PerspectivesAre you interested in submitting a Perspective Article? Be sure to read The Science Advisory Board's Editorial Guides for Perspective Articles. Click here. Post-Infectious Immunity: the Origin of its Strength and Duration by Sergey N. Rumyantsev, M.D., Ph.D. One of the ‘atomic facts’ of immunology is that the immunity naturally acquired through infection is usually incomparably stronger than vaccine induced resistance. Besides, it has no tendency towards decrease. In contrast, many vaccines need to be repeated to maintain immunity, induced by them. There exists a temptation to construct better vaccine that could give longer lasting immunity. Understanding of the nature of post-infectious immunity has become increasingly relevant. Meanwhile, nothing is known about the mechanisms, which provide the exclusive characteristics of post-infectious immunity. It is supposed that this form of immunity is not provided only by immunoglobulins, lymphocytes and other factors of inducible response but by some other mechanisms. However no ideas are discussed about what are these mechanisms. Moreover, for many decades the investigation post-infectious immunity was out of the mainstream of immunology. One of the current paradigms of the 20th Century’s immunology was that immunoglobulins and lymphocytes are exclusively responsible for strength of immunity both naturally acquired through infection and artificially induced by vaccination. Recently the protective function of naturally induced lymphatic system began to be doubted, because its first response is more inert and lazy than infectious pathogenesis is. An affected individual begin to develop a remarkable antibody response following primary infection by day six. If the infected organism is not dead at the moment, its lymphatic system provides him with a lot of acquired protective agents that are considered to be able to stop the primary infection as well as repeated infection with the same microbes. Moreover in some cases, such as tetanus and botulism, no post-infectious immunoglobulins can be produced, because even the lethal amount of their strongest toxins is not sufficient to induce lymphatic system. But in most cases the lymphatic system of a recovered individual acquired a memory for intensive antibody response to repeated infection with the same microbes. Intensification of protective potential of phagocytic mechanism is also observed during and after the primary and recurring disease. Nevertheless the existence of lymphatic and phagocytic immunogenesis cannot explain neither phenomenal duration of post-infectious immunity nor the cases of recurring diseases. Undoubtedly, all three known systems of immunogenesis (constitutional, phagocytic and lymphatic) are involved in the formation of post-infectious immunity. But because the post-infectious potential of lymphatic immunogenesis is equal to those of post-vaccination immunity the search of above specific characteristics of post-infectious immunity can be focused on its constitutional (genetic) components. Recent advances in molecular and cellular aspects of constitutional immunity fundamentally expand previous understanding of contra-infectious defense, and allow us to take a new look at the mechanisms of post-infectious immunity too. The role of constitutional mechanisms in formation of post-infectious immunity is considered below for the first time. Now we can consider the induction of constitutional components of post-infectious immunity as well as its duration during the life. For a long time these mechanisms of natural immunization were out of attention. The situation has now dramatically changed. To clear up what can we say about the nature of the phenomenon today, the features of this kind of immunity were interpreted here using the newest data of cellular and molecular immunology, molecular biology and genetics. Unlike individually induced response of lymphatic immunogenic system constitutional immunity is programmed in a genome. Like all other body's characteristics its mechanisms for protection are formed during ontogenesis in accordance with the genetic program of individual development but without individual induction by any particular parasite or parasitic product. Modern knowledge of constitutional immunity is based on observation of its epidemic and clinic manifestations supported by evolutionary ecological analysis of relevant molecular biological data. According to epidemic observations any given infection is able to affect only some parts of a species. Most members of humankind possess immunity although they never have been exposed to the infection before and have not any traces of immunoglobulins induced by previous infection or vaccination. They are preserved by constitutional immunity. Whereas such immunity is inherent, its manifestations are not adequate in all members of a species. There are variations between populations and individuals of the same species. The Mendelian ratios for the inheritance of immunity to microbial infections were stated firstly over 70 years ago by mating constitutive immune and constitutive susceptible organisms. After the first step, many genes that control constitutional immunity to some infections have been identified and mapped to a specific chromosomal location both in animals and humans. Thus, the CCR5 gene 32-base pair deletion provides strong constitutional immunity of human homozygotes to HIV infection. In the heterozygous state it may