The nature of immunity - Part IIML Kothari, Lopa A Mehta
Department of Anatomy, Seth G.S.Medical College, Parel, Bombay-400012, India
An unorthodox approach to the nature of immunity is presented differentiating it from reactivity. Immunity is a gestalt force, all to the good of an individual, staking the concept of auto-immunity ridiculous and rejectable. Reactivity is a vector force that may protect or persecute; it is basically concerned with restoring the integrity of the human body. The concept of cytologue amplifies the idea of integrity, and allows reactivity to fight a microbe, heal a wound, reject a graft, and gives rise to "auto-immune' disorders, by a concerted Cellulohumorovascular Response.
A science lacks direction when it lacks definition. (Incidentally, such a commonplace thing as diabetes mellitus  or essential hypertension  has remained undefined). Reactivity, therefore, must be defined, being open to definitional refinements with evolution of greater comprehension.
There are some terms to be understood before we go to the definition proper. Self/not-self idea makes no sense when one realizes that (a) a patently foreign cell-system can become part of one's self thanks to the natural or artificial chimerism, (b) one's own cells-"me own flesh and blood"-can too often prove foreign, to
There are, then, no self cells, but a selfing process that occurs, in man for example, during the later half of intrauterine existence and early part, of postnatal life (vide supra) whereby the body decides what it is going to treat as its own. The human embryo, constituting a more-or-less completely formed human individual by about the 10th week of gestation, , is made up of suicytes-its own cells. The process of "immunologic maturation," CARE, or selfing allows the suicytes to be classified into selfed/ CAREd suicytes and unselfed/unCAREd suicytes (neurones, for example). In a chimera, the guest cells are accepted as self, by being selfed. The guest cells, thus constitute, selfed allocytes. Anything else-cells, cell products, inanimate material - not belonging to the selfed category (suicytes/allocytes) constitutes not-self, Suicytes/sui-elements that, through injury, mutation, degenerationα or any other process like binding to a drug or microbial, cease to confirm to the selfed-pattern become deselfed, and turn into actants or "auto-antigens." (The reactocytic hell that a body lets loose on a kidney in SLE is because of the deselfing that the renal tissue undergoes from time to time. Deselfing is the basis of "autoimmunity"). While at terms, the good, bad, and indifferent aspects of reactivity can be acronymically expressed as PAR, CAR, and KAR. Par is ProAuto Reactivity, CAR is ContraAuto Reactivity, and KAR is a hybrid term to be read as Koremonai Aremonai Reactivity. Needless to elaborate, CARD stands for ContraAuto Reactivity Disease, hitherto called autoimmune disease. Severe anaphylactic reaction is an extreme example of CARD, while allergy or hypersensitivity represents it in milder form.
Any reactive process is made up of PAR, CAR and KAR in varying proportions: tuberculous meningitis, for example, is successfully combated by PAR, but it leaves behind a trail of paralyzed nerves engulfed in the fibrous tissue generated by the antitubercle PAR. May be, that is the reason why immunity stands for no reactive quarrel, as far as possible. As a wag put it, `in a war it is not important who is right, but who is left.' The body follows this lesson by insisting that immunity is absence ''avoidance of reactivity.
The above principle found its immediate and profound impact in the Listerian et Senimelweissian principles of asepsis and antisepsis which are, apart from immunity, the means of avoiding a confrontation or a reactive showdown with the microbes - a kind of Swiss neutrality, a refusal to enter into a potentially dangerous dialogue. The gains have been the tour de force of modern medicine: "Actually. in terms of lives saved, the development of sanitary measures such as antisepsis and sanitary control of food, water, and insect vectors, represents the greatest single lifesaving achievement in medical history.'' 
Reactivity may now be defined as cellulohumorovascular activity comprising focal, local and systemic formation and presence of extraneous specific and nonspecific cells and humours that aim penultimately at restoration of the body's integrity to as near to status quo ante possible, the reactivity response having been excited by disturbances in the cytologue due to the presence of (i) damaged, dead or deselfed suicytes/sui-elements, (ii) any inanimate material (iii) microbes, or (iv) all ocytes/allo-elements, the entire process passing through the phases of recognition, reaction, removal of the disturbing cells/elements, and restitution to status quo ante with the help of such processes as replication of missing cells (e.g., epithelial cells, liver cells), vascularization, devascularization, and contracture of the matriceal fibrous tissue. Nature's masterstroke vis-a-vis reactivity was to ask the ubiquitous fibroblast to provide the fibrous scaffold for any reactive focus, so that the inherent contractibility of the fibrous tissue would help eventually to reduce the focus to the smallest possible size, on completion of the job.
