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Defense system shortcuts and limits of scope
Medical Hypotheses (2000) 55(4), 277–282 © 2000 Harcourt Publishers Ltd doi: 10.1054/mehy.2000.1185, available online at http://www.idealibrary.com on
Defense system shortcuts and limits of scope E. Rewald, M.M. Francischetti Mar del Plata, Argentina
Summary Defense, as a key factor of life, shares the biological tendencies of simplicity and energy saving. We propose that, like the mind, defense tends to rely on shortcuts via immune memes. Also, response repetition may induce the formation of virtual ‘modules’ [toolkits] to simplify and perfect performance. Engaged modules may expand by proliferating or by capturing immune components from the ‘dormant’ and even perhaps from active ones. With regard to recovery and/or survival, complexity of the integrated defense system (IDS) (1) requires to be inside of what we call the ‘functional window’. In contrast to the physiological and common disease repair, energy is squandered when IDS perceives real danger. Our concern is the uncertain transition to conditions that do not fit into the IDS routine and, even worse, that are outside the functional window where the system is lacking. © 2000 Harcourt Publishers Ltd
PART I: THE IMMUNE MEME/MODULE TANDEM: OPTIMIZING DEFENSE YIELD? A. Immune meme Darwin did a lot of good thinking about biological evolution without a precise idea of genes. The concept of the meme was ‘invented’ by the zoologist Richard Dawkins as a foil to the idea that the evolutionary process applies only to genes (2,3). The idea gave rise to ‘memetics’ as an area of study now highly regarded in the mental sphere. Memeticists regard memes as being manifold.1 Considering immune memes, we basically refer to them as ‘tools’ that the immune system may develop to simplify immune input. A meme may allow identification of a foreign or antigenic subject on the basis of one or a few molecular structures out of perhaps a myriad of socalled epitopes. A constellation with uncommitted B and
Received 7 March 2000 Accepted 18 August 2000 Correspondence to: Ernique Rewald, Corrientes 3550, 7600 Mar del Plata, Argentina. E-mail: [email protected] or [email protected]
T cells should not be considered as a tabula rasa; it may have a say in selecting suitable memes out of an intruder’s complexity. The immune meme input may benefit the cognitive segment by speeding up decisionmaking and tuning possible responses. In other words, familiar immune memes may induce a response spectrum that ranges from nil up to the unleashing of selfdestruction. Here we consider both innate immunity and tailored response to selected antigenic peptides. As in the case of mental decay, in which memes tend to endure (4), what we call immune memes may perhaps come into their own by curbing an ongoing immune paralysis. Memes, as we understand them here, imply a clichélike simplification. For instance, identification of a cat or an umbrella is universally obvious. We hypothesize that similar shortcuts characterize the perception of many immune stimuli. An epitope can be representative of a target composed perhaps of a myriad of antigenic determinants. The natural tendency to simplify and save energy leads to defense-effective advantage by specific 1
A weapon of memes is imitation. In the era of communicative artifacts, it has been claimed that memes also have a say. We could also apply the theory to bugs which, precisely, camouflage the ‘identifying’ molecule that the hosts had selected out of their body mass, thereby influencing immune response.
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interaction, and the decision of mounting an effector reaction or not. Einstein did not rely on what Man perceives, so he reduced concepts like space and time to mere intuition. B. Effector modules harnessing Functional units may result from exposure to stimuli On the ladder of acceptance we refer to steps such as Burnet’s network approach (5). The IDS provides insight into many reactions (1), but further research is needed. Molecular biology now unveils similarities in tools, for connecting cells. Immune messengers, receptors, and also the whole costimulatory spectrum [ligands, etc.] participate to optimize ‘cell talk.’ Since 1964 (6–8), when highdose intravenous immunoglobulin infusions began to be used we became aware of its complexity. Although unable to assure success, the ‘hazard game’ often paid off. On the basis of such an uncertain background, we propose that the significant immune challenges to which an individual may become exposed may prompt the unfolding of ‘modules’. The virtual construct may be nourished either by a major impact or by stimulus repetition. Like a toolkit, a module is ready for a combined innate and adaptive immune response. Supporting cells, messenger, costimulatory, and ancillary molecules, hormones and nerve sources also contribute. Not necessarily all of them derive from the host. Neither does defense rely exclusively on the individual. Symbiotic interactions, especially with the associated microflora and with incoming microorganisms, must be taken into account (9,10). Healthy individuals carry about ten microorganisms per body cell, while the internal and external milieus undergo changes. Things are not that simple. An immune module as belonging to the effector arm is not always expected to produce an identical response. Molecular resources may run out, for example, due to simultaneous aggression facilitated by crowded living (11,12). Also, noise and stimuli from hormones and nerve sources may modify the modules effect. Back to memes: Supported by a psychosomatic point of view, the already established memes concept may also be a player. According to White and Moorey (13), psychosomatic illnesses are not ‘all in the mind.’ Symptoms such as anxiety have to be regarded as real (14). Seen from this angle, virtual memes from the mental sphere may acquire protagonism by stirring immune cell/molecule constellations. Immune modules may also belong to the physiologic and/or physiopathologic domain, hence also perhaps becoming motivated. It is conceivable that the underlying construct of cell/molecule constellation may produce symptoms to be identified as a psychosomatic [‘meme’] disease. All this may contribute to the fact that immune Medical Hypotheses (2000) 55(4), 277–282