provide relative immunity thus stopping or delaying the progression of HIV infection to AIDS in affected individuals according to individual differences in a degree of heterozygosity. Primarily cultured cells from constitutionally immune organisms cannot be affected by an infection whereas the same pathogenic agents destroy cells of constitutionally sensitive ones. Thus, constitutional immunity of an organism is provided by constitutional immunity of its cell and subcellular structures. High specificity and power of constitutional immunity is provided by precious congruence of its mechanism to the molecular agents of microbe/victim interaction. Success of the interactions depends on the chemical and stereo-chemical complementarity of the interacting molecules. Every mutation able to transform intermolecular complementarity creates constitutional insusceptibility. Thus, the pathogenic effects of microbes and microbial molecules on molecular targets of the victim depend on the genetically determined molecular structure of the victim. The mutations bringing about the origin of similar stereo-chemical modifications of the molecular constitution of the victim reduce or even liquidate the safety of adequate intermolecular interactions and, accordingly, reduce the successfulness of the microbial aggression. The organisms possessing this modified molecular constitution are incapable of being affected with the microbe; they are not susceptible to this disease and are constitutionally immune to it. On repeated exposure to a given pathogen, the progeny of genetically immune mutants will finally predominate in a population; an individual protective mutation becomes a property of a group, then of a population and finally most of the species. Thus epidemics delete susceptible individuals from a population and the population gets inherent constitutional immunity. Constitutional antimicrobial immunity encompasses several specific and common structures possessed by the attacked organisms and used in defense against molecular ecological aggression of harmful microorganisms. Molecular mechanisms underlying individual variations in infection responses are provided by the differences in molecular make-up of the targets of microbial pathogenic activity. These structures are presented with a variety of molecular barriers such as a lack of specific cell receptors, modification of the specific cell receptor, modification of specific nutrients, lack of a specific nutrient, presence of specific antibiotic and\or poison, nonspecific mechanisms. Although infectious disease is usually named as a generalized process, in fact, every infection has a diffuse location in a body with specifically or stochastically disseminated focal manifestations. The focal (mosaic) lesions of cutis are seen, for instance, during small poxvirus infection in human and animals. They consist of a number of skin-lesions scattered over the surface of the body, each of which is the seat of inflammation so intense as to lead in the course of four or five days to the formation of a small abscess. Beyond the edge of the lesions, the normal skin is represented. When the lesion is healed it leaves a scar. The number of lesions which are present may not amount to a dozen in a light case of the illness; or there may be many thousands of them, and they may be set so closely as to conceal almost the whole cutaneous surface in a very severe course of the disease. Mosaic distribution of susceptible and immune areas is also characteristic of hepatitis, tuberculosis, typhoid and paratyphoid fever, poliovirus and the plethora of other infections. This is a widely observed phenomenon to which nobody called special research attention before. The nature of the dapple infectious manifestations has completely eluded of investigation and interpretation. Evidently, the ubiquitous phagocytes and immunoglobulins cannot functional in this phenomenon. The focal nature of infection is not explained by the lack of uniform presence of microorganisms in the body. In such cases, the infectious agent is found within both the typical damaged elements and the adjacent areas, which have been left intact. Constitutional immunity explains why parts of one category are affected by a given microbe, while at the same time many other morphologically identical components of the organism remain uninvolved although both exist under the same conditions and may be equally attacked by the agent. The origin of those mosaic configurations within infected structures that seem homogenous is determined by genetic nature of constitutional immunity. The mating of immune and susceptible individuals gives rise to progeny with intermediate extent of infectious foci and degrees of infection. The constitutionally immune parent passes on a lack of susceptibility to a certain infection to the in some parts of the descendant' body, while its susceptible parts of a different molecular or subcellular structure are inherited from the second parent. There is no such thing as a hybrid between the two. Thus, different parts of a body are not equally liable to an infectious damage. The size of the susceptible parts and its dispersion along the body is very variable. The modes of the focal damages distribution are either characteristic of some kind of infections or stochastic of many others. In a population reliant to inherent constitutional immunity to an infectious agent, individuals can be conveniently divided into three