIVE reaction of the immune system = INFLAMMATION. The mortality rate was boosted because many, many people did die of inflammation itself rather than viral load. (Of course, this raises the question whether the immune system has yet been perfected by evolution and is there is room for "improvement". I am for the improvement argument).

Thus, if evolution must be believed there must be a defensive component, or AT SOME TIME in the past there must have been a "defensive" component that evolution used to develop an "immunity" system. (Is this the inflammation causing component?). I must thus come to the conclusion that the steady state of the immune system - day to day look and feel - APPEARS custodial, but can go into "defense" mode when the host is in danger. Whether the latter is good or bad depends on whether one considers the immune system perfectly evolved. I for one think evolution is still "perfecting" the immune system, and we should - theoretically - reach a point where dealing with outside threats does not put the host survival in jeopardy.

PS: Considering the number of combinations possible in the developing immune system, are there any humans that have more perfect immune systems than others? Has modern medicine "interfered" so much that we will never see evolutions final end, and the argument between "custodial" and "defensive" may never be settled?

Immunity is a term that goes back to the concept that by being exposed to disease rendered you protected from the disease recurrence, if you survived. With the discovery of innate immunity vs adapted immunity, we realized that this was much more complex than was thought. In the 1950's Lansteiner suggested that the amount of antibody that could be produced was infinite. The work of Burnett, Sir Peter Medawar, Robert Good, Zanvil Cohen, Rosenthal, Rosentrich and Shevach, Banaceraff and others gave us the cast of characters and how they interacted with one another. Lets remember that this is a dual system, recognition of invading disease and survalence of cellular mistakes. In this light defense responds to invaders and custodial responds to survalence.

Aren't custodial and defensive related terms? In addition to the custodial and/or defensive function the immune system have an in important role in homeostasis controlling/eliminating cells and nurturing others. This is not always good. For example, macrophages have an important role providing growth factors and other stimuli that promote tumor progression.

This is a very interesting question. I think it may be necessary to begin thinking about the “immune system” as not necessarily a separate system but more of an intricate part of the host. I once heard a statement, “and of course here is the node around which the breast tissue develops”, that made me wonder if there is a role for the “immune system” in the development of tissues and organs. Is there “talk” between the developing tissue and the “immune” cells in order to orchestrate and support an “orderly” development of the tissue? Once the tissue is fully developed, do the “immune” cells commence a role of surveilling the now developed organ, i.e. helping the host keep homeostasis of the organ? If this is the case then any changes in the status of the organ, regardless of whether the change is caused by a pathogen, a mutation, or any other change leading to the unhealth of the organ, could trigger the “immune” cells to take on a role of defense. Perhaps depending on what type of change has happened different arms of the “immune system” will be more or less activated.

If the “immune system” is a host defense system, why does it sometimes turn on the host to cause autoimmunity? Can such a turn on the host be caused by environmental factors altering how the Tissues/organs appear to the “immune’ cells?

That's interesting. Read. Ponder. I'd like to hear a definition of "immunity." There are various definitions.

Dear Michael,

This is such a refreshing question when we or at least I am, are so caught up with ever developing new technologies for the study of immune system only fixated with idea of "Defense". Thank you very much for this thought-provoking question and all others' helpful references.

Wonderful references for the Thanksgiving Holiday readings!

Happy Thanksgiving!

I would like to read about immunity and not personal correspondence.

I would say absolutely yes. Take for example the changes that occur to a womans immune system during pregnancy. During normal healthy pregnancies the "cytotoxic adapative immune system dependant on the classical recogintion of foreign antigen by APC's presenting to T cells and leading to B cell activation and antibody production is significanlty dampened. Instead increasing evidence suggests that the innate system becomes dominant and the maternal immune cells particulalry in the uterus transform into a tolerant and supportive angiogenic phenotype to support placental and fetal growth. Angiogenic immune cells are also associated with tumor metastasis . If you are interested look into classical and nonclassical macrophage activation M1 and M2.

The immune system is a "custodial" system, as well as a "defense" system.

A number of researchers do not consider the non-specific resistance of the body (when no antigen, which leads to the activation of humoral and cellular responses -Immunity (RV Petrov, RM Khaitov, Russia). Immunity - is a specific response to a specific antigen. In English literature unspecific resistance is called innate immunity.

I think that the unspecific resistance and adaptive immunity (activation of T-cell immunity and antibody synthesis of plasma cells) - a broad term - IMMUNITY!

Function of NK - cells - is immunity? Written both in Russia and in other countries - and non-specific resistance of the organism, and "immunity" (the immune response).

Is there a concept - "the immune homeostasis." I believe that yes, there is!

The immune system, as well as on other systems this concept is spreading.

The immune system so called is best thought of overall as a system to maintain system integrity.

System integrity refers to the organisms attempts to prevent depredation and disorganisation - it is the fight against entropy.

I like the metaphor of “integrity”. I have well formed views on this subject (easily found). What follows should be viewed as opinion.

The “integrity process” can respond to a whole range of disruptive biotic and abiotic influences or agents. These pathogenic influences can be grouped under the term “pathogens”. “Pathogen” is a generic term and its common – specific – restriction to mean only a pathogenic organism is just a lazy abbreviation. Integrity resolves crises and then restores order. “Order” itself is a helpful metaphor and this is most pertinent when applied to an animal or plant’s interaction with micro-organisms. I will restrict my comments here to bacteria. Most of these are identifiable by their Microbe Associated Molecular Patterns (MAMPs rather than PAMPs: if I had my way, I would permanently retire the PathogenAMPs acronym). Only a tiny fraction of the extant microbial species act in a primarily pathogenic way. However, a very large proportion of microbial species fulfil the important task of degrading the dead and dying tissues of plants, animals and other organisms. In this way these corpses are recycled. All but the pathogenic organisms are courteous and usually wait their turn until the animal or plant dies or become so sick that it is no longer capable of stemming the tide of entropy. Pathogenic bacteria, however, adopt the strategy of, somehow, damaging healthy host cells to provide themselves (discourteously) with a premature meal. They use a variety of means to do this; the direct injection of toxins; inhibiting the clearance of dying cells; encouraging the host to overreact and so damage its own cells; these are but a few.

Non-pathogenic bacteria do not pose the “integrity process” with much of a challenge. They are disposed of easily when they mix with living flesh. And, in animals, they are easily disposed of with little or no inflammation and do not need to provoke strong adaptive immune responses. Indeed, this would be metabolically wasteful. The simplistic idea that MAMPs (PAMPS if you really must) provoke strong aggressive adaptive immune responses is almost certainly a nonsense. The body’s response to the gut microbiome is a good and emerging example of this. We would simply autodestruct our intestines. So that leaves us with little choice but to accept that some second condition is necessary to augment an aggressive response to the MAMP signal.

So, I suspect, we will begin to realise that it is damage - particularly catastrophic self cell demise - that is the necessary accompaniment to MAMPs that helps trigger strong-adaptive-immune responses to bacteria. And that leads back to a major function of the phagocytic cell system; these cells clear away the corpses of dying self cells. The system prefers self cells that melt away in a pattern of controlled cell shutdown (apoptosis) and subsequent quiet disposal. This disposal of old self cells is the phagocyte population’s number one task – it overshadows any other assumed function by a great margin. And, of course, this leads us back to “integrity” and “order”.

In this view, strong adaptive immune responses to bacteria are the consequence of them being processed in the vicinity of self cell damage (some degree of uncontrolled shutdown). It is likely that all adaptive immune responses (aggressive or suppressive) evolved to remember pathogenic encounters and then caricaturise and amplify secondary inflammatory responses on any re-encounter. Inflammation thus finds itself armed with a memory – a point that has been very poorly emphasised.

Again, in this view, any memory provoked “attack” on bacteria is an emergent property of a drive to integrity. But, the way that the discipline of immunology had “grown up” has meant that we have assumed that “bug hunting and killing” are primary purposes. This has biased our questions, our observations and our interpretations so much that we have ignored alternatives. I think that a drive to integrity is the major “purpose” for the system and lymphocyte led attacks on bacteria are, basically, a snapshot of a previous inflammatory encounter (and that encounter is typified by a battery of representative antigens – both self and non-self). So, if your primary purpose is to damage cells to provide yourself with a meal, you will run the risk of getting noticed among the debris.

I have had a request to provide a copy of my paper. All are either free access (Scand J Immunol) or available through my morphostasis site.