response circuits seldom show linear patterns. Provided the psychic component becomes evident, virtual memes originating from the mind may perhaps convert immune modules from ‘bipolar’ [instructed by heterologous/autologous stimuli] to ‘tripolar.’ The relationship among modules reminds us of approaches in fields such as mathematics (15) and related ones, in which entities are studied and analyzed and may be regarded as certain particular sets. For example, loosely packed galaxies without apparent order, when clustering, are prone to collisions in proportion to their density. Rather than focusing on everyday immune dynamics, here we look for unconventional behavior when the system disrupts. MODULE IMBALANCE The idea of modules in no way contradicts the exchange of components. Also, if provoked, a module could get into a state of agitation, as distinct from the indolent wheeling of aimless scattered T cell and B cell populations. When activated, a module may expand by cell proliferation/activation at the expense of others, ‘dormant’ and/or functional. Borrowing again from astronomy, we may call this capturing ‘immune cannibalism’ and the expenditure of energy a ‘strong source of waves.’ Immune modules competing to prevail may also imply intermodular displacement and, perhaps, substratum competition. Could module constellations be linked to TH1/TH2-type prevalence or vice versa? Although their clinical significance is less clear in recent time (16), clonal expansion of CD4 T-cells may favor the TH1-cell type (cell-mediated orientation) or the TH2-cell type (humoral orientation). Uncertainty may raise questions such as: what about, for example, autoimmune disease triggered by vaccination excess? Here we think about the so-called ‘Gulf War disease’; servicemen had been ‘protected’ by about 35 preventive vaccination shots. CLASH OF INTERESTS? Evidently, anxiety doesn’t specifically induce immune response. But we do not know whether it could excite immune modules generically even when ‘dormant.’ Here, anxiety could produce a ghost-like activity. The question is: would this make a module less vulnerable as the prey of expanding ones? If so, memes from the psychosomatic sphere may interfere with ‘IDS mobilization’ to fight invaders. CONCLUSION I Taken together, the concepts of immune memes and immune modules seem appealing. They suggest that © 2000 Harcourt Publishers Ltd
Defense system shortcuts and limits of scope
daily IDS circuits simplify both the afferent cognitive and efferent effector arm. Streamlining may favor efficiency and energy saving. Besides influences of diverse nature, for better or for worse, virtual memes from the mental sphere seem to have the potential to play a regulatory role. Conceptual alternatives, such as ‘immune’ memes and modules, are also based on the awareness that, by the way complexity of IDS evolves, it may outperform the sum of genes plus environment. The types of mechanisms available to genes are, in fact, limited. So are those of the environment. Neither will determine kaleidoscopic interactions and timing of IDS in absolute terms.
PART II: IN THE FUNCTIONAL WINDOW Past events are not clearly in focus but interest in conditions supposedly reminiscent of what living beings might have been exposed to is increasing. As far as we know, Homo sapiens’ greatest challenge was climatic extremes, but harassment by predators and the propensity for infighting, shared with many species, were everpresent. Innate immunity (17,18), dating back perhaps since organized life began, produces significant generic responses. It remains a first-line defense against microorganisms. Recent evidence reveals that this arm of immunity did not evolve to be entirely nonspecific. Similarities between pathogen recognition, signalling pathway, and effector mechanisms of innate immunity in Drosophila and mammals, point to a common ancestry. With the advent of lymphocytes in vertebrates, the efficiency of the system made a significant leap forward. In conjunction with macrophages and active molecule libraries, wide-ranging specificities unfolded. A refined coordination between innate and adaptive immunity eventually evolved. Inside the normal frame with all the resources available, the IDS will perform an optimal job. The IDS is far more versatile than the traditional immune system concept as multiple messengers are shared despite differentiation diversity. Besides connecting their cell populations, they allow vital intersystemic links. The contribution of innate immunity, mainly acute-phase reaction and removal of hostile antigens, is basic. The same can be said for adaptive immune mechanisms. But endocrine and nervous participation are pillars that should not be underestimated. Furthermore, an individual is protected by complex surface layers supported by significant inflammatory responses. Skin and mucosae do not totally envelop the organism. But their importance becomes evident, for example, in the case of extensive burns. Among the protective mechanisms, fibrotic reaction has to be considered with possible attenuation over time (19). Common bugs tune ‘IDS reactions’ over eons to a remarkable balance. Inside the © 2000 Harcourt Publishers Ltd
279
functional window, most challenges induce healthy responses. This has to be viewed in the context of transformations as determined by leading and lagging immune disorder. But beyond that, the virtual system will collapse. Distinguishing silent and noisy IDS action An important characteristic of the IDS routine is ‘surveillance,’ a vital mechanism (20) that protects the subject from aberrations of its own cell constituents – in other words, by eliminating single cells or, perhaps, small cell clusters that had mutated to malignancy; normal IDS function prevents the development of cancer. Somehow, this also shows systemic patterns of action. Although the mechanisms may vary, most daily clearing processes are fleeting and ephemeral, the host not even becoming aware of what is happening. We may ascribe this to the ‘weak immune force’ that silently gets rid of incoming microorganisms, be it from public transportation or from contaminated food and