Reconciliation

As far as distribution is concerned about half of all recognized disease causing organisms are worldwide in their distribution. In these days when travelling between continents is common this proportion may increase in time. The restrictions on distribution in part relate to differences in distribution of vectors such as mosquitoes, ticks and sand flies of particular kinds. It is also clear that many diseases are more common and rampant in tropical developing countries than in the temperate regions. The class of organism was put in for the sake of completeness and will not comment further on here except to point out the obvious fact that the more severe and dangerous diseases are largely caused by viruses or bacteria. If we were to look at domestic animals that in the tropics are ravaged by a wide variety of protozoan parasites a different story would emerge. Diseases in cattle in Africa include, on a potentially enormous scale, Trypanosome and Theilerial infections. For this table the old WHO classification which gave an indication of the reporting category to both local and global health authorities has been retained (Table 8).

Table 8: Approximate Percentage of Diseases in Various Categories.

The impact classification indicates roughly how important a disease was but the one plus, two plus, three plus categories adopted are too crude and of necessity applied arbitrarily. In some instances the numbers of people dying annually are recorded but in some instances this is not stated in the Manual. The various diseases in addition to their lethality and morbidity, that impose strains on the health care services, have economic consequences on for example the labour force. There are other sources of information dealing with these issues but overall figures of economic impact would perhaps be useful for PH officials to get some idea of the import of the diseases in question. These things are not written in criticism of the Manual, that clearly is written for American practitioners primarily but, faut de mieux, there seems little else enabling a global look at communicable diseases and the Manual does not confine its approach to diseases that are only significant in N America.

The target organ category looks at in broad terms what seem to be the primary disease sites. Clearly with many of the diseases in their worst and later manifestations major organ failure will be common often starting with the lung and heart. There are one or two things that stand out, ie the neurotropicity of some viruses emerges as does the predilection of bacteria to cause skin disease. Many of the diseases are recorded as systemic in relation to protozoa, bacteria and viruses. One of the most striking things that emerged is the high frequency with which it is recorded that susceptibility is universal or widespread. With the exception of the fungi and to some extent protozoan infections almost all human hosts, as far as we know, are susceptible to invasion by all the disease causing organisms. There are very few exceptions. All the organisms to which attention is drawn cause disease in the broad sense the human species is, ipso facto, susceptible to the diseases in question. What the manual shows many times is that susceptibility to invasion is in many instances not a good indication of whether disease will develop. Nor, if disease does develop, what will be the outcome. Rabies virus, for example, in Iran it is written in the 17^th edition , only caused disease in 40% of those known to have been bitten by rabid dogs. On the other hand the statement that when the disease caused by rabies virus develops it is always lethal indicates clearly the difference between being infected and developing disease. It should also be noted that a comparable statement does not exist in the 20^th edition. In foxes epidemiological studies [12] showed that disease was more rampant when the fox population density was highest.. Is it ridiculous to see such organisms as rabies being part of the strategy for population density control at least in some wild animals!? There are many organisms with which we come in contact that live within us without causing disease or which do cause disease relatively rarely but not in a manner that leads suspicion to fall on a named organism? CMV is not far off such an organism nor, perhaps, is EBV. Both the organisms in question are essentially ubiquitous but only rarely cause disease.

There is a lovely statement in the 1964 Topley and Wilson, Vol 11 [13] as follows:

‘The scientist shares with Humpty Dumpty the privilege of making words mean what he/(she) likes. But if we are to avoid confusion we must at least give our words definite orders and see that they are obeyed. It happens that the state suggested by the word that we have chosen as a generic label for the phenomenon we wish to study is one about which we know very little; because the study of true immunity, in the sense of complete natural insusceptibility to infection, does little to illuminate the relations of host and parasite that are our chief concern’.