All organisms, from the most primitive forms to mammalians, permanently meet multiple pathogenic viruses and bacteria, and effectively resist to infection in spite of lacking of adaptive immune system (AdIS) in the most multicellulars. Nevertheless, the adaptive immune system, which is represented by T- and B- lymphocytes and products of their secretion, began to originate in relatively late stages of evolution, no earlier than cartilage fishes appeared. To be more precise, it happened only after the general number and variety of cells in the vertebrates’ specialized organs and tissues reached a certain level which created a need for additional mechanisms to coordinate their functional activity. Therefore, it is doubtful whether antimicrobial activity is the main function of AdIS. It is rather the innate immune system (InIS), which appeared much earlier phylogenetically and is still present in superior vertebrates, is the main antimicrobial defender. While the key mission of the relatively young AdIS is the self-identification and mutually coordinated adjustment of multiple cellular, sub- and epicellular organism components, as well as continuous molecular screening, and providing molecular and cellular homeostasis as necessary condition for normal functioning of the organism throughout whole individual’s life. AdIS also can participate in extermination of potentially dangerous microorganisms, however, this form of activity seems to be accessorial and is not determined by the “foreignness of microbes” as such, but depends straightly on the extent of microbial danger to homeostasis. It should be noted that homeostatically neutral microorganisms, inhabited the host, are ignored by the immune system, and the potentially useful ones are even guarded.

It has been known since Norbert Wiener’s times that a regulatory block can control the functioning of a complicated system only when provided with an internal “image” (model) of the whole system and when using multiple feedbacks. Consequently, as one of the main participants of bodily functions control and regulation system, (neuroimmunoendocrine regulatory metasystem), AdIS needs both a model of the regulated object (“image” of the organism) and multiple feedbacks. In other words, to provide self-recognition and self-preservation, AdIS requires special instruments for the identification of the organism’s native structures.

The key instruments for immune self-recognition is an autoreactive system based on a complicated net of natural autoantibodies (auto-Abs) known as “Immunculus” or self-reactive entity. The idea of Immunculus as an image of the organism molecular-and-functional state was laid by hypothesis of Immunologic homunculus by Irun Cohen. The totality of auto-Abs with different antigenic specificities could be considered as a sui generis mosaic picture formed up by a great number of “bits of smalt” (auto-Abs with peculiar specificity). Quantitative change in each “bit of smalt” depends directly from changes in expression and secretion of according antigen. Therefore the immune system can “use” this image for permanent screening the current antigenic situation in different compartments of the body, and for comparison between now presented state and the desired one. Prolonged deviations from the optimal state are the trigger for induction of compensatory and reparative processes of different kind aimed to restore homeostasis. Thereby Immunculus may be considered not only as passive “mirror” of the organism’s state but rather as a component of active gyroscope-like device for maintenance of antigenic and metabolic homeostasis.

The self-recognition phenomenon is based on a system of natural auto-Abs that are complementary to the totality of antigens of the organism. Antigen-specific autoreactive T- and B- lymphocytes also contribute to this phenomenon. Both molecular and cellular elements are permanently present in any healthy organism throughout his whole life.

The desired (non-destructive) level of physiologic autoreactivity is provided by the system of “internal security”. This system eliminates lymphocytes which express highly affine anti-self receptors (negative selection), as well as lymphocytes which do not express anti-self receptors, or if receptors characterized by too low affinity to self-antigens (positive selection). As a result, any initial T- or B- lymphocytes that have successfully passed the selection are moderately autoreactive by definition, however, their autoreactivity does not reach the threshold of autodestructiveness. It is beyond doubt that this evolutionally determined mechanism is biologically reasonable.

The clonal selection theory by Burnet was an enormous contribution and shed light upon the misty terra incognita which immunology was nearly half a century ago. From the positions of the clonal selection theory, the immune system was referred to as “system” only nominally, while in fact it was considered as a sum of almost independent lymphocyte clones. Each of clones was believed to react exclusively with “Aliens”, and be designed for carrying out two effector functions: 1) the recognition of complementary antigens and 2) to eliminate any recognized ones. While the appearance of autoreactive lymphocytes (“prohibited” clones) that recognize self-antigens was regarded as a random abnormal deviation, the idea of physiological or natural autoimmunity simply couldn’t emerge: any forms of autoimmunity were considered to be pathological. Previously non-numerous indications of the presence of auto-Abs in healthy individuals were mainly ignored so as contradicting to the theory.

The “Danger hypothesis” by Polly Matzinger better corresponds to experimental data and ideas about AdIS regulatory and homeostatic function and does not exclude natural auto-immunity. According to Matzinger, AdIS itself cannot “decide” when and in what way to act, but is activated on tissue request. Any local organ or tissue can generate AdIS-activating signals as a sign of their need for additional immunologic support, e.g. for intensifying the elimination of damaged cells, for activating regeneration, etc. In other words, in the absence of molecular signals or requests from a certain tissue or organ, the immune system remains in the “standby mode”. Thereby, it is not the emergence of some foreign molecular stimulus that is important for inducing the AdIS response, but the information about the hazard to homeostasis, accompanied with tissue damage and increased release of corresponding molecular signals into intracellular space. In case the immune system begins to act autonomously, beyond tissue “requests”, e.g. under the influence of lymphotropic viruses or toxins), this probably may be a cause of autoimmune disorders or other immunopathologic conditions. Matzinger does not shut her eyes to natural autoimmunity related to tissue damage of any origin, and considers this phe-nomenon as a universal indication of any tissue damage however and unfortunately, making no attempt to explain its meaning.

According to the ‘network theory’ by Niels Jerne, a healthy individual initially has a well-balanced self-reactive and self-reflective (self-recognizing) idiotype-antiidiotypic network presented by molecular (antibodies) and cellular (lymphocytes) components of AdIS. Excessive antigenic stimuli may induce imbalances of this initially balanced network. It does not mat-ter whether the antigenic stimuli are endogenous or exogenous in origin; it is only important that they be complementary to the components of the global network. Network imbalance is equivalent to system activation. This state is unstable and, over a period of time, is replaced with the previous stable state or the transition to a new one. It is important that, unlike other immunologic concepts, Erne’s network theory does not operate with the “Self – Non Self” or “Hazard – Non-Hazard” categories. In other words the Immune Network is not engaged in any discrimination. Activity of the Network is based upon STATES (Disturbance – Resting).

Clinical immunology within the last twenty years has been characterized by the emerging of paradoxes contradictive to adopted positions, and the puzzle of natural auto-Abs is a fitting example. Previously auto-Abs were associated exceptionally with the pathogenesis of auto-immune diseases. However, as it is known since the 1980s auto-Abs are produced permanently in any healthy organism. And it is not the presence of auto-Abs as such that are associated with the pathologic processes, but the anomalies in their production and serum concentration. Today it has become commonplace to refer to the pathologic increase in the levels of auto-Abs as to a hallmark of a number of non-autoimmune diseases and conditions, including strokes, cancer, myocardial infarction, or complications of pregnancy.

It has been experimentally proved that molecular danger signals from any damaged tissue induce transitory autoimmune reactions which are accompanied by an increase in the serum concentrations of respectively tissue-specific auto-Abs. And we find strong reasons to re-consider the role and importance of injury-associated autoimmune reactions from a physiological point of view, and moreover, from needs of medical practice.

It is known that original clones of lymphocytes are initially moderately autoreactive due to the combined negative-&-positive selection process they pass during maturation. Thus, the continuous production of a certain amount of auto-Abs with various specificity, is an innate feature of the immune system. Empirical observation proves that the damage (of mechanical, chemical, infectious or any different nature) of specialized cells, expressing certain antigen settings, acts as a trigger for increasing the production of auto-Abs to corresponding antigens. So, should inborn AdIS autoreactivity be considered as a potentially hazardous fortuity? Could an increase in the production of autoAbs of certain specificity, induced in response to tissue damage, be functionally senseless? From an evolutionary point of view this appears more than doubtful. That brings up a question about the physiological predestination of auto-Abs and the role of secondary increase in their production in case of tissue damage.

Multitude of natural auto-Abs of IgG and IgM classes against very different self-antigens has been permanently synthesized, secreted, and presented in the blood serum of any healthy person. Even “exclusively pathological” (as it was accepted earlier) auto-Abs, such as antibodies against myeloperoxidase, proteinase 3, and the glomerular basement membrane are present in normal individuals, as well as antibodies reactive with autologous ABO blood group antigens. I would like to highlight some empirical data: over the last 30 years together with my colleagues I have studied above 500 antigens belonging to various organs and tissues, and among them, there was not a single antigen that would not serve as a target antigen for specific IgG autoAbs, present in the bloodstream of healthy individuals. Thus, it is more likely that all self-antigens are objects for the activity of natural auto-Abs.