so on. This also includes silent annulment of microbial invasion when regarded as a real menace. Manifestations are mostly vague when defensive activity becomes revealed to us. A so-called disease outbreak would be a step further, possibly ignited by signals that immune cognition considers alarming. There may be crescendo reaction with symptoms like chills, fever, flu-like weakening, which may lead to a volcanic-like eruption with catastrophic consequences. Distinction in fighting invaders appears to justify terms like ‘weak’ and ‘strong force’, which in physics point to sharp alternatives (21). There is indeed a noteworthy parallel between life-long unawareness of the routine removal of microbes and the historical ignorance of worlds of possibilities inherent to the ‘weak force’ of physics. Up till little more than a century ago, people did not imagine how much life would be changed by radio communications, TV, the Internet, Xrays, ultrasonography, etc. Conversely, mega-manifestations, from the ‘strong force’ in physics, cannot be ignored. Pulling the rug out from under immune conventions? On the edge and beyond the functional window After a fleeting reference to IDS routine, we may briefly deal with conditions, physiological or otherwise, that alter the usual response profile. Although they may be considered as belonging to the periphery of the functional window, the fact that all these variants evolve in the system is important. Obviously, pregnancy is a transitory event; so perhaps are parasitic infections. The duration of autoimmune disease manifestations and of immunopathology caused by the increasing numbers of Medical Hypotheses (2000) 55(4), 277–282
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organ transplants may be considered undetermined. Advanced age is irreversible. A. Pregnancy, parasitism, transplants It remains to be fully clarified how the host will comply in each case. Hetero-transplants had added a new dimension. B. Autoimmunity: from physiology to pathology – targeting when, where and why The autoantibody repertoire is already present at birth. We still have no precise answer about why and when these autoantibodies or similar ones become triggered in an explosive mixture. The fact is that, in many autoimmune diseases, an immune impairment unfolds. We may also cite increased incidence of autoimmune manifestations in chronic lymphocytic leukemia which, characteristically, associates with immune deficit. Aging is also a risk factor. Microbes often appear to be involved, either as a complex triggering factor or by confusing specific immune response by means of mimetism. The last few decades reveal a sharp increase in autoimmune diseases (9). Historically, they seem to have been a rarity, afflicting rather affluent people. Present geographic distribution also points to hygiene, allergic and regular autoimmune manifestations being led by countries such as Japan and Sweden. The fact is that, in these countries, the risk of industrial pollution is trailing the ‘disease of hygiene.’ The multifaceted systemic lupus erythematosus (SLE) may provide an insight into the way in which autoimmune conditions move away from daily IDS activities: (A) SLE tends to strike certain body constituents selectively; (B) The enigma is why certain joints become affected and others are spared; (C) Unexplained migratory tendencies may affect almost all organ systems; (D) Variability in the inflammatory manifestations and their timing also remain to be clarified. SLE symptoms may perpetuate, the disease is rather prone to exacerbations but may remit with time. It remains to be seen if infighting, either immune or microbial, could affect the manifestations. In contrast, inflammatory bowel disease (22) is often considered as related to a quasi-mutinous colonic microbial microhabitat. Like SLE, the focus may be multifactorial with possible links to the immediate or mediate habitat. This does not necessarily indicate the involvement of exact microbial aggression. It does not exempt us from considering omnipresent genetic conditions. But understanding local circumstances may possibly clarify physiopathologic mechanisms. When aging exhausts an individual, he invents a disease to die. Medical Hypotheses (2000) 55(4), 277–282
C. Senescence: beware of hasty conclusions – Present knowledge supports age-conditioned decay with IDS as part of it In spite of confusing variables, statistics of epidemics underscore old age as the risk factor for deadly outcomes. Recently, the traditional viewpoint came under challenge. For example, Lesourd and Mazari (23) distinguish between primary, intrinsic, and secondary, environmentally conditioned, changes. They claim that primary immune changes per se may not explain the increased incidence and severity of infections in the elderly. To attempt to resolve the dilemma, we propose considering immune defense as a continuum rather than the sum total of the impressive number of facts on which present laboratory research relies (24,25). Consider that astonishing progress in physics rather depends on complex ‘low force’ network interaction than on particular particles’ behavior or on energy expenditure. By adopting the terms ‘strong’ and ‘weak’ from those forces, many circumstances, including senility, evidently require further consideration. A holistic view might allow a proper perspective on the evident handicap in the outcome of the elderly. It may perhaps disclose a deficit in the highly complex mechanism of IDS’ coordination. For now, a clue that stands for all factors of IDS age-conditioned decay is not at hand. A boxer, at the edge of KO, will not give up, but with no system fighting turns grotesque. Immune research mainly focuses on the fields of physiologic and disease repair. But, as always, there are limits. Inside this frame, manifestations sharply distinguish from the shattered events when defensive attempts become overwhelmed by aggression. Some transition will be discussed but, basically, beyond the ‘functional window,’ the system ceases throughout. Aggression in excess may lead to ‘immune paralysis.’ There will no longer be such a thing as the IDS and any attempt at a ‘general mobilization’ will result in chaos, like a beheaded chicken running around the yard.
