or many decades the investigation of post-infectious immunity’s strength and duration was out of the main-stream of immunology，and no ideas had been discussed about the nature of this specific phenomenon.In the try to fill the gap the most archetypal manifestations of different infectious diseases and their development during the clinical course and recovering have been analyzed from the viewpoint of recent advances in molecular and cellular aspects of constitutional （genetic） immunity.It has been stated that because intra-individual diversity in cells susceptibility to infection every disease is a diffuse process with disseminated focal manifestations.Thus，each infectious disease expresses in the infected organism at least 2 clones of the same tissue，outwardly identical and differing only in their either immunity or susceptibility to a given infection.The formation of constitutional component of post-infectious immunity is provided by the death of constitutionally susceptible cell clones which are eliminated out of the body during a relevant infectious process.The individual becomes constitutionally immune against re-infection.In a case of equally high sensitivity to the infection of both mature and cambial parts of the affected clone the latest is eliminated radically and the formed post-infectious immunity is very strong and durable for all the life.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.

【关键词】  biodiversity cell immunity genetic immunity heterozygosity individuality intra-individual diversity

　　INTRODUCTION

    One of the “atomic facts” of classic immunology is that the immunity naturally acquired through infection is incomparably stronger and durable than vaccine induced resistance.As a rule post-infectious immunity is characterized by stability and has no tendency towards decrease during all the life.Many childhood infectious diseases are the archetypal examples.For instance，persons having had measles，smallpox，chickenpox，scarlet fever，mumps have no need in additional protective measures irrespective of the time elapsed after the disease.In contrast，many vaccines need to be repeated to maintain immunity.The today’s anti-anthrax immunisation consists，for example，of a series of six doses.Meanwhile no cases of anthrax have been occurred in exposed individuals known to have recovered from a previously confirmed anthrax infection ［1,2］.

    It is usually supposed that this form of immunity is not provided only by immunoglobulins，lymphocytes and other factors of inducible response but by more stable other mechanisms.However no ideas are discussed about what are these mechanisms.Moreover，for many decades the investigation of special features of post-infectious immunity was out of the main-stream of immunology.According to PubMed-2006 the newest special publications on the factors of post-infectious immunity appeared at 1967 ［3］.

    To clear up what we can say about the nature of the phenomenon today，the features of this kind of immunity should be interpreted using the newest data of cellular immunology，especially its molecular and genetic aspects.It is to be supposed that all three known systems of immunogenesis （constitutional，phagocytic and lymphatic） are involved in the formation of post-infectious immunity.But because the post-infectiouspotential of lymphatic and phagocytic immunogenesis is now discussed very widely［4］，the chief objective of the present analytical investigation were constitutional （genetic） components of post-infectious immunity.Recent advances in molecular and cellular aspects of constitutional immunity fundamentally expand previous understanding of contra-infectious defense，and allow to take a new look at the mechanisms of post-infectious immunity.

    MAIN PRINCIPLES OF IMMUNOGENESIS

    Immunity is a state of being immune，e.g.having a degree of inherent or acquired resistance to a disease ［5］.Three principles of immunity maintenance are known today-constitutional （innate），phagocytic and lymphatic （Figure 1）.Human and vertebrate animals possess all three systems of immunogenesis.Constitutional and phagocytic mechanisms are performed by specific inherent qualities that are ready to counteract infection at the moment the last begins its attack［6-12］;they serve as a first and second line of defense.In a case they proved to be ineffective，the organism，if it has been attacked by infectious agents，has chances to be rescued by specific immunoglobulins after the last will begin to be produced by lymphatic system of reactive immunity.

    Figure 1  The main principles of immunogenesis：1-constitutional，2-phagocytic， 3 -lymphatic［11］

    One of the paradigms of 20 th 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 urgent protective function of naturally induced lymphatic system begins to be doubted，because its first response is more inert and lazy ［4］than infectious pathogenesis is.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［13］.