Halliday,  the author of "Glossary of Immunological terms" defines immunocytes as "Cells concerned in immunity, especially antibody-formation". The latter italicized part of the definition betrays the all too common antibody-ism. When it comes to defining immunocompetence, the antibody-obsession is no less: "Immunocompetent cell: Any cell which can be stimulated by antigen to either form antibodies or give rise to cells which form antibodies".  If the oversung antibody has proved such a grand illusion as far as immunity goes, why not extend the honour of immunocompetence to a macrophage or to an epithelial cell which, with palpable competence, provide positive protection to an individual. Any cell, then, that partakes in offering immunity is an immunocyte/immunocompetent cell. The "immunocyte" in the definitions stated above can be reactocytically understood by being designated specific. A specific reactocyte is one which secretes a specific reactin against an actant or can combine directly and specifically with that actant. When such a process occurs in vivo, the background but vital performance is by the unsung macrophages, complements, reticuloendothelial cells, and so on each of which is a reactologically competent in its own right.
Vaccination, often called active immunisation, illustrates very well the fundamental differences between immunity and reactivity. Firstly, it is wrong to call such a procedure as immunisation for what is gained is not immunity but reactivity which may be absent, adequate, injurious or fatal. (The fallacy is much greater when injection of ATS or any other serum is called passive immunisation, which could be but a way of killing a person). Small pox vaccination presents a case in point. It may not take. So often, it succeeds in arming the individual with adequate reactivity against the virus. It may prove a nuisance, since the reaction of the body to the vaccine may lead to "progressive necrosis of the skin at the vaccination site and the development of metastatic lesions in other areas of the skin and in the viscera".  H Sometimes, it may lead to "postvaccinial perivenous encephalitis" which is nothing but fatal.  It should thus become clear that vaccination - no longer to be turned immunisation - is blessed with PAR, fraught with CAR and is basically a process of eliciting in the individual what may be called thwartive reactivity, outlined below.
Thwartive (from thwart - "to oppose successfully; to prevent from. accomplishing a purpose"  ) reactivity (also called thwartivity) is the ability of an individual to knock a microbe, an allocyte or an allo-element out of action by means of cells and/or humours, specific and/or nonspecific on the latter entering the individual's body past the immunity barrier, this being an active arrestive response by the organism against the intruding element with which it came in contact earlier, accidentally or by design.
The evolution of thwartivity is important both ontogenically and phylogenically-as a phenomenon evolving both horizontally (in a herd) and vertically (through generations). For example, infection with tubercle bacilli, for the first time, in an individual or a group excites a reaction that may be mild, moderate or severe, silent or symptomatic. This can be called the initial reaction which serves to (a) fight against the intruder, but more importantly, (b) to prime the organism/s to react thwartively-thwartive reaction - against subsequent infections by the mycobacteria. At phylogenic level, the evolution is slightly different. A generation gets infected by tubercle only to succumb to it. The lethal brush with the microbe however does not go wasted, for the subsequent genera ions grow more and more resistant to the bacillus, by exhibiting strong thwartive capabilities. It is a little emphasized fact of macromicrobial. interaction that, without any help from the much-vaunted antibiotics, mankind in a generation and through generations has emerged victorious against this or that microbe - fantastic feat by Nature at mass "immunization" or vaccination, allowing us to generalize that thwartive reactivity is our license to sur vive.
The above is best illustrated by a few, justifiably lengthy, quotes from some leading works on microbiology: "In observing
"In spite of the cellular reaction, there is little resistance to the multiplication of the tubercle bacilli, and soon after infection, dissemination from this focus occurs. This dissemination is primarily by way of the lymphatics, and there is early extensive involvement of The regional (hilar) lymph nodes. At the same time, there is spillover from the lymphatics into the bloodstream with a seeding of virulent tubercle bacilli in all of the organs and tissues of the body. In a small proportion of persons thus affected, this process advances until widespread tuberculous disease, and possibly death, occurs, provided treatment is not given. In the majority of such persons, however, after a period of a few weeks the following dramatic changes are seen. The rate of multiplication markedly decreases, the pneumonic process resolves, and the dissemination of tubercle bacilli, to other organs ceases. The same changes also occur in all other tissues where tubercle bacilli may reside. Resolution of the disease process may proceed to a point such that, in many people so infected, little or no residue of the infection remains. In some, particularly in infants and children, all that may remain may be a Ghon complex; that is, a small calcified nodule in the lung and enlarged hilar lymph nodes.