DIFFERENTIATION IS NOT PERENNIAL We learn about erythroid cells that may switch to neuronal function, provided that they adapt to integrate an appropriate nerve-tissue environment. Conversely, a neuron that derives from ectoderm is induced to thrive within the particular molecular constellation of the bone marrow, mainly coming from the mesoderm. It may initiate hematopoiesis (26,27). Surprising? Not really, if we consider that even a hair cell has potential to build a complete being. © 2000 Harcourt Publishers Ltd
Defense system shortcuts and limits of scope
BURNET’S FORBIDDEN CLONES THEORY LOOSENS STRAIT JACKET For some years, a series of observations tended to shed some doubt on the forbidden clonal-selection theory. Now it has been shown that it is possible that mature B cells can be induced by antigen to re-express the recombinant-activating genes RAG1 and RAG2. Previously, the genes were supposed to ‘disappear’ after completing the development periods of variable, diversity, and joint recombination [V(D)J] at the pro- and prelymphocyte stages. In effect, a supposedly stable specificity may become erased like a school blackboard and immunoglobulin-gene recombination may have potential to generate new B cell receptor specificities. The question is to what extent these brilliant research results (28–30) can be applied for practical purposes. For example, in case of emergency, can a legion of specificities switch to focus at a target like a laser beam? RESILIENCE Careful biological scrutiny revealed in a number of species the possibility of astonishing performances by technically crushed specimens. Might this be because of wild sprouting surrogates? Even in the absence of IDS, the ontogenetically ancient innate immunity may show activity by the expressing acute phase reaction. Remnants of adaptive immunity could perhaps act as an additional tool. Any impact, supposedly, will surprise most lymphocytes at rest. To date we don’t know how far they can be reprogrammed for an emergency. To consider an attempt to deploy all remaining resources (general mobilization in military terms) to reverse chaotic breakdown, abstraction from routine is mandatory. A HISTORICAL EQUIVALENT? Long before the fragmented German regions became united into a state, Heinrich Heine (1797–1856), pondering about French philosophers who helped to open the gates of their great revolution, prophetically alerted the French that Germans were, by far, more meticulous. ‘Once it’s their time to fight, no trace of their superb philosophy will remain. Blindly they will produce death and destruction all around’. Could we say that French but not German historic transformation evolved inside a functional window? CONCLUSION We have borrowed words and ideas like memes, modules, constellations, windows, rivalry, infighting, cannibalism, and weak and strong forces in a modest attempt to make the complex IDS easier to approach. © 2000 Harcourt Publishers Ltd
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While the IDS is absolutely ignored by us while healthy, it turns out to be a major event with the outbreak of disease. ACKNOWLEDGMENTS We wish to thank Lia Barberis, a medical sciences-orientated English professor, for her friendly and professional support, and also the staff in the library at the Centro Médico de Mar del Plata.
REFERENCES 1. Rowat S. C. Integrated Defense System Overlaps as a Disease Model: With Examples for Multiple Chemical Sensitivity. Rev Environm Health Perspectives 1998; 106 [Suppl 1]: 85–109. 2. Dawkins R. The Selfish Gene. Oxford: Oxford University Press, 1976. 3. Blackmore S. The Meme Machine. Oxford: Oxford University Press, 1999. 4. Aunger R. The latest from culturology: infectious, selfreplicating social analogues of genes. But the ends of explanation justify the memes? The Sciences 1999; September/October: 36–43. 5. Burnet F. M. The Clonal Selection Theory of Acquired Immunity. Cambridge: Cambridge University Press, 1959. 6. Rewald E., Suringar F. ‘Substitutive-inhibitory gamma globulin therapy’ as prevention of stillbirth in Rh-incompatibility. Acta Haematol 1965; 34: 209–214. 7. Rewald E., Suringar F. Tolerance of intravenous gamma globulin. Bibl Haematol 1968; 29: 337–339. 8. Rewald E. Intravenous gammaglobulin to prevent stillbirth in Rhesus incompatibility [Letter]. Lancet 1985; ii: 208. 9. Rook A. W., Stanford J. L. Give us our daily germs. Immunol Today 1998; 19: 113–116. 10. Strauss E. A symphony of bacterial voices. Science 1999; 284: 1302–1304. 11. Rewald E., Francischetti M. M., González C. No man is an island: does the immune network extend beyond the limits of skin? Med Hypotheses 1999; 52: 325–327. 12. Rewald E. Immune Crossover – The Two Faces of Immunity. London: Parthenon Publishing, 1998. 13. White P.D., Moorey S. Psychosomatic illnesses are not ‘all in the mind’. J Psychosom Res 1997; 42: 329–332. 14. Wessely S. Responding to psychogenic mass illness. N Engl J Med 2000; 342: 129–130. 15. Suppes P. Axiomatic Set Theory. Holland: International Student Editions, 1960. 16. Allen J. E., Maizels R. M. Th1–Th2: reliable paradigm or dangerous dogma? Viewpoint. Immunol Today 1997; 18: 387–392. 17. Hoffmann J. A., Kafatos F. C., Janeway Jr C. A., Ezekowitz R. A. B. Phylogenetic perspective in innate immunity. Science 1999; 284: 1313–1317. 18. Catania R. A., Chaudry I. H. Immunological consequences of trauma and shock. Ann Acad Med Singapore 1999; 28: 120–132. 19. Rewald E. Antifibrotic tendency as complement to inflammatory burnout? Six year IVIG treatment in a case with atherosclerosis and chronic hepatitis C. Transf Sci 1999; 21: 3–5. 20. Benjamini E., Leskowitz S. Immunology: A Short Course, 2nd edn. New York: Wiley Liss, 1991. 21. Kaku M., Thompson J. Beyond Einstein. The Cosmic Quest for the Theory of the Universe. New York: Anchor Books, Doubleday, 1995.