Serum concentrations of auto-Abs with different specificity may vary dramatically. However, concentrations of auto-Abs with the same specificity is roughly equal in each healthy individual (having no tissue or organ damage to express corresponding antigens), and in contrast, notable deviations in serum content of particular auto-Abs accompany the plurality of diseases. Probably, a secondary rise (induced by “dander signals”) in the production and secretion of auto-Abs against antigens of damaged cells, is not a side-effect, but a reflection of one of the major functions of AdIS, i.e. the activity of autoclearance. Obviously, the importance of autoclearance for homeostasis increases dramatically in case of initial damage of any tissue, which determines an evolutionally fixed phenomenon of a secondary increase in the production of auto-Abs against antigens of damaged tissue.

A variety of disorders (mostly chronic ones) is directly associated either with the activation of cell necrosis or apoptosis or with deviations in the production and/or excretion of certain antigens. A stable increase in the extracellular concentration of any endogenous antigen is inevitably accompanied by quantitative deviations in the synthesis of auto-Abs of respective specificity.

General logic of the living systems indicate: quantitative changes in different physiologic parameters usually aimed to correct, compensate or prepare to abnormal situation. For example tremendous physical efforts will accompany by elevation of blood pressure, tachycardia, rise of blood glucose level, etc., untypical for the rest state. Such reactions provide additional resources for fight or escape are physiological and justified evolutionally. Principally the same (secondary, sanogenic) physiological activation of autoimmune reactions may be seen, for ex-ample, in patients suffered by ischemic stroke: prominent but temporal elevation of different “neurotropic” auto-Abs of IgG class in blood serum, if observed soon after stroke and saved during few weeks, is favorable prognostic sign. In opposite – absence of stroke-induced secondary autoimmune reaction – that is preservation of normal or low levels of “neurotropic” auto-Abs during the first days and weeks after stroke is bad prognostic sign, which is typical for patients which will died later, or if alive, be characterized by prominent motor and/or cognitive deterioration.

Unlike the formerly shared ideas about the immanent autoagressiveness of any forms of autoimmunity (“horror autotoxicus”), today it is known that secondary increase in the production of natural auto-Abs, following tissue damage, in most cases is not related to the auto-destructive activity of the immune system. Thereupon E.Metchnikoff, P.Matzinger, O.Parnes we should to admit: the global function of the adoptive immune system is the maintenance and regulation of an optimal molecular homeostasis of the body (including struggle against hazard microbes in necessity).

Lots of words, but it is a lost cause. There are no autoantibodies forming an immunculus and cannot be, taking into consideration the evolutionary “purpose” or “sense” of the AdIS. Which, IMHO, is still to differentiate between self and non-self, and neutralize the non-self without (much) harming the self.

>>>"The self-recognition phenomenon is based on a system of natural auto-Abs that are complementary to the totality of antigens of the organism."

This is purely illogical and would be eliminated by natural selection if ever occurred! The intrinsic feature of all antibodies (immunoglobulins) is to bind the epitope against which they were manufactured in the B/plasma cells, with higher or lower affinity and avidity. Each and every antibody made in an organism by AdIS is binding to its ‘designated’ epitope (usually non-self, but sometimes self; see below). Thus, “natural auto-Abs that are complementary to the totality of antigens of the organism” would BIND to the totality of bodily antigens, effectively preventing bound proteins from functioning properly. Autoantibodies which appear and DO NOT cause pathological destruction of targeted tissue (the autoimmune disease), albeit not rare, are appearing transiently, have low affinity, and associated harm is subclinical.

>>> "However, as it is known since the 1980s auto-Abs are produced permanently in any healthy organism."

Not permanently, but transiently, against specific autoantigens only and under specific conditions. The knowledge of their appearance (and potential significance) had vastly grown since the 80s. See below.

>>> "Today it has become commonplace to refer to the pathologic increase in the levels of auto-Abs as to a hallmark of a number of non-autoimmune diseases and conditions, including strokes, cancer, myocardial infarction, or complications of pregnancy."

Yes, also in chronic infections, and in healthy elderly. However, as it was demonstrated by people studying the problem, these increases in autoantibodies are transient and of no consequence – do not result directly in pathological symptoms; also, these “auto”antibodies frequently are quite normal antibodies appearing in response to real antigenic stimulation and reacting with autoantigens by token of molecular mimicry; this is true if the process relates to prior infection. If it relates to cancer – cancers are notorious to activate genes that were last in use early in embryonic growth – their products are unknown to the AdIS (could not be tolerized by clonal selection and related mechanisms) and yet frequently similar to antigens present in an adult (especially hybrid genes leading to production of hybrid proteins). Also stroke or MI leading to tissue necrotization (in fact ANY process that leads to it) release some potential NEW antigens (e.g heart- or neuron-derived proteins that were strangely cleaved by proteases during ischemia-dependent tissue lysis). Finally pregnancy consists of half of foreign (father's) antigens, so the AdIS is physiologically suppressed during it. If not, pregnancy (even occurring of it) is in danger. Summarizing, these “non-autoimmune” diseases have clearly immune components.

>>> "It has been experimentally proved that molecular danger signals from any damaged tissue induce transitory autoimmune reactions which are accompanied by an increase in the serum concentrations of respectively tissue-specific auto-Abs."

Well, it cannot happen, unless there are the ‘forbidden clones’ of T lymphocytes present, i. e. not eliminated during intrathymic education towards precise distinction between self (autoantigens) and nonself (alloantigens, potentially pathogenic/harmful) OR the autoantigen was NOT EXISTENT at the time of intrathymic tolerization. The tolerogenic processes leading to clonal selection are well known. The only situations, where tissue damage leads to actual appearance of autoantibodies in an individual in whom clonal selection had occurred properly, are those when actual antigen only appeared in the organism AFTER the clonal selection process had been completed or, the region of the body where potential; autoantigen couyld exist, was from the very beginning of development isolated (sequestered) from any contact with the cells and products of the immune system. Clinical situations: A. mumps (common viral parotiditis); the virus infects male testes and breaks the sequestration barrier – in a prepubertal boy it does not do much harm, as the antigens of immature spermatogonia present in immature testes were there early enough to be tolerized during the clonal selection and anergy induction. If an adult man catches mumps, the virus breaking the sequestration barrier allows for release of sperm and related antigens, which were unknown to the developing AdIS – and they are reacted to as foreign, sometimes leading to cytotoxic damage to the testes, oligo- azoospermia and infertility.; B. perforating damage to an adult eye, releasing sequestered antigens unknown to the AdIS (e.g. arrestins)– the eye develops in the embryo and its interior is sequestered prior to the full development of the AdIS. Released Ags stimulate the response (are “foreign”, nontolerized) and the antibodies may damage both the injured eye and the other one (so called “sympathetic” inflammation of the uvea).; C, damage (mechanical or viral) to the thyroid, releasing the contents of thyroid vesicles (the ‘colloid”, containing thyroglobulin and other proteins) into the blood stream. The interior of the vesicles is originally sequestered early in the development, so thyroglobulin epitopes are unknown to the AdIS. If and when they become known, they are reacted to, binding autoantibodies appear, and damage to the thyroid occurs.

Summarizing, the above described appearance of autoantibodies as consequence of tissue damage is not and cannot be generalized.

Dear Dr. Witkowski,

Thanks a lot for your comments. I should to note: your ideas are common for bacteriologists and persons involving in study of autoimmune diseases - that is non related directly to the problems of immunophysiology. None the less I’d read it with great pleasure because, as it seems, you know all about everything (in opposite to Socrates). Without doubtful you know also idiomatic expression: “predestination of the Science is not worshipping to The Sacred Dogmas, but permanent doubts and asking for inappropriate and harsh questions”. Let us try to touch some of questions of such kind.

1) Is the Immune System (ISYS) one of common physiologic system of the body? Or in other words: is own organism the main “object of interest” of ISYS? Or something else (i.e. microbes)? Is the main vector of ISYS activity directed inward or outward?

2) Why ISYS does ignore biologically neutral microorganisms (present in the host-organism), the potentially useful ones are even guarded, and only hazardous microbes are the object for the immune attack [Dembic, Scand J Immunol 2004; 60: 3]? Is noted phenomena indicate that antimicrobial activity of ISYS is not related directly to “Non-selfness” of microbes (any of them are aliens), but depends upon the ratio of potential “hazard” and “utility” of the lasts?

3) If its activity of is mostly related to the internal needs of organism (similar to cardiovascular, or endocrine, or nervous system, etc.) which molecular instruments can be used by ISYS for homeostatic needs? Is there something beyond natural autoantibodies and cytokines for realization of inward directed ISYS activity?