Coincident with the changes described above, two immunologic manifestation appear. First, the affected individual becomes tuberculin positive. In other words, he shows reactions of delayed hypersensitivity to certain low molecular weight proteins or polypeptides which are found in the tubercle bacillus. We have already noted that mycobacteria markedly promote induction of delayed hypersensitivity to other proteins so it is no wonder that they exert the same effect for their own protein constituents. Secondly, the macrophages within which the tubercle bacilli previously were able to multiply so readily now have acquired the ability to markedly inhibit the multiplication of virulent tubercle bacilli. Therefore, since the tubercle bacilli are now unable to grow within these cells, the disease process is arrested and, with time, many of the virulent cells are destroyed. In other words, the diseased person has now become immunized as a consequence of the reaction of his immunologic system to the infection. This type of immunity is known as acquired cellular immunity."  . The foregoing drives home the evolution of thwartivity at individual (ontogenic) and group level. A passage from Dubos  renders clear the phylogeny of thwartivity: "Precise observations are available concerning the changes in the clinical manifestations of tuberculosis among some Indian tribes of North America. In the first and the second generations to suffer from the tuberculosis epidemic in the Qu'Appelle Valley reservation, extensive glandular involvement was the rule in school-age children. Meningitis, generalized miliary disease, and bone and joint disease were extremely frequent-evidence of inability of the host to localize infection. In 1921, at a time when the generalized epidemic was in the third generation, the disease showed a greater tendency to localize in the lung and to exhibit a chronic course; the mortality was falling, and glandular involvement had dropped to 7 per cent among school children. This latter manifestation of high susceptibility to tuberculosis has continued to decline steadily and was seen in less than 1 per cent of children in the 4th generation. In other words, while tuberculosis among the Amerindians exhibited at first a very acute course, different in character front that observed in people who have had contact with the tubercle bacillus for several generations, now it is undergoing a change which makes it resemble the more chronic type of disease commonly seen among Western people under normal conditions." Antia  makes a comparable observation about mankind's thwartive resistance to the much-feared leprosy bacillus, the resistance having evolved over generations: "The human being is much less susceptible to leprosy than to tuberculosis or many other diseases; and even if he should develop the infection, about 80 per cent of the cases are self-healing."
Having presented the concept of thwar tivity-the arrestive cellulohumoral response by an organism against an actant (microbe, toxin, a graft) by which the organism was primed earlier-a few important generalizations on it are in order: (1) If reactivity against a foreign element can be described as a double-edged weapon, thwartivity represents the self-preserving edge, while combativity (combative reactivity) (see below) represents the self-destructive edge. (2) Apart from providing the faculty of wound healing, the CelluloHumoroVascular Reactive System is basically evolved and geared to provide thwartivity against the microbes so as to minimise reactive quarrels and the attendant dangers. Evolutionally, it has little to do with either tumor immunity or transplant immunity, either Robert Good or Christiaan Barnard. Immunity has nothing to do with the fetal engraftment onto a mother. Maternal reactivity is concerned in this process, by being conspicuously kept out through means not yet understood, but sialomucincoating of fetal trophoblast is the prime suspect. Sialomucin, or whatever the substance be, illustrates the principle  that in Nature, functional necessity is the mother of structural innovation. (3) Next to immunity, thwartivity represents the second line of defense mediated largely by the mopping macrophages (phagocytes) and the inactivating antibadies. (4) Resistance is another name for uncompromised immunity and/or good thwartivity, while susceptibility implies compromised immunity and/or poor/absent thwartivity. The state of resistance/susceptibility, in an individual, is determined by a dynamic balance that could change from hour to hour. (5) All forms of vaccination aim at induction of thwartivity, and often take advantage of cross-reactivity - Jerner successfully exploiting, in 1796, cowpox virus to thwart smallpox is a classic example;  others are the use of attenuated organisms (BCG) and toxoids. (6) Antimicrobial agents act by preventing/cutting short a reactive quarrel, hence affording thwartivity of a kind. Their extraneous nature and their multiple effects have been responsible for the dangers they pose. (7) Thwartivity may uncommonly be too severe - anaphylactic (truly, hyperphylactic), proving once more that reactivity is not an unmixed blessing. Generalizations (1) to (4) merit elaboration, as follows.
In absence of thwartivity, an organism enters into a regular combat - an eye for an eye, a tooth for a tooth - with the intruding microbe, and the result is not always good for the host. A reperusal of the large quotations above would show that both in ontogeny and in phylogeny, until such time that thwartivity develops as a force, combativity involves sacrifice of tissues or lives. Viral hepatitis, thanks to successful combativity and to the enormous regenerative power of liver, can mean a normal liver again, but during the acute quarrel, the host is on a precipice. The victory may sometimes be pyrrhic for the eventual outcome may be cirrhosis. Combative reactivity may pull the host out of tuberculous meningitis, but the aftermath may be bilateral oph1halmoplegia from nerves paralyzed by fibrous engulfment. Like in day to day life, a reactive quarrel averted, is a quarrel won.