It is a minor paradox that since 1964 our understanding of the genetic basis of susceptibility to infection on the one hand and development of disease once infection has occurred seems to have evolved relatively little. (pace the nice work that has been done largely in experimental systems on the genetic basis of the quantity of immune response to certain defined antigens. As far as I know this kind of work has not been extended to the more earthy fields of parasitic disease). Perhaps the genes we are looking for are for susceptibility to infection that really does seem ubiquitous. Perhaps we should be looking for other genes or other environmental factors that make this susceptibility to infection at least occasionally hazardous as a consequence of the development of disease. In standard thinking for susceptibility to infection to be a genetic characteristic it would seem sensible to suppose that there are advantages to the organisms that will become infected. Is this an outrageous suggestion? Man, for example, is a huge conglomerate of organisms with bacterial genes in all the mitochondria and 8% of the whole genome initially of extrinsic retro-viral origin. As Todaro [2] suggested many years ago the possession of viral genetic material may be highly advantageous particularly in enabling constant replacement of epithelia, even if it carries the occasional disadvantage of making development of cancer, usually in old age, more likely. Surely we did not acquire all these other organisms that are an integral part of our make up without susceptibility to infection being genetically determined? Can it seriously be suggested that infectious disease does not have a largely negative evolutionary impact. The hackles of all the immunologists and parasitologists will rise with such an idea as the war game within which they plot their experiments and house their thinking is itself attacked as not necessarily the natural way of thinking about host/parasite interactions.

Nevertheless, as Topley and Wilson in the same introductory context go on to write ‘Our main business is with those interactions between host and parasite that are characterised by a fluctuating equilibrium, and with the factors that shift this equilibrium, so that sometimes the parasite, sometimes the host, gains the upper hand’. Special risk factors, again out of curiosity. It reveals some of the factors that shift the Topley Wilson equilibrium referred to above.

As far as immunity is concerned in some instances there are no known immune mechanisms afoot. This corresponds to what I, to my surprise, found in the experimental systems which my colleagues and I developed in the ‘70s. I also note that most but not all viruses seem to elicit immune responses. The view among many immunologists is that the adaptive immune response is all purpose and designed to respond to any antigen but this seems not to be entirely true. Not all infective organisms elicit immune responses. Perhaps the most evocative experience which justifies such an alarming statement derives from some studies fifty or so years ago which gave what we thought at the time was a totally negative result and would therefore be unlikely to be accepted for publication. In retrospect the study provides much information which is fascinating. My colleagues and I had conducted a reasonably systematic study of the histopathological consequences of stimulating, or not as the case turned out, the adaptive immune response. We used sheep red cells as tried and tested means of eliciting a response in mice and with a slightly different intent, oxazolone a powerful inducer of delayed type hypersensivity. We used pneumococcal polysaccharide as a third material as the response of T-cells to that was probably negligible. These T-cells, which we had played a large part in discovering, were, not surprisingly, a main interest for us. We discovered that there was a regular repeatable sequence of histopathologically perceptible stimulation of cells in responding lymphoid organs. Mitotic activity involving T-cells was followed by the development of germinal centres and the appearance of antibody forming cells (ref 23 leads to the published versions of this work). The picture was clear and being ambitious we elected to look at what happened when gnotobiotic mice were taken out of their bacteria proof containers and exposed to bacteria for the first time. It there was an adaptive immune response to such a huge influx of antigenic material we felt it would have spectacular consequences putting what we had found with sheep red blood cells and oxazolone to shame. We found that when put into clean boxes the retrieved gnotobiotic animals died overnight. Our microbiologist said it was due to opportunistic infection by Clostridium difficile or a similar organism. This finding offers another obvious lesson which will not be spelled out here. We then took out the gnotobiotic mice and put them into boxes that had been used by mice and which were festooned with mouse faeces. They all lived and seemed very happy in their new environment. We culled five off these mice each day for ten days using gnotobiotic and normal mice as negative and positive controls. From each mouse we retrieved the Peyer’s patches, the mesenteric lymph nodes and the spleen all of which were prepared for histopathological examination. The 450 or so sets of slides were coded and read blind by an expert in the histopathological consequences of elicitation of an adaptive immune response. The result was to us, at the time, felt to have been a total waste of , effort . Aside from a few metamyelocytes in the spleens of the ‘contaminated’ mice there was not the slightest sign of any immune activity. As a slight bonus, of which we thought nothing at the time, the germinal centres in the Peyers patches of gnotobiotic mice were the same in number as those from normal (laboratory bred) mice, We seemed to have an answer to a conundrum which had puzzled us for some time – does a mouse, or a human being for that matter, make a vigorous adaptive immune response to and keep control by such means of its gut flora. As far as we could see from our massive, properly controlled and blindly read study the answer was no. The humble earth worm that, along with the other triploblastic invertebrates, does not have an adaptive immune response, must be grateful, nevertheless, for being able to ingest, every day, a diet largely consisting of microorganisms without adverse consequences. Huge contemporary interest in the microbiome is illuminated in part from the negative outcome of our study. The signs of adaptive immunity in the gut associated lymphoid aggregates of gnotobiotic mice suggests perhaps that standard feed components play a role in the lymphoid activity in the normal GALT (gut associated lymphoid tissue). There are other indications that the immune response to introduced biochemically complex living organisms is only a pale imitation of what might have happened if responses to all the potential epitopes capable of eliciting an adaptive response had been enabled but, sadly, this is not the place to pursue such a line of thought.