4) If autoantibodies are synthesized by ISYS during all lifespan of any healthy person should these molecules be considered as pathogenic factors only? Thyrotoxicosis is not too rare event, none the less nobody talk about thyroid hormones as pathogenic factors.

NB: take in mind please also the next items:

• Any autoantibodies are synthesized by any healthy persons from intrauterine period to death not transiently in some peculiar conditions, but permanently (see for example bright review by Lacroix-Desmazes a.o., J Immunol Methods 1998;216:117). Besides, affinity of natural autoantibodies may be quite high (up to 10-11 M - Bendtzen a.o., Immunol Today 1990;11:167).

• In accordance with some estimates, 20 to 30% of all lymphocyte clones in healthy persons produce 20 to 30 thousands natural autoantibodies molecules per minute (few grams of different natural autoantibodies daily) during the entire life-span [Kulberg AY, Molecular Immunology. Moscow: Meditsina, 1986]. Should this phenomenon be considered as potentially hazardous wastefulness of the body?

• Some notes about inconsistency Burnet’ idea of ‘forbidden clones’ to reality you can see review by M.E. Gershvin and me (J. Autoimmunity, 2008, 30: 68).

• Rise of production of autoantibodies as consequence of any tissue damage is generalized phenomenon (see Matzinger Science 2002; 296: 301).

• Natural autoantibodies provide more effective macrophage-dependent consumption of garbage of degrading cells and augmentation of clearance of affected organ. The autoclearance is seemingly the most ancient (archetypic) function of the immune system, and a lot of immune functions derived from auto-clearance, including antimicrobial defense [Grabar P. About Autoantibodies. In: Ado AD, Ed. Problems of Reactivity in Pathology. Moscow, Meditsina, 1968, 35; Kovaliov IE, Polevaya OYu. Biochemical grounds of immunity against low-molecular chemical compounds. Nauka Publishers, Moscow, 1985].

• Maternal changes in thegeneral immunity state (during pregnancy) are significant, but can not be equalized with immune suppression [Entrican J. Comp. Pathol., 2002, 126:79]. Immune suppression at pregnancy is pathology [Howes M. (2007). Maternal agency and the immunological paradox of pregnancy. In: H. Kincaid and J. McKitrick (eds.) Establishing Medical Reality, 179–198, Springer].

I will be glad to continue our scientific discussion. Especially if you will use not only emotionally tinged arguments (“it can not be because it cannot be never!” - Anton Chekhov). If you will prove your personal opinion by references (special publications by other authors) it be especially interesting.

Thank you other time, A.B.Poletaev

This is a very interesting comment.

Dear Dr. Poletaev,

Socrates I admittedly am not, so I cannot frankly say after him “I know one thing, and that is that I know nothing”. On the other hand, I most certainly do not know “all about everything” as you aptly put it. I know very well the limitations of my knowledge (whether perused while doing scientific projects or while teaching general pathology, basic and clinical immunology, cell biology, biogerontology and basic evolutionism to medical students), and am more then opened to new ideas, as long as they are substantiated by knowledge and scientific facts already accrued. I do not contest the existence of autoantibodies without the symptoms of an autoimmune disease. In fact, I do frequently observe their transient (!) appearance in clinically healthy elderly (albeit never in healthy young adults or children.

Now, to answer your questions:

1) Is the Immune System (ISYS) one of common physiologic system of the body? Or in other words: is own organism the main “object of interest” of ISYS? Or something else (i.e. microbes)? Is the main vector of ISYS activity directed inward or outward?

The primary evolutionary ‘purpose’ of the ISYS is protection against pathogens, both external (bacteria, viruses etc.) and internal (products of changed – mutated – genes, as well as adversely modified cells (senescent, neoplastic). So the answer to your question is “BOTH”. From the evolutionary point of view, existence of any biological feature, be it biochemical reaction, an organ or whole system like the ISYS, is only useful (and therefore maintained by the mechanisms of natural selection) if promoting the survival of organism and propagation of own genotype by proliferation. Both inward and outward functions of the ISYS as defined above are pro-survival. The autoantibodies can only be pro-survival if performing a service to the organism prevailing over their intrinsically detrimental (potentially) properties. Effective (i.e., binding antigen(s) with some level of affinity) autoantibodies, if present at concentrations which, if bound to an autoantigen, would block it or otherwise incapacitate its function – leading to symptomatic autoimmune disease - are anti-survival. Their potential or factual regulatory functions (e.g. within anti-idiotypic network or via binding of their Fc fragments by appropriate FcRs) can only prevail over harmful effects if they are present at low quantities and only temporarily (to prevent cumulative effects of their activity against specific autoantigenic targets. Let me quote something you would most certainly recognize: “Lymphocytes are eliminated during selection and maturation in the thymus if their affinity for SELF is either too high or too low [6]. Hence, any lymphocytes present in a body are anti-SELF by definition, and do not recognize anything really foreign, principally different from any components of SELF.” Well, either it is a semantic play, or a gross misunderstanding. What good (from the evolutionary point of view) would perspire from any/all lymphocytes of the body being essentially anti-self?!

2) Why ISYS does ignore biologically neutral microorganisms (present in the host-organism), the potentially useful ones are even guarded, and only hazardous microbes are the object for the immune attack [Dembic, Scand J Immunol 2004; 60: 3]? Is noted phenomena indicate that antimicrobial activity of ISYS is not related directly to “Non-selfness” of microbes (any of them are aliens), but depends upon the ratio of potential “hazard” and “utility” of the lasts?

There are NO ‘biologically neutral microorganisms’ in our body, and none of the bacterial pathogens present e.g. in the gut (or the GI in general), epidermis, mouth, upper respiratory or uro-genital systems is ignored by the ISYS, as long as it has a chance to see and recognize it via its dedicated receptors. Mind that each and any of these spaces is topologically outside of the organism. As soon as any of your “biologically neutral microorganisms” happen to cross (or break) the natural barriers and enter the ‘inside’ of the organism, it becomes the target for ISYS, whether potentially useful or not. Consider an average kilogram of gut microorganisms (microbiota) consisting of hundreds of already identified and potentially many more unidentified species. It does not harm us, as long as two conditions are met: 1, the physiological barrier of gut epithelia and mucosa is unbroken and not leaky, and 2, the immune subsystem of the gut (gut-associated lymphatic tissue GALT, the antigen presenting M cells in the epithelia, and the local macrophages) are working properly and hard to keep the pathogens at bay (i.e. in the gut lumen, where their products and enzymatic activities are of use). If any of these two conditions fail (e.g. some process makes the mucosa leaky allowing for penetration of the gut microbiota inside it, and further into other tissues, but first of all allowing its contact with both innate and adative immune cells), the immune reaction of either kind always occurs. Ultimate form of this reaction is generalized inflammation culminating in sepsis. Same if the GALT system is compromised. The ISYS has no means to KNOW potentially hazardous molecules from potentially benign and useful ones ( the ISYS does not recognize and deal with cells, bacterial or otherwise, it deals with molecules. It can only recognize and react to those molecules, which fit the sequence/structure patterns defined by selection of allowed T- and B-cell receptors. In this sense, there are NO ‘natural autoantibodies’ that you invoke in your papers: production of both auto- and alloantibodies is only possible if a B cell equipped in a BCR specific for the epitopic fragment of the particular auto- or alloantigen is triggered by this specific antigen; only then any level of affinity between the antibody and antigen is possible – otherwise any antibody would bind any antigen. So, ‘natural’ autoantibodies’ production must have been triggered by the cognate, i.e. BCR-recognized, epitope.

3) If its activity of is mostly related to the internal needs of organism (similar to cardiovascular, or endocrine, or nervous system, etc.) which molecular instruments can be used by ISYS for homeostatic needs? Is there something beyond natural autoantibodies and cytokines for realization of inward directed ISYS activity?

The homeostatic role of the ISYS is to maintain the topological interior of the organism pathogen-free. For this sole purpose it utilizes all and every means evolution had built into it.

4) If autoantibodies are synthesized by ISYS during all lifespan of any healthy person should these molecules be considered as pathogenic factors only? Thyrotoxicosis is not too rare event, none the less nobody talk about thyroid hormones as pathogenic factors.

The latter is a flawed argument. Thyroid hormones are not pathogens as such, neither is insulin or glucose in that matter. What counts is the deviation from the homeodynamic ‘norm’; too much thyroid hormones is pathogenic and leads to thyreotoxicosis, too much insulin (or too little glucose) is conductive to hypoglycaemic shock, too much glucose is the basic cause for diabetic damage to the tissues. Not the presence of a biologically effective molecule counts for its proper physiological or improper pathological effects, but its concentration (basic homeodynamics). Concerning autoantibodies: at low concentrations, especially occurring transiently as is mostly the case, they would rather not do much harm in a form of autoimmune damage to the target tissues; at these concentrations, their regulatory effects (Fc, anti-idiotypic et caetera) may show and prevail. The change of role would be quantitative in nature, not qualitative.