A stage in between good thwartivity and combativity (or a combination of the two) is the stage of chronic, but localized, inflammation or granuloma, where the protracted battle restricts itself to a focus without endangering the life or some vital parts of the organism. Reference to the quote from Dubos, above, will now amplify the significance of his statement that, "the disease showed a greater tendency to localize in the lung and to exhibit a chronic course." Most of the chronic granulomas represent this combination of combativity and thwartivity-the former unable to reach a definitive result in favour or against the host, the latter successful enough to contain the disease to a small area.
Often these terms are used in an abstract manner, but this conceptual vacancy can be mitigated in the light of our appreciating the nature of compromised immunity and/or nil/impaired thwartivity.
As was pointed out much earlier, a prime immunity mechanism is an intact epithelial cover. A large closed fracture may have an uneventful course but a small compound fracture may not, for the in the latter case, immunity was compromised for want of a few epithelial cells. The modern therapy of "immunosuppression" involves the use of almost lethal cytotoxic agents that destroy epithelia from head-to-foot and inside-out., and it is then not surprising that the hitherto most harmless commensals turn into lethal pathogens.  The fault lies not with the pathogens but with the compromised immunity barrier. Cosmetics to decdorize the vagina may only lead to resistant vaginitis and candidiasis-a price paid for disturbing the normally operative mechanism. Lack of asepis and antisepsis, in surgery, is a flagrant violation of the immunity barrier, an error that many an antibiotic may fail to rectify. The change of normal microbial flora, so common thanks to the modern antibioticism ,, can mean impaired immunity with resultant susceptibility. Resistance, in immunological terms, then means uncompromised immunity mechanisms - of every type and on every front.
The entry of a microbe into a virgin individual or a population is not resisted for want of thwartivity, with the result that a person, group or a generation appears as susceptible to the microbe, the susceptibility being expressed as combative reactivity with the odds often against the host. The susceptibility, however, changes into resistance wish the evolution-individually, groupwise, phylogenically-of good thwartivity. On the other hand thwartivity, natural to an individual, may be impaired under varied conditions. Protein malnutrition may mean poor digestive enzymes right at the level of the scavenging macrophages so that the engulfed tubercle bacilli instead of being digested and eliminated, may multiply uninhibitedly  to eventually excite combative foci called clinically and pathologically as active tuberculosis. Hypercorticism, resulting from stress  or by medication, seriously impairs thwartivity, converting resistance into susceptibility. 
The foregoing discussion on resistance/ susceptibility may drive home a point that in an encounter between a microbe and man, the latter may play a more decisive role in inviting/avoiding infection. Such eulogistic accounts of man's "success" against microbe as Paul de Kruif's Microbe Hunters and such anthropocentric labelling of microbes as "microassasins"  have fostered the idea, in minds medical and lay, that the microbes are the villain-of-the-piece. In reality, the Homo sapiens may be the greater villain. Such elaboration is pertinent in the present article for "immunity" from within  and antibiotics from without  have been hitherto held as "protecting" man against the microbial "enemy." The truth is probably different as follows.
In the heading above, ordinarily Man would have had the pride of place, but biorealistically he can't, for he is too puny in comparison with the Microbes: "Their prevalence is stupendous; it has been calculated that by weight they exceed all animal life on earth twenty times. Their numbers are incalculable and beyond comprehension."  Notwithstanding this awesome microbial dominance, clemency seems to be the rule, cruelty an exception. "By far the most common type of relationship between an infectious agent and the host," Wood  generalizes, is of the "nondestructive' symbotic or commensal" variety. The human population explosion has had its start as early as 1400 A.D.,  much before Pasteur, Lister or Domagk had offered anything against the "micro-assasins." Man is, what he is, because of-and not despite-the microbes.
In interactional terms, the microbial plagues of the past were an outcome of man's alarmist  combative reaction against a particular microbe, this being man's initial reaction towards any microbe. Later, symbiosis prevailed, on the dawning of thwartive wisdom-the principle that a quarrel avoided was a quarrel won. This axiom had its most impressive application-"the greatest lifesaving achievement in medical history"  -in the simple practices of sanitation, antisepsis, and asepsis, Man's penchant for entering into a combat with a microbe has been, is, and will be his own undoing.