As far as vaccines are concerned the lack of some of these in relation to disease is related to the fact that it is has not been a commercial proposition to produce them. I have not seriously addressed the issue of whether live or dead vaccines are to be preferred. This is an argument that needs more space than is available here. There is however something that needs to be written. Some dead vaccines lead to lifelong immunity; for example diphtheria toxoid and to a great extent tetanus toxoid. The immunologists are in the main happy with this as they suppose, perhaps rightly, that the immunological orchestra (Lancet leader 1967, 185-186) has a clear memory of the music it has played in the past. If that is true then, all the various categories of memory T and memory B cells with which the immunologists play games are secure and reasonably part of the mantras with which they punctuate their days. Also it could seem quite ridiculous to suppose that there is an ongoing response to the injected toxoid when it was administered sixty years previously.

There are nevertheless various possibilities other than the immune response, like the nervous system, possessing a long memory. For example after administration of the toxoid the immunised individual might have encountered the relevant bacterium (carrying the relevant phage that codes for the toxin) and taken it on board as a chronic asymptomatic infection in relation to which there is a continuous ongoing immune response that, under normal circumstances is stable; the fluctuating equilibrium that Topley and Wilson allude to but with no significant amplitude to the fluctuations. There is another explanation Corynebacteria are not uncommon neither are bacterial toxins. Also the host organism has an enormous library of bacterial species with which it is in continuous intimate contact. Is it impossible that, given the initial priming injection with toxoid, the response is maintained as an ongoing affair by epitopes that are found in the host but which without the priming injection will not elicit sufficient immunity to negate any marauding toxins? If this is the case can vaccinologists, as suggested previously in this document, tailor the gut microbiota to deliver the required trickle of cross reacting antigenic material? In veterinary practice the concept of trickle infections, particularly in relation to multicellular parasites, is thought to play a role in maintaining resistance to further infection.

The design of vaccines could perhaps be influenced by such considerations as these. At the moment it seems largely to be determined by the classic view of the immunologists that sterile immunity is an achievable state. The evidence in the manual suggests that it is not common nor one to which is it necessarily reasonable to aspire. As far as the point of access category it is not particularly helpful. In many instances in a parasite gains access through the skin and that at the site of introduction there is an inflammatory lesion. If I were a parasite and I wanted to creep in to the host in the dead of night and kill him or her stone dead and quickly I would not advertise my presence. I would not be antigenic. I would hide my light under a bushel (or whatever is handy). I would certainly not alert the host to my presence by bringing all his various inflammatory foot soldiers to the shore on which I had landed. Have we got it wrong? Is the parasite quite deliberately trying to persuade the host to produce a reaction that if it is successful will lead to a state, as Topley and Wilson put it, of (safe?) fluctuating equilibrium?

As an experimentalist I was much influenced by some experiments we undertook with mice some of which were variously immunologically impaired. Basically the animals concerned with either normal or T-cell deprived with all the relevant controls that I will ignore as they did not detract from our conclusions. I want to draw particular attention to some work we [7] did with Trypanosoma musculi. This is a parasite that is found in various species of small rodent. As far as I know in the wild it does little harm. In the laboratory in normal mice injection of as few as one live tryps would give substantial otherwise asymptomatic parasitaemia evident from twelve days or so and declining quite quickly twelve days later. The infected animals gained weight at the normal rate and, as far as we could tell were hale and hearty. Their spleens, unusually for laboratory mice, were replete with very healthy looking germinal centres indicative of an ongoing systemic immune response. The infected animals were solidly resistant to further challenge. For the parasitologists, with whom I was working, this was an indication that the parasite had been exterminated and that the immune response was doing what it should do. In T-cell deprived mice a different story pertained. The parasitaemia developed at the same rate but continued to grow often over many months with eventually a fulminant condition arising and death following soon afterwards. This shows clearly that without T-cells control over the growth of the parasite cannot be achieved. ‘Cell-mediated immunity in action’ mutter the immunologists sagely. But was it?