• Any autoantibodies are synthesized by any healthy persons from intrauterine period to death not transiently in some peculiar conditions, but permanently (see for example bright review by Lacroix-Desmazes a.o., J Immunol Methods 1998;216:117).

Well yes, this early paper by Lacroix-Desmazes is relatively convincing and defending the non-pathogenic role of autoantibodies. However, if you would read newer papers by the same author (Dimitrov JD, Lacroix-Desmazes S, Kaveri SV, Vassilev TL. Insight into the mechanism of the acquired antibody auto-reactivity. Autoimmun Rev. 2008 Jun;7(6):410-4. Epub 2008 Apr 18. Review. PubMed PMID: 18558353.; Dimitrov JD, Lacroix-Desmazes S, Kaveri SV, Vassilev TL. Transition towards antigen-binding promiscuity of a monospecific antibody. Mol Immunol. 2007

Mar;44(8):1854-63. Epub 2006 Nov 9. PubMed PMID: 17097144.) you would find that their ‘natural autoantibodies’ dwindle to nothing more than antibodies to MODIFIED autoantigens. Thus, the ISYS is in fact recognizing and trying to neutralize – with the autoantibodies - the antigen that is foreign to it (was not there when self-tolerance developed). Neither of the Lacroix-Desmazes’ papers proofs that the autoantibodies made in an infant are the same after that infant becomes an adult (no longitudinal observations!).

• In accordance with some estimates, 20 to 30% of all lymphocyte clones in healthy persons produce 20 to 30 thousands natural autoantibodies molecules per minute (few grams of different natural autoantibodies daily) during the entire life-span [Kulberg AY, Molecular Immunology. Moscow: Meditsina, 1986]. Should this phenomenon be considered as potentially hazardous wastefulness of the body?

Could not access this paper by Kulberg (not in the PUBMED; would you be so kind to provide?). Other papers by this author (including the latest one published in 1999) are inconvincing in the light of modern (13 years older) knowledge of the functioning of the ISYS, antibodies etc.

• Rise of production of autoantibodies as consequence of any tissue damage is generalized phenomenon (see Matzinger Science 2002; 296: 301).

Precisely! Damaged tissue is a source of new antigens; proteins are hydrolysed, oxidated, glycated… And the ISYS is responding to perceived “foreign”.

• Natural autoantibodies provide more effective macrophage-dependent consumption of garbage of degrading cells and augmentation of clearance of affected organ. The autoclearance is seemingly the most ancient (archetypic) function of the immune system, and a lot of immune functions derived from auto-clearance, including antimicrobial defense [Grabar P. About Autoantibodies. In: Ado AD, Ed. Problems of Reactivity in Pathology. Moscow, Meditsina, 1968, 35; Kovaliov IE, Polevaya OYu. Biochemical grounds of immunity against low-molecular chemical compounds. Nauka Publishers, Moscow, 1985].

Possibly important, but inaccessible via PUBMED or other easy means and thus impossible to comment about. Still, papers published locally more than 40 years ago are quite possibly outdated and made obsolete by more modern discoveries.

• Maternal changes in the general immunity state (during pregnancy) are significant, but can not be equalized with immune suppression [Entrican J. Comp. Pathol., 2002, 126:79]. Immune suppression at pregnancy is pathology [Howes M. (2007). Maternal agency and the immunological paradox of pregnancy. In: H. Kincaid and J. McKitrick (eds.) Establishing Medical Reality, 179–198, Springer].

Sure! Pregnancy does not result in a common immune suppression, otherwise all pregnant women would be permanently ill due to infections by opportunistic pathogens. Yet, a level of suppression is necessary and related to the action of pregnancy-sustaining steroid hormones. In fact, this hormone-dependent immunosuppression can be seen also in the second stage of the menstrual cycle, when the levels of progesterone etc are much lower than during pregnancy (Trzonkowski P, Myśliwska J, Tukaszuk K, Szmit E, Bryl E, Myśliwski A. Luteal phase of the menstrual cycle in young healthy women is associated with decline in interleukin 2 levels. Horm Metab Res. 2001 Jun;33(6):348-53. PubMed PMID:11456283.).

As you see, I do use the citations of relevant papers when deemed necessary for our discussion. Remember, it is a free platform, where not only rigorously cited literature, but also own thoughts count and can be presented, with an emotional tinge or not, and patronizing is out of place here. Summarizing, IMHO there is no Immunculus other than your Institute name. The bulk of your related papers forms an interesting, but so far unsubstantiated hypothesis.

Dear Dr. Witkowski,

As it seems to me ours positions begin to draw a bit closer.

And now some my comments to your comments:

1) Is own organism the main “object of interest” of ISYS? Or something else (i.e. microbes)? Is the main vector of ISYS activity directed inward or outward?

(Witkowski): “The primary evolutionary ‘purpose’ of the ISYS is protection against pathogens, both external (bacteria, viruses etc.) and internal”

(Poletaev): What do you think about more universal and a little bit not so aggressive definition? Something like: “The primary evolutionary ‘purpose’ of the ISYS is maintenance of homeostasis of the organism” – this nuance may be important methodologically. Not WAR, but PEACE in organism is the biological predestination of the ISYS (the ISYS is rather housekeeper, not policeman).

(Witkowski): The autoantibodies can only be pro-survival if performing a service to the organism prevailing over their intrinsically detrimental (potentially) properties. Effective (i.e., binding antigen(s)) autoantibodies, if present … would block it or otherwise incapacitate its function – are anti-survival.

(Poletaev): Do not forget: interaction with specific antigen in vivo as well in vitro can not only block, but also activate, or modify its function – the effect depends from peculiar epitope specificity and some additional conditions (Zaichik, Churilov, Pathophysiology. vol. II. Pathochemistry., 3rd edition, ElBi Publ., St.Petersburg, 2007); moreover binding of antigen, especially labile peptides may be important with point of view prolongation and enhancement biologic activity of the last (Wang a.o., Mol Immunol 1992;29:313); specific ligand-like activity of receptor-interacting Abs also well known (Zaitchik a.o., Pathophysiology 2008; 15: 191); lot of other biologically important forms of Abs activity in vivo were described (Rüiz-Argüelles, Alarcon-Segovia, IMAJ, 2001; 3: 12). So your opinion: Autoantibodies = Harm for body is not quite correct.

2) Why ISYS does ignore biologically neutral microorganisms (present in the host-organism), the potentially useful ones are even guarded, and only hazardous microbes are the object for the immune attack [Dembic, Scand J Immunol 2004; 60: 3]? Is noted phenomena indicate that antimicrobial activity of ISYS is not related directly to “Non-selfness” of microbes (any of them are aliens), but depends upon the ratio of potential “hazard” and “utility” of the lasts?

(Witkowski): There are NO ‘biologically neutral microorganisms’ in our body, and none of the bacterial pathogens present e.g. in the gut (or the GI in general), epidermis, mouth, upper respiratory or uro-genital systems is ignored by the ISYS, as long as it has a chance to see and recognize it. Mind that each and any of these spaces is topologically outside of the organism. As soon as any of your “biologically neutral microorganisms” happen to cross (or break) the natural barriers and enter the ‘inside’ of the organism, it becomes the target for ISYS, whether potentially useful or not. Same if the GALT system is compromised. The ISYS has no means to KNOW potentially hazardous molecules from potentially benign and useful ones.

(Poletaev): Do not forget: we discuss there not complicated interrelations between the body and its micro-inhabiting. None the less some information to this point from Trevor Marshall (T. Marshall in: Metagenomics of the Human Body. Nelson Karen E. (Ed.) 1st Edition., Springer, 2011;

“Today, the National Institutes of Health (NIH) estimates that a mere 10% of the cells that comprise Homo sapiens are human cells. The remaining 90% are bacterial in origin. We may best describe the human being as a super-organism in which communities of different organisms flourish in symbiosis with the host. There are still huge gaps in our understanding of how the microbiota contributes to human health and disease. ... Medicine has become comfortable acknowledging that bacterial populations exist in the areas of the body in contact with the external environment, such as the airways, gastrointestinal tract, mouth, skin, and vagina/penis. Yet microbes have also been shown to persist in many other body tissues including joints and blood vessels. Bacterial DNA has been detected in the blood (20). Recently, 18 different bacterial taxa were detected in the amniotic fluid, which was previously believed to be completely sterile (21), etc.)”.