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22. Heresbach D., Semana G., Bretagne M. G. An immunomodulation strategy targeted towards immunocompetent cells or cytokines in inflammatory bowel diseases. Eur Cytokine Netw 1999; 10: 7–16. 23. Lesourd B., Mazari L. Nutrition and immunity in the elderly. Proc Nutrition Soc 1999; 58: 685–695. 24. Fedorko M. E. Secretion of cytokines and modulation of function of immunologically competent cells. Med Hypotheses 1999; 53: 107–109. 25. Savitzky A. Cognition, emotion and the brain: a different view. Med Hypotheses 1999; 52: 357–362. 26. Vogel G. Harnessing the power of stem cells. Science 1999; 283: 1432–1434.
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27. Pittenger M. F., Mackay A. M., Beck S. C. et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999; 284: 143–147. 28. Yu W., Nagaoka H., Jancovic M. et al. Continued RAG expression in late stages of B cell development and apparent re-induction after immunization. Nature 1999; 400: 682–687. 29. Monroe R. J., Seidl K. J., Gaertner F. et al. RAG2:GFP knockin mice reveal novel aspects of RAG2 expression in primary and peripheral lymphoid tissues. Immunity 1999; 11: 201–212. 30. Schatz D. G. Developing B-cell theories. Nature 1999; 400: 614–617.
© 2000 Harcourt Publishers Ltd
Defense system shortcuts and limits of scope E. Rewald, M.M. Francischetti Mar del Plata, Argentina
Summary Defense, as a key factor of life, shares the biological tendencies of simplicity and energy saving. We propose that, like the mind, defense tends to rely on shortcuts via immune memes. Also, response repetition may induce the formation of virtual ‘modules’ [toolkits] to simplify and perfect performance. Engaged modules may expand by proliferating or by capturing immune components from the ‘dormant’ and even perhaps from active ones. With regard to recovery and/or survival, complexity of the integrated defense system (IDS) (1) requires to be inside of what we call the ‘functional window’. In contrast to the physiological and common disease repair, energy is squandered when IDS perceives real danger. Our concern is the uncertain transition to conditions that do not fit into the IDS routine and, even worse, that are outside the functional window where the system is lacking. © 2000 Harcourt Publishers Ltd
PART I: THE IMMUNE MEME/MODULE TANDEM: OPTIMIZING DEFENSE YIELD? A. Immune meme Darwin did a lot of good thinking about biological evolution without a precise idea of genes. The concept of the meme was ‘invented’ by the zoologist Richard Dawkins as a foil to the idea that the evolutionary process applies only to genes (2,3). The idea gave rise to ‘memetics’ as an area of study now highly regarded in the mental sphere. Memeticists regard memes as being manifold.1 Considering immune memes, we basically refer to them as ‘tools’ that the immune system may develop to simplify immune input. A meme may allow identification of a foreign or antigenic subject on the basis of one or a few molecular structures out of perhaps a myriad of socalled epitopes. A constellation with uncommitted B and
Received 7 March 2000 Accepted 18 August 2000 Correspondence to: Ernique Rewald, Corrientes 3550, 7600 Mar del Plata, Argentina. E-mail: [email protected] or [email protected]
T cells should not be considered as a tabula rasa; it may have a say in selecting suitable memes out of an intruder’s complexity. The immune meme input may benefit the cognitive segment by speeding up decisionmaking and tuning possible responses. In other words, familiar immune memes may induce a response spectrum that ranges from nil up to the unleashing of selfdestruction. Here we consider both innate immunity and tailored response to selected antigenic peptides. As in the case of mental decay, in which memes tend to endure (4), what we call immune memes may perhaps come into their own by curbing an ongoing immune paralysis. Memes, as we understand them here, imply a clichélike simplification. For instance, identification of a cat or an umbrella is universally obvious. We hypothesize that similar shortcuts characterize the perception of many immune stimuli. An epitope can be representative of a target composed perhaps of a myriad of antigenic determinants. The natural tendency to simplify and save energy leads to defense-effective advantage by specific 1
A weapon of memes is imitation. In the era of communicative artifacts, it has been claimed that memes also have a say. We could also apply the theory to bugs which, precisely, camouflage the ‘identifying’ molecule that the hosts had selected out of their body mass, thereby influencing immune response.