categories, as follows: 1) totally resistant organisms (no susceptible structures); 2) mildly susceptible organisms in which a few foci appear and the infection runs a benign course; 3) organisms in which the number of susceptible structures is high and the infectious process develops in a severe form with formation of many foci of specific lesions. In fact, every infection reveals in every affected organism at least two clones of homogeneous cells which differ sharply from each other with regard to one highly specific feature: cells of the first clone are immune to the infection, whereas those of the second one are susceptible to the same agent. After the patient’s recovery the structure appears changed because the susceptible parts of the body were eliminated during infectious process. Every infection eliminates the susceptible parts from the body affected by it, and the strength of post-infectious immunity is provided by absence of susceptible structures in the recovered organism. Just as epidemics delete susceptible individuals from a population and the population gets inherent constitutional immunity, infectious process deletes susceptible cell clones from an individual providing the organism with constitutional components of post-infectious immunity. Formation of constitutional component of post-infectious immunity is provided by death of cells, which were constitutionally susceptible to the infection before. The individual gets constitutional immunity, which will provide him with defense against re-infection. Because it is individually acquired variant of constitutional immunity, it cannot be inherited by offspring. The strong post-infectious immunity for all the life is formed by many viral (measles, small pox, scarlet, mumps, rubella) and bacterial infections (anthrax, whooping-cough, diphtheria, plague). Meanwhile patients with herpes, dysentery, influenza, malaria, and erysipelas may be suffered by recurred attacks. In the case of equally high sensitivity to the infection both mature and cambial parts of the affected clone the latest will be eliminated radically and the formed post-infectious immunity will be very strong and long. If the cambial part of the discussed clone unlike its mature part is resistant to the pathogen, the duration of post-infectious immunity can be restricted by regeneration of susceptible cell population. Because the formation of molecular constitution of every organism is controlled by a genetic program of individual development the constitutional status of immunity/susceptibility to infection in some cases may change also during ontogenesis of the organism. A general characteristic of most infections is the changed resistance to disease that develops in the course of growth and maturation of the possible victim. The changes are particularly dramatic in the neonatal period. Most infections, for instance influenza, can be very severe in neonatal period. Paradoxically, children and teenagers certainly seemed more resistant to anthrax infection than adults. Analogous paradoxical increasing of individual constitutional susceptibility with age is characteristic of meningococcal infection. References Rumyantsev S.N. Observations on constitutional resistance to infection. Immunology Today 1992; 13: 184-187. Rumyantsev S.N. AIDS: Fears are exaggerated, Moscow News (Les nouvelles de Moscou), 1992; 35:7. Rumyantsev S.N. Chemical ecology and biomolecular evolution. Acta Biotheoretica 1997, 45, 65-80. Dovzhansky S.I. Rumyantsev S.N. Regarding the location of clinical manifestations in dermatoses. Journal of the European Academy of Dermatology and Venerology (JEADV), 1997, 8, 256-257. Rumyantsev S.N. Constitutional and nonspecific immunity to infection. Rev. sci. tech. Off. Int. Epiz., 1998, 17 (1), 26-42. Rumyantsev S.N. Defend only the defenseless. Genetic variation and vaccination. HMS Beagle, The BioMedNet Magazine, 54, May 14-16, 1999. http://ny.hmsbeagle/54/viewpts/op_ed Rumyantsev S.N., Shabalov N.P., Pyasetskaya M.F., Rogacheva N.M., Bardakova L.I. Species, population and age diversity in cell resistance to adhesion of Neisseria meningitidis serogroups A, B and C. Microbes and Infection, 2000,5, 447-453. Rumyantsev S.N. Structural predestination of individual diversity in the course and severity of infectious diseases. TheScientificWorldJOURNAL, 2002, 2; 205-216. Rumyantsev SN: The best defence against bioweapons has already been invented by evolution. Infection Genetics and Evolution 2004, 4;159-166. Rumyantsev S.N. Bioweapon: The Emperor’s New Suit! The Science Advisory Board. Perspectives 2004, http://www.scienceboard.net/community/perspectives.104.html Rumyantsev S.N. Defend only the Defenseless. The Science Advisory Board. Perspectives 2003, http://www.scienceboard.net/community/perspectives.84.html Rumyantsev SN: Toward molecular level of the “Salmonella-Victim” ecology, genetics, and evolution. TheScientificWorldJOURNAL, 2004, 4, 193-199. Rumyantsev S.N. Constitutional immunity and its molecular ecological principles. (in Russian) Leningrad: Nauka, 1983, 210 pp. In: Contribution of Fundamental Sciences in Medicine edited by USSR Academy of Sciences and USSR Academy of Medical Sciences. Sergey N. Rumyantsev, M.D., Ph.D. has been a member of The Science Advisory Board since April 2002and is currently serving as a member of the Board’s 2004-2005 Steering Committee. ### << Previous Next >> [ View All Perspectives ] |
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