(Witkowski): The ISYS does not recognize and deal with cells, bacterial or otherwise, it deals with molecules. It can only recognize and react to those molecules, which fit the sequence/structure patterns defined by selection of allowed T- and B-cell receptors.

(Poletaev): Certainly! The ISYS deals with molecules and only molecules. But to what purposes inter-molecular interactions serve? Not for self-satisfaction evidently. Lets non stop at reductionistic position, but bear in mind the physiological consequences of AG-Ab (and lot of other). Each one interaction is not senseless but sensible from point of view of the biological system! (There are no illnesses of molecules; “Concept of illness can be used for organism, not for molecules” L.P.Churilov, 2001).

3) If its activity of is mostly related to the internal needs of organism (similar to cardiovascular, or endocrine, or nervous system, etc.) which molecular instruments can be used by ISYS for homeostatic needs? Is there something beyond natural autoantibodies and cytokines for realization of inward directed ISYS activity?

4) If autoantibodies are synthesized by ISYS during all lifespan of any healthy person should these molecules be considered as pathogenic factors only? Thyrotoxicosis is not too rare event, none the less nobody talk about thyroid hormones as pathogenic factors.

(Witkowski): Thyroid hormones are not pathogens as such, neither is insulin or glucose in that matter. What counts is the deviation from the homeodynamic ‘norm’; too much thyroid hormones is pathogenic and leads to thyreotoxicosis, too much insulin (or too little glucose) is conductive to hypoglycaemic shock, too much glucose is the basic cause for diabetic damage to the tissues. Not the presence of a biologically effective molecule counts for its proper physiological or improper pathological effects, but its concentration (basic homeodynamics). Concerning autoantibodies: at low concentrations, especially occurring transiently as is mostly the case, they would rather not do much harm in a form of autoimmune damage to the target tissues; at these concentrations, their regulatory effects (Fc, anti-idiotypic et caetera) may show and prevail. The change of role would be quantitative in nature, not qualitative.

(Poletaev): Certainly! You are right other time! Concentrations of biologically active endogenous molecules (intensity of production) will be crucial factor in any case - independently have we deals with thyroid hormones, insulin, or autoantibodies, etc.

(Witkowski): Neither of the Lacroix-Desmazes’ papers proofs that the autoantibodies made in an infant are the same after that infant becomes an adult (no longitudinal observations!).

(Poletaev): There are such phenomenon as maternal-dependent immune imprinting (see for ex. Lemke, Lange, Scand. J. Immunol., 1999, 50, 348)

Rise of production of autoantibodies as consequence of any tissue damage is generalized phenomenon (see Matzinger Science 2002; 296: 301).

(Witkowski): Precisely! Damaged tissue is a source of new antigens; proteins are hydrolysed, oxidated, glycated… And the ISYS is responding to perceived “foreign”.

(Poletaev): Hurrr-a-a-a-a! I see at least you agree – secondary elevation of auto-Abs production related to tissue damage is universal phenomenon. In any words if we will look in a “mirror” of auto-Abs of investigated person – we may see injured structures of organism (I’d like to add: even before clinical manifestation pathology – sometimes months and years). This phenomenon become the base of “ELI-Tests” (from Enzyme-Linked-Immino-Tests; its other name “The Immunculus Technology”). Methods ELI-Test group were elaborated soon after Chernobyl Disaster. These methods were intended for observation large populations and early revealing pathology changes in different organs. ELI-Tests are used now in Russia Many thousands peoples were investigated by these methods during last 20 years. Great number of catamnestic observations indicates for its real prognostic descriptiveness. We can argue by years pro- and against idea that rise of auto-Abs production is triggered by neo-antigens or old ones.

(Witkowski): I do not contest the existence of autoantibodies without the symptoms of an autoimmune disease. In fact, I do frequently observe their transient (!) appearance in clinically healthy elderly (albeit never in healthy young adults or children.

(Poletaev): Well, I was very glad to read this your note. If you have some practical experience in ELISA or immunoblotting it will quite easy to see in reality - is the phenomenon transient or permanent? I mean permanent production auto-Abs of IgG class with very different antigen specificity in quite healthy children and adults. I don’t like the idea to argue with you by using references (there are lot of them) because I work with the phenomenon in experiments and in clinical diagnostic and prognostic more then 20 years. Try it by yourself. Take in mind: normal (physiologic) serum level different IgG auto-Abs in a healthy pre-pubertal children is 1,5-2-fold below compare to a healthy adults.

I see no essential contradiction between the views of Alexander Poletaev and Jacek Witkowski.

Dear Dr. Poletayev,

As it seems to me ours positions begin to draw a bit closer.

(Witkowski): That may well be, although still… Anyway, I like this discussion, so here are my comments to your comments to my comments...

(Poletaev): What do you think about more universal and a little bit not so aggressive definition? Something like: “The primary evolutionary ‘purpose’ of the ISYS is maintenance of homeostasis of the organism” – this nuance may be important methodologically. Not WAR, but PEACE in organism is the biological predestination of the ISYS (the ISYS is rather housekeeper, not policeman).

(Witkowski) Ah well, this seems a bit of semantics. Agreed, the ISYS is a part of the homeostatic (homeodynamic) machinery of the organism, working according to evolutionarily defined “program”. I could agree, that the general definition of homeostasis (I prefer ‘homeodynamics’ for living organisms, as ‘stasis’ seems to require holding of whatever parameter at strictly defined value/position, while in an organism there is always a range of such value, which is tolerated and does not arouse the built-in homeostats) could be transformed into ‘activities to make peace in an organism’. However, in case of the ISYS, this peace is to be kept by constant war with external and internal pathogens (illustration: broken ISYS in severe combined immunodeficiency (SCID) or advanced AIDS; do these patients die because of lack of homeodynamics, or of lack of anti-pathogen defense? I have seen such patients (e.g. AIDS patient whose internal organs were grown-through by molds), I opt for the latter.

(Poletaev): Do not forget: interaction with specific antigen in vivo as well in vitro can not only block, but also activate, or modify its function – the effect depends from peculiar epitope specificity and some additional conditions (Zaichik, Churilov, Pathophysiology. vol. II. Pathochemistry., 3rd edition, ElBi Publ., St.Petersburg, 2007); moreover binding of antigen, especially labile peptides may be important with point of view prolongation and enhancement biologic activity of the last (Wang a.o., Mol Immunol 1992;29:313); specific ligand-like activity of receptor-interacting Abs also well known (Zaitchik a.o., Pathophysiology 2008; 15: 191); lot of other biologically important forms of Abs activity in vivo were described (Rüiz-Argüelles, Alarcon-Segovia, IMAJ, 2001; 3: 12). So your opinion: Autoantibodies = Harm for body is not quite correct.

(Witkowski): The only feature antibodies can DIRECTLY manifest is to bind – either to the epitope via the (super)variable parts of the Fabs, or to multiple Fc receptors via the Fcs. Consequences of this binding are known to be different, including activation of a receptor protein rather than blocking it as in Hashimoto’s disease, or known enzymatic activities. Regarding the Rüiz-Argüelles, Alarcon-Segovia paper you cite above: it stems from their own 34-years old observation (Alarcon-Segovia D, Ruiz-Arguelles A. Fishbein E. Antibody to nuclear ribonucleoprotein penetrates live human mononuclear cells through Fc receptors. Nature 1978;271:67- 8.) of antibodies binding via the Fc receptors (FCRs) to the mononuclear cells (monocytes and lymphocytes of blood), becoming internalized and inside the cells rather than undergoing total proteolysis, performing some activities, e.g. binding nuclear RNPs. So, you still need a specific ligand-receptor binding. Quoting their 1978 paper: “We show here that anti-RNP IgG can penetrate viable human mononuclear cells (MNC), by their surface Fc receptor, and react with their nuclear RNP.” I do not contest the possibility and their results. Could such binding of the RNPs by an auto (or rather allo-; antibodies used by Alarcon-Segovia et al were not isolated from the patients themselves) antibody regulatory? I would say yes, as anything that binds RNA/RNP affects the cellular protein output and gene regulation (vide shRNAs, miRNAs…). However, I did not find any follow-up to these papers considering such a regulatory function, and that would be interesting… Even if we assume that anti-RNP antibodies able to penetrate inside the cell and while inside, also into the nucleus, can arise, they are still made by the ISYS machinery either in response to MODIFIED (by whatever process, making them foreign to the system) RNPs (or rather their epitopic fragments presented in the context of MHC/HLA II) or, erroneously, to UNMODIFIED RNPs that had not become tolerized during intrathymic education stage. First case is ‘fighting the alien’, second – erroneously fighting the ‘self’. Both are or may be leading to pathology (as we agreed, tha matter is also in quantity of the response. Thus the question is: could such potentially regulatory (auto/allo)antibodies arise for purpose, or is it a stochastic event?