    In most cases lymphatic system of a recovered or vaccinated 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 ［8］.Nevertheless the existence of lymphatic and phagocytic immunogenesis can not explain phenomenal strong and duration of post-infectious immunity.

    CONSTITUTIONAL IMMUNITY

    Unlike individually induced response of lymphatic immunogenic system the innate constitutional immunity is inherent and is characteristic of a body before the last have been attacked by disease-causing agents.Its mechanisms for protection have been formed during ontogenesis in accordance with the genetic program of individual development but without induction by parasite or parasitic product ［7,11,14］.

    Whereas such immunity is inherent，its manifestation is not adequate in all members of a species.There are variations between populations and individuals.For example，a significant proportion of humans have genetic immunity to typhoid fever ［15］.In a special experiment a minority of tested people fall ill having ingested only a few microbes while others may harmlessly ingest 10，000 times larger doses of the agent ［16］.

    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 strains of mice［17］.Today the genes which control constitutional immunity to some infections have been identified and mapped to a specific chromosomal location both in animals and humans ［18,19］.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  delaying  the progression of HIV infection to AIDS in affected individuals［20］ according to individual differences in degree of heterozygosity ［21,22］.

    Primarily cultured cells from constitutionally immune organisms can not be affected by an infection whereas cells of constitutionally sensitive ones are destroyed by the same pathogenic agents［23,24］.Constitutional immunity of an organism is provided by constitutional immunity of its cells and sub cellular structures ［11,12,14,15,25～27］.

    High specificity and unprecedented power of constitutional immunity is provided by precious congruence of its mechanism to the molecular agents of microbe/victim interaction by the means of specialized molecular ecological substances （adhesins，toxins，enzymes，cytolysins，polynucleotides） that interact with the specific molecular structures of the affected body.Success of the interactions depends on the chemical and stereo-chemical congruence of interacting molecules.Every mutation able to transform intermolecular congruence 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，thereby defining either constitutional susceptibility or immunity to infection.For instance，mice lacking the Perutz gene-encoding a protein tyrosine phosphates receptor type 2 expressed in gastric glands-are immune to gastric ulcer induced by Helicobacter pylori［28］.

    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.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 ［11,26,29］.On repeated exposure to a given pathogen，the progeny of genetically immune mutants will finally predominate in a population （Figure 2）;an individual protective mutation becomes a property of a group，then of a population and finally most of the species ［10,30］.Thus epidemics delete susceptible individuals from a population and the population gets inherent constitutional immunity.

    CONSTITUTIONAL PREREQUISITES OF POST-INFECTIOUS IMMUNITY

    Although infectious disease is usually named as a generalized process，in fact，every infection is a diffuse process with specifically or stochastically disseminated focal manifestations.The focalized lesions of cutis is seen，for instance，during small pox virus infection in human （Figure 3） and animals.They consist of a number of skin-lesions scattered over the surface of the body.Beyond the edge of the lesions，the normal skin is represented.The number of lesions which are present may not amount to a dozen in a light case of 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 disease ［31］.Poliovirus infection picks out nerve cells at random although virus is present throughout all the nervous system ［32］.This can only mean that the nerve cells in certain areas are susceptible to viral damage but resistant in another ［33］.In the worst cases，nearly every skeletal muscle may be paralyzed.In the mildest cases，paralysis may be limited to part of one muscle.

    Mosaic distribution of susceptible and immune areas is also characteristic of hepatitis，tuberculosis，HIV and many other infections that affect chiefly internal organs［33,34］.Typhoid and paratyphoid fever can produce inflammatory foci in many organs.Necrotic or inflammatory foci are commonly seen in the spleen.and the liver，and sometimes in the kidney，the meninges，the bones，the endocardium，the joints and many other places ［33］.Increased sensitivity to  Helicobacter pylori infection which forms  the  base  of  peptic  ulcer  and gastritis， is  also characteristic  not  of  entire epithelial layer of  gastrointestinal tract，but of  its dispersed small areas （Figure 4） ［35］.One can note that if  a lesion of

    Figure 2  Transformation  of a population’s constitutional immune structure by epidemic process （［11］，modified）

    Figure 3  Mosaic focal distribution of specific lesions in a case of human smallpox   Figure 4  The microulcerarion of the stomach mucosa induced by  H.pylori （［35］，modified）

    multilayer gastric  mucosa is of  microscopic size it forms a cone thus demonstrating  that superficial cell layers  are more vulnerable than the lower i.e.cambial  layers  of the same epithelial tissue.