"The fault dear Brutus, is not in our stars but in ourselves." (Shakespeare). We must now realize that it is not the microbe that is pathogenic, but man's reaction to it that makes it so. Either every microbe is pathogenic, or none is. This has been stated very well in The Biologic and Clinical Basis of Infectious Diseases, published in 1975. In an early chapter, Youmans  points out that although we have so far regarded "pathogens" as microbes possessing some unique disease-producing power, it must be emphasized that such special pathogenic characteristics of microbes are probably the exception rather than the rule. "It is now recognized that many bacteria not ordinarily regarded as pathogens have the capacity to produce infection and disease, and this capacity will depend more upon host defense mechanisms than upon any special characteristics of the microbial cell."  Man, know thyself, and the limitations of the powers of thy "immunity", and antibiotics.
Antibiotics generate "immunodeficiency."  This they do by interfering with the macromicrobial dialogue, a necessary prelude to the emergence of effective thwartivity in an individual or a group. They also render a person vulnerable to other infections by upsetting the microbial flora. The dangers they pose led Raeburn  to prophesize, in 1972, that "In years to come, the story of antibiotics may rank as Nature's most malicious trick" on man. Hard-core statistical facts more than support the above prognosis: Dubos  begins his chapter on microbial diseases with a cynical heading-"THE SO-CALLED CONQUEST OF MICROBIAL DISEASES," pointing out that despite so much blah blab on victory over microbes, paradoxically the percentage of beds occupied by patients suffering from infection is now as high as it was 50 years ago. A recent editorial  in the BMJ painfully generalizes that the mortality from cerebellar abscesses has risen from 25% in the fifties to 55% in the seventies despite all the antibiotics now available, and that today brain abscesses carry the same mortality as they did in the hand of Macewen in 1893. Paterson  concedes that antibiotics had, had their day, but the gains have been more than offset by a steady increase in the incidence of infections caused by microbes previously considered much less pathogenic or even non-pathogenic. Youmans too is justifiably cynical in attributing the foregoing to "Medical Progress. He concludes that while managing-an intractable infection, what is needed is not the "right"antibiotic, but an understanding and the rectification of the disturbed macromicrobial interrelationship. No antibiotic, extant or on the horizon, could ever compensate for a combative focus that a ventricular shunt or a valve excites by the mere fact of being foreign, nor could it mitigate the cytotoxic ravage perpetrated by modern immunosuppressive advances. The unsurmountable problem of microbial resistance to antimicrobials is too self-evident to merit any detailing here.
The handwriting on the "immunological" wall is clear: Fleming and his followers have had a past, but Semmelweiss and Lister have a perennial future. The best "immune" response is one that is not needed-as a response or a reaction. Notwithstanding the eulogies by Robert Good-"the dominant figure of modern immunology"  - so-called "immunity" and "immune-reaction" are poorly trustworthy in man's battle against microbes. It has been customary to call the latter parasites; the truth is that microbes are the host, and man is but a guest in ' the microbial world. It will be a great day for mankind when "so useless" modern medicine will stop bragging about antibiotics and antibodies, and come to ecological terms with the mighty microbes.
Biorealistic appraisal -of the nature of "immunity". renders imperative. the. realization thatt the era of immunologism, Leleism (Immunity as everyone's: fool); and Goodism (Immunity can knock off microbes with one hand, malignant cells with another) should come to an end, the sooner the better. The swelltide of immunologismic arrogance has bred researchosis, papyrosis, and confusion worse confounded from unintelligible double-speak, all climaxed recently by "the scientific scandal of the century," the famous la a ffaire de Summerlin from the prestigious Sloan-Kettering Institute, New York.  Perusal of Burnet's  Genes, Dreams and Realities makes it painfully clear that the much-vaunted molecular biology is failing us everywhere to which immunology is no exception. The future of immunologic research is clear-there is no future. The discovery of "auto-immunity" has added a cancerous mass of facts, unlikely to make much beneficial sense vis-a-vis man and his maladies.
Immunity and reactivity are gestalt processes that, like most natural processes, permit wider understanding but little interference. Immunity is the liaison officer between the self of man and the not-self microbes, and sees to it that man keeps afloat in the microbial ocean. Reactivity is far more complex, but its raison d'etre is to recognize any disturbance in cytologue, react and reject the disturber be it from without or within, and finally to restore things to status quo ante. No wonder, then, that aseptic inflammation, septic inflammation, "auto-immunity," wound healing, graft rejection or the rejection of an implanted glass piece, one and all, evoke basically the same CelluloHumoroVascular Response.