(Poletaev): Do not forget: we discuss there not complicated interrelations between the body and its micro-inhabiting. None the less some information to this point from Trevor Marshall (T. Marshall in: Metagenomics of the Human Body. Nelson Karen E. (Ed.) 1st Edition., Springer, 2011;

“Today, the National Institutes of Health (NIH) estimates that a mere 10% of the cells that comprise Homo sapiens are human cells. The remaining 90% are bacterial in origin. We may best describe the human being as a super-organism in which communities of different organisms flourish in symbiosis with the host. There are still huge gaps in our understanding of how the microbiota contributes to human health and disease. ... Medicine has become comfortable acknowledging that bacterial populations exist in the areas of the body in contact with the external environment, such as the airways, gastrointestinal tract, mouth, skin, and vagina/penis. Yet microbes have also been shown to persist in many other body tissues including joints and blood vessels. Bacterial DNA has been detected in the blood (20). Recently, 18 different bacterial taxa were detected in the amniotic fluid, which was previously believed to be completely sterile (21), etc.)”.

(Witkowski): I fully subscribe under this statement; still, I would argue that it is the evolutionary role of the innate and adaptive ISYS to keep all of these prevailing bacterial inhabitatnts of our body at bay, i.e., preventing their uninhibited outgrowth to our doom.

(Poletaev): Certainly! The ISYS deals with molecules and only molecules. But to what purposes inter-molecular interactions serve? Not for self-satisfaction evidently. Lets non stop at reductionistic position, but bear in mind the physiological consequences of AG-Ab (and lot of other). Each one interaction is not senseless but sensible from point of view of the biological system! (There are no illnesses of molecules; “Concept of illness can be used for organism, not for molecules” L.P.Churilov, 2001).

(Witkowski): Clearly self-satisfaction has nothing to do with intermolecular interactions (although, half-jokingly, I could say that the FEELING of self-satisfaction is the result of intermolecular interactions occurring between and within our neurons). And this puts us in perspective: molecular interactions in the neurons and their networks are evolutionarily selected to convey information and produce reactions to it, within the physiological ‘role’ of the system for the organism (of course, there would be plenty of life-important molecular interactions in the neurons that do not directly convey these informations and reactions); molecular interactions in the ISYS are evolutionarily ‘made’ to prevent the topological inside of the organism from being invaded by external or internal pathogens (of course, there are life important molecular interactions in and among the ISYS cells that do not directly serve these evolutionary purposes; they can even convey information to the CNS (as do proinflammatory cytokines IL1, IL6 etc, for example; antibodies or autoantibodies do not do it). Yet, does it prove that the ISYS has another evolutionarily ascertained purpose than fight? IL1 entering our brains in case of an infection makes us sleepy and unwvilling to perform physical activities, and shifts the central body temperature homeostat in the brain stem to higher values producing fever; both are beneficial in fighting pathogenic microorganisms (no physical activity – more resources for fight of the ISYS; fever – better performance of the ISYS)…

(Poletaev): There are such phenomenon as maternal-dependent immune imprinting (see for ex. Lemke, Lange, Scand. J. Immunol., 1999, 50, 348)

(Witkowski): Well, it is a hypothesis paper, based on authors’ interpretation of some observations made by others (and only very little by themselves); even if valid as a hypothesis, it has not been later proven by those or other authors, and the interpretations could be different (actually, the authors themselves suggest anti-idiotypic activity of maternal Abs in the child as major factor – I do not contest such a possibility; anti-idiotypic Abs (whether own or maternally acquired) are meant to regulate the available idiotypes).

(Poletaev): Hurrr-a-a-a-a! I see at least you agree – secondary elevation of auto-Abs production related to tissue damage is universal phenomenon. In any words if we will look in a “mirror” of auto-Abs of investigated person – we may see injured structures of organism.

(Witkowski): Right, but it is semantics again: I perceive an AUTO-antibody as such only, if it is made to UN-changed own antigen/epitope. And would argue that such ones do exist, but their existence comes from error in tolerization and their role is pathological. On the other hand, an antibody rising to a MODIFIED own antigen would be recognizing something alien (as it evolutionarily should!).

(Poletaev): (I’d like to add: even before clinical manifestation pathology – sometimes months and years). This phenomenon become the base of “ELI-Tests” (from Enzyme-Linked-Immino-Tests; its other name “The Immunculus Technology”). Methods ELI-Test group were elaborated soon after Chernobyl Disaster. These methods were intended for observation large populations and early revealing pathology changes in different organs. ELI-Tests are used now in Russia Many thousands peoples were investigated by these methods during last 20 years. Great number of catamnestic observations indicates for its real prognostic descriptiveness. We can argue by years pro- and against idea that rise of auto-Abs production is triggered by neo-antigens or old ones.

(Witkowski): It looks interesting! Of course I do not know anything about your Imunculus Technology, but if it yields pathology-revealing information, then it is good. Now, you only mention its diagnostic/prognostic values for imminent pathologies, and not its role in assessment of homeostatic/dynamic function of autoantibodies (ok, I know, this IS a provocation on my side!).

(Poletaev): Well, I was very glad to read this your note. If you have some practical experience in ELISA or immunoblotting it will quite easy to see in reality - is the phenomenon transient or permanent? I mean permanent production auto-Abs of IgG class with very different antigen specificity in quite healthy children and adults. I don’t like the idea to argue with you by using references (there are lot of them) because I work with the phenomenon in experiments and in clinical diagnostic and prognostic more then 20 years. Try it by yourself. Take in mind: normal (physiologic) serum level different IgG auto-Abs in a healthy pre-pubertal children is 1,5-2-fold below compare to a healthy adults.

(Witkowski): I work in the biogerontology/imunosenescence filed more than 30 years. It could be that we were looking at different auto-antibody specificities, seen in the aged, but never in children/adults. Still, what does it prove? As I said – I do not contest the existence of autoAbs, and believe you if you say you do see them also in younger people at lower amounts; yet, this does not imply they have any other ‘meaning’ than binding of molecules they had risen against, clinically relevant or not; it would have to be demonstrated beyond doubt that an autoantibody in a child has homeostatic/dynamic properties (unless of course it is an anti-idiotypic Ab.

Dear Dr. Witkowski,

O.K., I like the term ‘homeodynamics’ for living organisms; let’s accept . I can agree to your “In case of the ISYS, the peace is to be kept by constant war with external and internal pathogens” only with position Alberts Sent-Djerdji who said – the brain is organ for survival just as fangs and claws. Figuratively speaking we can tell the same about each organ and system of the body. None the less we do not tell usually about liver, kidney or cardio-vascular system with using language of battle. The ISYS is ordinary physiology system of the body. So I repeat: Its predestination is PEACE, not WAR. As I see it (there I am ardent follower Polly Matzinger’ ideas) – without specific “request” the ISYS stay usually in state of relative resting, and only in response to primary request from damaged tissue (the reason can be hazard microbes, ischemia, etc. - any etiology) the ISYS has been activated and takes part in intensifying of local clearance, in tissue reparation and functional compensation (regulatory properties!), and, of course, in destruction of HAZARD microbes (non-hazard ones, that is non-inducing any kind of tissue injury are ignored).

(Poletaev): Do not forget: interaction with specific antigen in vivo as well in vitro can not only block, but also activate, or modify its function – the effect depends from peculiar epitope specificity and some additional conditions (Zaichik, Churilov, Pathophysiology. vol. II. Pathochemistry., 3rd edition, ElBi Publ., St.Petersburg, 2007); moreover binding of antigen, especially labile peptides may be important with point of view prolongation and enhancement biologic activity of the last (Wang a.o., Mol Immunol 1992;29:313); specific ligand-like activity of receptor-interacting Abs also well known (Zaitchik a.o., Pathophysiology 2008; 15: 191); lot of other biologically important forms of Abs activity in vivo were described (Rüiz-Argüelles, Alarcon-Segovia, IMAJ, 2001; 3: 12). So your opinion: Autoantibodies = Harm for body is not quite correct.