    Gastric antrum is the predominant site of colonization and affection by H.pylori,Changes are always patchy  （Figure 5） ［36］ but the whole body of the stomach can be involved in severe cases ［37］.In any case，the areas adjacent to the ulcers are left unaffected by the initial process and subjected only to reactive inflammation.The interaction between H.pylori and the mucosa can result in either multiple damages of smallest  size （chronic gastritis），single crater  of middle size （ulcer of stomach or duodenum），few craters （multiple gastric ulcers） or gastric carcinoma ［38］.Individual location  of the affections is variable.

    Figure 5  The variants of dislocation of the stomach chronic ulcers［36］

    In bacillary dysentery，the specific pathological changes are located in the colonic mucosa.［33］.Focal bone lesions were characteristic of some infections in Pleistocene bears which lived over 10，000 years B.C［39］.Thus，each infection is expressed in the infected organism by at least two categories of the same tissue，outwardly identical and differing only in their relationship to a given infectious agent.Every infection is a diffuse process with specifically or stochastically disseminated focal manifestations.In such cases，the infectious agent is found within both the typical damaged elements and the adjacent areas which have been left intact ［33,40,41］.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 that mosaic configuration within infected homogenous structures 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 ［21,22,40,41］.Thus，it must be concluded that 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 other.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 ［21,22］.

    The clonal histochemical architecture of small intestine，oesophagus，breast，and thyroid was demonstrated in  normal，as opposed to mosaic animals，using a diversity of the X-linked enzyme glucose-6-phosphate dehydrogenase （G6PD），as a clonal marker.The results were found to depend upon the simultaneous study of tissue from normal mice，mice homozygous for abnormal G6PD levels，and heterozygous mice.A dual population of cells was found in the heterozygous animals in all tissues studied ［42］.

    Constitutional immunity may involve only a few cells or the majority of cells in a population.As judged by the immunofluorescence assays of samples from HIV-positive persons，HIV-infected cells accounted for no more 10% of all cells tested ［43］.Cell strains spontaneously immune to the lethal effect of diphtheria toxin have been selectively isolated from human cell lines.The toxin immune cells were found to be 100,000  to 1,000,000 times more resistant to toxin than toxin-sensitive cells of the parent cell population ［23,24］.When a susceptible cell culture was affected by some microbial pathogenic factor，most cells were killed.At the same time，however，a number of outwardly undistinguishable cells fully preserve their basic functions despite the unfavourable conditions.In all cases，the culture contains cells which are not susceptible to the infection along  with those cells  which are susceptible to contamination and thus died.Infection can eliminate all susceptible cells from a cell  culture and the culture becomes constitutionally  immune.

    THE ORIGIN INTRA-INDIVIDUAL GENETIC DIVERSITY

    Most biologists focus today on various intriguing aspects of biological diversity of species and populations ［44］.There is，however，a not less attractive but yet overlooked form of biodiversity：a secret intra-individual diversity of organisms that is usually invisible but is revealed by relevant forms of pathology and development.An explosive growth in interests of this kind of biodiversity has not yet occurred.Although genes influencing inherent immunity/susceptibility should be present in all organs，tissues and cells the discussed  characteristic vary widely amongst different tissues as well as within a tissue.According to data of many experiments and observations the unequal quality of analogous structures  of the  same  genetic origin in an entire organism arises as a result of intra-species hybridization ［17,20,41,42,45］ of individuals with opposite genetic susceptibility to the infection （Figure 6）.Following to［46］ one can agree that Mendel’s classic paradigm cannot explain this kind of biodiversity.Molecular genetic mechanisms of these events may be discovered，for example，on the base of Barbara McClintock’s molecular genetic theory ［47］.According to the cited author’s opinion the process of development is regulated by structural changes that lead to the activation （or suppression） of different segments of DNA at different stages of organism development.Such a specific sequence of DNA  would be capable of reversing its orientation during the course of organism development.In one orientation，the switch is “on” and one type of features is produced;in the other orientation the switch is “off” and   the other type is produced.Similar genetic elements function，for instance，in aging-the genes that cause senescence （senescence effector genes），and those that oppose its effects （senescence resistor genes） ［48］.