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interaction, and the decision of mounting an effector reaction or not. Einstein did not rely on what Man perceives, so he reduced concepts like space and time to mere intuition. B. Effector modules harnessing Functional units may result from exposure to stimuli On the ladder of acceptance we refer to steps such as Burnet’s network approach (5). The IDS provides insight into many reactions (1), but further research is needed. Molecular biology now unveils similarities in tools, for connecting cells. Immune messengers, receptors, and also the whole costimulatory spectrum [ligands, etc.] participate to optimize ‘cell talk.’ Since 1964 (6–8), when highdose intravenous immunoglobulin infusions began to be used we became aware of its complexity. Although unable to assure success, the ‘hazard game’ often paid off. On the basis of such an uncertain background, we propose that the significant immune challenges to which an individual may become exposed may prompt the unfolding of ‘modules’. The virtual construct may be nourished either by a major impact or by stimulus repetition. Like a toolkit, a module is ready for a combined innate and adaptive immune response. Supporting cells, messenger, costimulatory, and ancillary molecules, hormones and nerve sources also contribute. Not necessarily all of them derive from the host. Neither does defense rely exclusively on the individual. Symbiotic interactions, especially with the associated microflora and with incoming microorganisms, must be taken into account (9,10). Healthy individuals carry about ten microorganisms per body cell, while the internal and external milieus undergo changes. Things are not that simple. An immune module as belonging to the effector arm is not always expected to produce an identical response. Molecular resources may run out, for example, due to simultaneous aggression facilitated by crowded living (11,12). Also, noise and stimuli from hormones and nerve sources may modify the modules effect. Back to memes: Supported by a psychosomatic point of view, the already established memes concept may also be a player. According to White and Moorey (13), psychosomatic illnesses are not ‘all in the mind.’ Symptoms such as anxiety have to be regarded as real (14). Seen from this angle, virtual memes from the mental sphere may acquire protagonism by stirring immune cell/molecule constellations. Immune modules may also belong to the physiologic and/or physiopathologic domain, hence also perhaps becoming motivated. It is conceivable that the underlying construct of cell/molecule constellation may produce symptoms to be identified as a psychosomatic [‘meme’] disease. All this may contribute to the fact that immune Medical Hypotheses (2000) 55(4), 277–282
response circuits seldom show linear patterns. Provided the psychic component becomes evident, virtual memes originating from the mind may perhaps convert immune modules from ‘bipolar’ [instructed by heterologous/autologous stimuli] to ‘tripolar.’ The relationship among modules reminds us of approaches in fields such as mathematics (15) and related ones, in which entities are studied and analyzed and may be regarded as certain particular sets. For example, loosely packed galaxies without apparent order, when clustering, are prone to collisions in proportion to their density. Rather than focusing on everyday immune dynamics, here we look for unconventional behavior when the system disrupts. MODULE IMBALANCE The idea of modules in no way contradicts the exchange of components. Also, if provoked, a module could get into a state of agitation, as distinct from the indolent wheeling of aimless scattered T cell and B cell populations. When activated, a module may expand by cell proliferation/activation at the expense of others, ‘dormant’ and/or functional. Borrowing again from astronomy, we may call this capturing ‘immune cannibalism’ and the expenditure of energy a ‘strong source of waves.’ Immune modules competing to prevail may also imply intermodular displacement and, perhaps, substratum competition. Could module constellations be linked to TH1/TH2-type prevalence or vice versa? Although their clinical significance is less clear in recent time (16), clonal expansion of CD4 T-cells may favor the TH1-cell type (cell-mediated orientation) or the TH2-cell type (humoral orientation). Uncertainty may raise questions such as: what about, for example, autoimmune disease triggered by vaccination excess? Here we think about the so-called ‘Gulf War disease’; servicemen had been ‘protected’ by about 35 preventive vaccination shots. CLASH OF INTERESTS? Evidently, anxiety doesn’t specifically induce immune response. But we do not know whether it could excite immune modules generically even when ‘dormant.’ Here, anxiety could produce a ghost-like activity. The question is: would this make a module less vulnerable as the prey of expanding ones? If so, memes from the psychosomatic sphere may interfere with ‘IDS mobilization’ to fight invaders. CONCLUSION I Taken together, the concepts of immune memes and immune modules seem appealing. They suggest that © 2000 Harcourt Publishers Ltd
Defense system shortcuts and limits of scope
daily IDS circuits simplify both the afferent cognitive and efferent effector arm. Streamlining may favor efficiency and energy saving. Besides influences of diverse nature, for better or for worse, virtual memes from the mental sphere seem to have the potential to play a regulatory role. Conceptual alternatives, such as ‘immune’ memes and modules, are also based on the awareness that, by the way complexity of IDS evolves, it may outperform the sum of genes plus environment. The types of mechanisms available to genes are, in fact, limited. So are those of the environment. Neither will determine kaleidoscopic interactions and timing of IDS in absolute terms.