(Witkowski): The only feature antibodies can DIRECTLY manifest is to bind – either to the epitope via the (super)variable parts of the Fabs, or to multiple Fc receptors via the Fcs. Consequences of this binding are known to be different, including activation of a receptor protein rather than blocking it as in Hashimoto’s disease, or known enzymatic activities. So, you still need a specific ligand-receptor binding. Could such binding of the RNPs by an auto (or rather allo-; antibodies used by Alarcon-Segovia et al were not isolated from the patients themselves) antibody regulatory? I would say yes, as anything that binds RNA/RNP affects the cellular protein output and gene regulation (vide shRNAs, miRNAs…). However, I did not find any follow-up to these papers considering such a regulatory function, and that would be interesting…

(Poletaev): New data about regulatory function of auto-Abs you can find such recent papers as: Zaitchik a.o., Pathophysiology 2008; 15: 191. Dragun a.o., N Engl J Med 2005;352:558. Martínez a.o., Frontiers in immunology, April 2012 | V. 3 | Article 94 | doi: 10.3389/fimmu.2012.00094. Tasignon a.o., J Clin Endocrinol Metab 1998; 82: 3464, and many others. From evolutionary position the answer to your question (could such potentially regulatory auto/allo-antibodies arise for purpose, or is it a stochastic event?) is quite evident

(Poletaev): Certainly! The ISYS deals with molecules and only molecules. But to what purposes inter-molecular interactions serve? Not for self-satisfaction evidently. Lets non stop at reductionistic position, but bear in mind the physiological consequences of AG-Ab (and lot of other). Each one interaction is not senseless but sensible from point of view of the biological system! (There are no illnesses of molecules; “Concept of illness can be used for organism, not for molecules” L.P.Churilov, 2001).

(Witkowski): Clearly self-satisfaction has nothing to do with intermolecular interactions (although, half-jokingly, I could say that the FEELING of self-satisfaction is the result of intermolecular interactions occurring between and within our neurons).

(Poletaev): You are right. Any CHEMICAL EVENTS (inter-molecular interactions) in living systems by definition serve to PHYSIOLOGY NEEDS. Activity of the ISYS-produced molecules (natural auto-Abs, cytokines) is not exclusion from this rule.

(Poletaev): There are such phenomenon as maternal-dependent immune imprinting (see for ex. Lemke, Lange, Scand. J. Immunol., 1999, 50, 348)

(Witkowski): Well, it is a hypothesis paper, based on authors’ interpretation of some observations made by others (and only very little by themselves); even if valid as a hypothesis, it has not been later proven by those or other authors, and the interpretations could be different.

(Poletaev): I’d like to note – the phenomenon of maternal immune imprinting it is not observation by Hilmar Lemke only. The same phenomenon was described five years before Lemke by my (Life Sci., 1994; 54:1377), or Merbl a.o., (J. Clin. Invest. 2007; 117:712), or Steinhoff a.o. (NEJM, 2010; 362:1644), or Zaman a.o., 2008, N Engl J Med 2008;359:1555) and many others.

(Poletaev): The secondary elevation of auto-Abs production related to tissue damage is universal phenomenon. In any words if we will look in a “mirror” of auto-Abs of investigated person – we may see which structures of organism are injured.

(Witkowski): Right, but it is semantics again: I perceive an AUTO-antibody as such only, if it is made to UN-changed own antigen/epitope. And would argue that such ones do exist, but their existence comes from error in tolerization and their role is pathological. On the other hand, an antibody rising to a MODIFIED own antigen would be recognizing something alien (as it evolutionarily should!).

(Poletaev): As it was initially found and experimentally proved by Kovaliov and his colleagues, production of auto-Abs is regulated by availability of self-AG by feed-back principle (there are lot of examples in this book: Kovaliov, Polevaya. Biochemical grounds for immunity against low molecular chemical compounds. Nauka, Moscow, 1985). Compensatory elevated expression of p53 does accompanied by secondarily rise of production of according auto-Abs which binds to native epitopes of p53; in accordance to Lubin a.o. that extensive accumulation of p53 is reason for “self-immunization” and appearance of surplus of anti-p53 Abs in patient’s serum (Cancer Res, 1993, 53, 5872). Women received excess of human chorionic gonadotropin (hGT) during preparation to IVF; as a result most of them produce excess of auto-Abs to hGT (Poletaev, Maternal Immunity, Pregnancy and Child's Health, in From Preconception to Postpartum, ISBN 978-953-51-0353-0, ed. by Sifakis, Vrachnis. 2012, InTech - Open Access Publisher). In all noted, as well as in many other cases we can tell about auto-Abs against NATIVE (non-modified) AGs. Of course Abs against modified (glycosilated, phosphorilated, etc.) self-AGs can be produced too.

(Poletaev): The phenomenon became the base of “ELI-Tests” (from Enzyme-Linked-Immino-Tests; its other name “The Immunculus Technology”). Methods ELI-Test group were elaborated soon after Chernobyl Disaster. These methods were intended for observation large populations and early revealing pathology changes in different organs. ELI-Tests are used now in Russia Many thousands peoples were investigated by these methods during last 20 years. Great number of catamnestic observations indicates for its real prognostic descriptiveness. We can argue by years pro- and against idea that rise of auto-Abs production is triggered by neo-antigens or old ones.

(Witkowski): It looks interesting! Of course I do not know anything about your Imunculus Technology, but if it yields pathology-revealing information, then it is good. Now, you only mention its diagnostic/prognostic values for imminent pathologies, and not its role in assessment of homeostatic/dynamic function of autoantibodies (ok, I know, this IS a provocation on my side!).

(Poletaev): I ought to repeat – as it has been proven experimentally that molecular “danger signals” from injured tissue induce transitory autoimmune reactions that are accompanied by increased production of tissue-specific auto-Abs [Matzinger. Science 2002; 296: 301]. As noted by Tveita, a temporary rise in autoreactivity per se is a temporal physiological (normal) aspect of all tissue inflammation, and this phenomenon is principally distinct from pathological autoimmunity [Tveita. Rheumatology 2010; 49: 632]. Empirical testing of huge number of serum samples with using very different techniques (by the trial and error method) had had lead us – my colleagues and me – to very similar ideas 20 years before (at the end of 80-th) and to working out the methods of ELI-Test group. To my mind one of the most important (but not the only one!) functions of the ISYS is its participation in autoclearance provided by pair Macrophages + auto-Abs. Obviously, the homeodynamics importance of local activation of autoclearance mechanisms increases dramatically in the case of tissue damage (of any etiology). That primary tissue damage then induces (and may be mirrored by) an evolutionarily-fixed phenomenon of a SECONDARY increase in the production of auto-Abs against tissue-specific antigens.

Regret that such the interesting question came in exchanges only between Dr. Alexander Poletaev and Dr. Jacek Witkowski ...

@ Dr. Zabrodskii

True, everybody is invited to particip[ate.

@ Dr. Poletayev - I am busy now, will try to answer to your interesting remarks later tonight.

Hey, Peoples, Colleagues, you are welcome!

Thank you. I should note that your discussion with a colleague to me is very interesting. I (see above), as immunotoxicologist, wanted to hear the answers to my questions. No I did not answer. The question is simple. I am interested in the opinion of Immunologists. For monographs on Immunology (Petrov, Khaitov) in Russian, I'm a little doubtfully.

Dear Dr. Zabrodskii,

I would not reject Russian monographs and scientific thought altogether. Of course, especially the older ones, were written based sometimes on scarce contact with the "Western" science, so sometimes it was kicking at a door already opened, but sometimes, new ideas would rise. I believe the Immu nculus and the ideas presented by Dr. Poletayev belong to the latter category and DO bring some novelty into our thinking about 'what really happens in the immune system'. As you realize, I dio not agree with all of them, but remain open to this type of scientific discussion. Who knows - with time perhaps one of us (Dr. Poletayev or myself) will get convinced to the other's reasoning or we will achieve some compromise...

Dear Pavel Francivich,

I would like to recommend you the next books:

Зайчик А.Ш., Чурилов Л.П. - Основы патохимии. ЭЛБИ-СПб, 2005.

Зайчик А.Ш., Чурилов Л.П. – Общая патофизиология с основами иммунопатологии. 4-е издание. СПб : ЭЛБИ-СПб, 2008.

These books has proposed for medical students as textbooks. But it is not simple textbooks (usually bored). Belive me - it is real pleasure to read it! There are lot of new ideas (as well as some old but now forgotten) related to immunophysiology.

I read Russian and teach pathophysiology and immunology, so I woluld gladly read the textbooks you mention. Are they available outside Russia?

And a more general comment: even the best written textbook becomes obsolete after some time. In the slowly developing disciplines this time-to-obsolescence may be quite long; however, in a fast changing and developing disciplines, as (currently) pathophysiology AND immunology, a 5-year old textbook (which was written at least a year, or sometimes more than that ago) usually is partially inadequate and obsolete due to novel breakthroughs and discoveries, changing our understanding and perspectives...