    DISCLOSURE AND ELIMINATION OF SUSCEPTIBLE STRUCTURES DURING INFECTION

    In fact，every infection reveals in every affected organism at least 2 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 are susceptible to the same agent.Infection discloses the immune mosaic

    Figure 6  Origin of intra-individual immune diversity：A-Father，B-Mother，C-Offspring［53］Figure 7  Transformation of constitutional immune structure of a body by infectious process：A-before infection （susceptible structures are hidden），B-during the disease （susceptible structures are disclosed）， C-after recovering （susceptible structures are eliminated）

    which has been hidden before.In the course of infectious process the susceptible parts of the body are eliminated After the patient’s recovery this mosaic body’s structure appears to be changed （Figure 7）.In dysentery，the relevant parts of the affected body which have been eliminated by infection ［3］ can be replaced by immune clones of specific cells or by immune scar tissue.The areas of undamaged i.e.constitutionally immune mucosa may proliferate and attempt to cover the denuded areas with new epithelium ［33］.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.Formation of constitutional component of post-infectious immunity is pperformed by death of cells which were constitutionally susceptible to the infection.

    DURATION OF POST-INFECTIOUS IMMUNITY

    The strong post-infectious immunity for all the life is formed by many viral and bacterial infections.Meanwhile patients with herpes，dysentery，influenza，malaria，H.pylori infection，erysipelas may be suffered by recurred attacks.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 （Figure 4）.In a case of equally high sensitivity to the infection of both mature and cambial parts of the affected clone the latest is eliminated radically and the formed post-infectious immunity is very strong and durable for all the life.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.

    About 15 percent of all cases of childhood meningitis are  due  to  the  meningococcus ［49］，children under one month very seldom are known to fall ill with meningococcal infection.In a large  series of 211 cases of neonatal meningitis，N.meningitidis was an uncommon organism.Only two of 211 were  due  to N.meningitidis［50］.In concordance with these epidemic and clinical observations cells of human newborns are absolutely resistant to attachment of meningococci.Meanwhile in neonatal and followed  periods the cells become far different individually sensitive to meningococcal adhesion ［14］.But the cells of  two-day-old chicks are more sensitive to rabies  virus adhesion than those of adult chickens ［51］.Children and teenagers certainly seemed more resistant to anthrax infection than adults ［52］.

    CONCLUSION

    It got evidential，that constitutional mechanism of anti-microbial resistance forms a mighty component of specific immunity created in the course of infectious diseases.Its origin is based on the phenomenon of intra-individual diversity in genetic sensitivity to infection formed by hybridization of constitutionally sensitive organism and constitutionally immune one.The genetic component of post-infectious immunity is created in a course of a disease by eradication of constitutionally sensitive structures of the body.The new look at induction of post-infectious immunity is of general interest both in the entire discipline of immunology and in its practical application for epidemic and clinical work.

    ACKNOWLEDGEMENTS

    The author respectfully thanks all his genetic ancestors who formed his mosaic genotype，as well as all his tutors，educators，colleagues and opponents，who provided him with tools to find and promote new knowledge.Special thanks are expressed to Dr.J.Lederberg and Dr.D.Thaler of Rockefeller University，as well as to Dr.F.Rosen of Harvard Medical School and Dr.V.Gerasimov of Saint-Peterburg Medical Academy for their helpful support of and advices for development of the author’s ideas about the origin and functions of intra-individual biomosaics.

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（Editor Jaque）