PART II: IN THE FUNCTIONAL WINDOW Past events are not clearly in focus but interest in conditions supposedly reminiscent of what living beings might have been exposed to is increasing. As far as we know, Homo sapiens’ greatest challenge was climatic extremes, but harassment by predators and the propensity for infighting, shared with many species, were everpresent. Innate immunity (17,18), dating back perhaps since organized life began, produces significant generic responses. It remains a first-line defense against microorganisms. Recent evidence reveals that this arm of immunity did not evolve to be entirely nonspecific. Similarities between pathogen recognition, signalling pathway, and effector mechanisms of innate immunity in Drosophila and mammals, point to a common ancestry. With the advent of lymphocytes in vertebrates, the efficiency of the system made a significant leap forward. In conjunction with macrophages and active molecule libraries, wide-ranging specificities unfolded. A refined coordination between innate and adaptive immunity eventually evolved. Inside the normal frame with all the resources available, the IDS will perform an optimal job. The IDS is far more versatile than the traditional immune system concept as multiple messengers are shared despite differentiation diversity. Besides connecting their cell populations, they allow vital intersystemic links. The contribution of innate immunity, mainly acute-phase reaction and removal of hostile antigens, is basic. The same can be said for adaptive immune mechanisms. But endocrine and nervous participation are pillars that should not be underestimated. Furthermore, an individual is protected by complex surface layers supported by significant inflammatory responses. Skin and mucosae do not totally envelop the organism. But their importance becomes evident, for example, in the case of extensive burns. Among the protective mechanisms, fibrotic reaction has to be considered with possible attenuation over time (19). Common bugs tune ‘IDS reactions’ over eons to a remarkable balance. Inside the © 2000 Harcourt Publishers Ltd
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functional window, most challenges induce healthy responses. This has to be viewed in the context of transformations as determined by leading and lagging immune disorder. But beyond that, the virtual system will collapse. Distinguishing silent and noisy IDS action An important characteristic of the IDS routine is ‘surveillance,’ a vital mechanism (20) that protects the subject from aberrations of its own cell constituents – in other words, by eliminating single cells or, perhaps, small cell clusters that had mutated to malignancy; normal IDS function prevents the development of cancer. Somehow, this also shows systemic patterns of action. Although the mechanisms may vary, most daily clearing processes are fleeting and ephemeral, the host not even becoming aware of what is happening. We may ascribe this to the ‘weak immune force’ that silently gets rid of incoming microorganisms, be it from public transportation or from contaminated food and so on. This also includes silent annulment of microbial invasion when regarded as a real menace. Manifestations are mostly vague when defensive activity becomes revealed to us. A so-called disease outbreak would be a step further, possibly ignited by signals that immune cognition considers alarming. There may be crescendo reaction with symptoms like chills, fever, flu-like weakening, which may lead to a volcanic-like eruption with catastrophic consequences. Distinction in fighting invaders appears to justify terms like ‘weak’ and ‘strong force’, which in physics point to sharp alternatives (21). There is indeed a noteworthy parallel between life-long unawareness of the routine removal of microbes and the historical ignorance of worlds of possibilities inherent to the ‘weak force’ of physics. Up till little more than a century ago, people did not imagine how much life would be changed by radio communications, TV, the Internet, Xrays, ultrasonography, etc. Conversely, mega-manifestations, from the ‘strong force’ in physics, cannot be ignored. Pulling the rug out from under immune conventions? On the edge and beyond the functional window After a fleeting reference to IDS routine, we may briefly deal with conditions, physiological or otherwise, that alter the usual response profile. Although they may be considered as belonging to the periphery of the functional window, the fact that all these variants evolve in the system is important. Obviously, pregnancy is a transitory event; so perhaps are parasitic infections. The duration of autoimmune disease manifestations and of immunopathology caused by the increasing numbers of Medical Hypotheses (2000) 55(4), 277–282
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organ transplants may be considered undetermined. Advanced age is irreversible. A. Pregnancy, parasitism, transplants It remains to be fully clarified how the host will comply in each case. Hetero-transplants had added a new dimension. B. Autoimmunity: from physiology to pathology – targeting when, where and why The autoantibody repertoire is already present at birth. We still have no precise answer about why and when these autoantibodies or similar ones become triggered in an explosive mixture. The fact is that, in many autoimmune diseases, an immune impairment unfolds. We may also cite increased incidence of autoimmune manifestations in chronic lymphocytic leukemia which, characteristically, associates with immune deficit. Aging is also a risk factor. Microbes often appear to be involved, either as a complex triggering factor or by confusing specific immune response by means of mimetism. The last few decades reveal a sharp increase in autoimmune diseases (9). Historically, they seem to have been a rarity, afflicting rather affluent people. Present geographic distribution also points to hygiene, allergic and regular autoimmune manifestations being led by countries such as Japan and Sweden. The fact is that, in these countries, the risk of industrial pollution is trailing the ‘disease of hygiene.’ The multifaceted systemic lupus erythematosus (SLE) may provide an insight into the way in which autoimmune conditions move away from daily IDS activities: (A) SLE tends to strike certain body constituents selectively; (B) The enigma is why certain joints become affected and others are spared; (C) Unexplained migratory tendencies may affect almost all organ systems; (D) Variability in the inflammatory manifestations and their timing also remain to be clarified. SLE symptoms may perpetuate, the disease is rather prone to exacerbations but may remit with time. It remains to be seen if infighting, either immune or microbial, could affect the manifestations. In contrast, inflammatory bowel disease (22) is often considered as related to a quasi-mutinous colonic microbial microhabitat. Like SLE, the focus may be multifactorial with possible links to the immediate or mediate habitat. This does not necessarily indicate the involvement of exact microbial aggression. It does not exempt us from considering omnipresent genetic conditions. But understanding local circumstances may possibly clarify physiopathologic mechanisms. When aging exhausts an individual, he invents a disease to die. Medical Hypotheses (2000) 55(4), 277–282
C. Senescence: beware of hasty conclusions – Present knowledge supports age-conditioned decay with IDS as part of it In spite of confusing variables, statistics of epidemics underscore old age as the risk factor for deadly outcomes. Recently, the traditional viewpoint came under challenge. For example, Lesourd and Mazari (23) distinguish between primary, intrinsic, and secondary, environmentally conditioned, changes. They claim that primary immune changes per se may not explain the increased incidence and severity of infections in the elderly. To attempt to resolve the dilemma, we propose considering immune defense as a continuum rather than the sum total of the impressive number of facts on which present laboratory research relies (24,25). Consider that astonishing progress in physics rather depends on complex ‘low force’ network interaction than on particular particles’ behavior or on energy expenditure. By adopting the terms ‘strong’ and ‘weak’ from those forces, many circumstances, including senility, evidently require further consideration. A holistic view might allow a proper perspective on the evident handicap in the outcome of the elderly. It may perhaps disclose a deficit in the highly complex mechanism of IDS’ coordination. For now, a clue that stands for all factors of IDS age-conditioned decay is not at hand. A boxer, at the edge of KO, will not give up, but with no system fighting turns grotesque. Immune research mainly focuses on the fields of physiologic and disease repair. But, as always, there are limits. Inside this frame, manifestations sharply distinguish from the shattered events when defensive attempts become overwhelmed by aggression. Some transition will be discussed but, basically, beyond the ‘functional window,’ the system ceases throughout. Aggression in excess may lead to ‘immune paralysis.’ There will no longer be such a thing as the IDS and any attempt at a ‘general mobilization’ will result in chaos, like a beheaded chicken running around the yard.
DIFFERENTIATION IS NOT PERENNIAL We learn about erythroid cells that may switch to neuronal function, provided that they adapt to integrate an appropriate nerve-tissue environment. Conversely, a neuron that derives from ectoderm is induced to thrive within the particular molecular constellation of the bone marrow, mainly coming from the mesoderm. It may initiate hematopoiesis (26,27). Surprising? Not really, if we consider that even a hair cell has potential to build a complete being. © 2000 Harcourt Publishers Ltd
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BURNET’S FORBIDDEN CLONES THEORY LOOSENS STRAIT JACKET For some years, a series of observations tended to shed some doubt on the forbidden clonal-selection theory. Now it has been shown that it is possible that mature B cells can be induced by antigen to re-express the recombinant-activating genes RAG1 and RAG2. Previously, the genes were supposed to ‘disappear’ after completing the development periods of variable, diversity, and joint recombination [V(D)J] at the pro- and prelymphocyte stages. In effect, a supposedly stable specificity may become erased like a school blackboard and immunoglobulin-gene recombination may have potential to generate new B cell receptor specificities. The question is to what extent these brilliant research results (28–30) can be applied for practical purposes. For example, in case of emergency, can a legion of specificities switch to focus at a target like a laser beam? RESILIENCE Careful biological scrutiny revealed in a number of species the possibility of astonishing performances by technically crushed specimens. Might this be because of wild sprouting surrogates? Even in the absence of IDS, the ontogenetically ancient innate immunity may show activity by the expressing acute phase reaction. Remnants of adaptive immunity could perhaps act as an additional tool. Any impact, supposedly, will surprise most lymphocytes at rest. To date we don’t know how far they can be reprogrammed for an emergency. To consider an attempt to deploy all remaining resources (general mobilization in military terms) to reverse chaotic breakdown, abstraction from routine is mandatory. A HISTORICAL EQUIVALENT? Long before the fragmented German regions became united into a state, Heinrich Heine (1797–1856), pondering about French philosophers who helped to open the gates of their great revolution, prophetically alerted the French that Germans were, by far, more meticulous. ‘Once it’s their time to fight, no trace of their superb philosophy will remain. Blindly they will produce death and destruction all around’. Could we say that French but not German historic transformation evolved inside a functional window? CONCLUSION We have borrowed words and ideas like memes, modules, constellations, windows, rivalry, infighting, cannibalism, and weak and strong forces in a modest attempt to make the complex IDS easier to approach. © 2000 Harcourt Publishers Ltd
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While the IDS is absolutely ignored by us while healthy, it turns out to be a major event with the outbreak of disease. ACKNOWLEDGMENTS We wish to thank Lia Barberis, a medical sciences-orientated English professor, for her friendly and professional support, and also the staff in the library at the Centro Médico de Mar del Plata.
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