I persuaded my parasitological colleagues to look at recovered normal mice for live parasites as we had a very sensitive infectivity test. Eventually they found them in the kidney in very healthy condition and ostensibly doing no damage. The tryps would be spending their days bathed in antibody (dare it be said that this was probably their main food?). Thus in the absence of T-cells the infection eventually led to disease and death. In the presence of T-cells antibody was produced in buckets full and the parasite, albeit on a restricted scale, lived on. I found it difficult, with this example, not to suppose that the immune response functioning properly was responsible for safe retention not rejection of the parasite. It was in fact probably the most important factor in maintaining the equilibrium between host and parasite [13] without, in this instance, any obvious pathology. My hard working parasitological colleagues, for whom I should say I had and still have the greatest respect, went on to try to persuade the parasite to ‘come out’ from the kidney otherwise there would not be any continuity of infection. In ‘hyperimmune’ mice with infected kidneys they tried steroids and, post thymectomy, total body irradiation and restorative implantation of fresh syngeneic bone marrow to produce animals with few T-cells but nothing disturbed the equilibrium until, one day, in a burst of genius, they discovered that pregnancy in long term infected normal mice led to parasitaemia(personal communication). There were no adverse consequences noted of this disturbance of the equilibrium which could anyway be designed to pass the parasite to the foetuses. Sadly we did not look for this. This small example coupled with much other evidence inadvertently provided by APHA began to push me to the view that the war paradigm of sterile immunity in relation to parasites was not totally satisfactory.

The last categories in the reconciliation table show that many infections can be asymptomatic and that some can recrudesce after long periods probably of equilibrium. The immune status of organisms with latent infections is not adequately researched but such research could be helpful in enabling us to decide which patients are likely to be stable with their latent infections. It is already known in AIDS patients in which latent infections, often of Pneumocystis carini or Mycobacterium tuberculosis, are thought to become active but the exact reasons why, except to show that in the broad sense the immune mechanisms probably regulate the equilibrium, is obscure. Also, as far as Mycobacteria are concerned, it may also be that a different sp. to that of the original infection causes the later problems. The main diseases that kill many humans globally of which, incidentally, there are very few, all show the majority of the infected individuals have few if any symptoms. Particularly for tuberculosis the statement that 90% of those in regions of the world where the disease is indigenous show no symptoms when first encountering the organism but are nevertheless probably carrying the Mycobacterium which causes the disease for life illustrates what seems to be counter intuitive.

Overall Discussion

Biological Advantage

The most usual method of teaching Biology without evocation of Special Creation, which will not be done here, is to suppose that a process of evolution of living organisms has occurred. The fossil record supports such a way of proceeding and the monumental work of Darwin, on the selection of advantageous forms of life capable of better succeeding in our diverse global climate, provides a framework for the process to occur. The relatively recent discovery of the genetic apparatus in the early days of the last century [14] offered a mechanistic basis for evolution to occur by selection of genetic constructs, point mutations as they are often called, offering survival advantage to their possessors. The role of point mutations in the process of natural selection will not be queried but it will be suggested, on the basis of the survey of the APHA handbook that it is far from the only method of genetic selection that exists. Most recent biological teaching, to make sense of the tremendous morphological diversity of living organisms particularly the multicellular eukaryotes of which the human species is an example, has continually posed the questions involved in deciding on the possession of properties of biological advantage. For example, the fins of fish facilitate their movement in a liquid environment, the wings of birds enable them to move in air, the possession of chlorophyll by many plants enables them to fix solar energy, a process on which humans are presently totally reliant, and the hair of mammals helps to keep an homoiothermic organism such as Homo sapiens warm in cold climates. Students of biology have laboured over such issues ever since Darwin published his ground breaking study on diversity as the basis of biological evolution but it will be suggested that the concept of monophyletic evolution of single species should be queried and replaced by an alternative with many species of organisms working together to constitute the units for evolutionary advancement.

Communicable Diseases and Vaccination

It is in reference to such studies, exploring the biological advantage of possession of an immune response, that the present review of communicable diseases in man has been conducted. On the face of it, organisms that can invade and clearly in some instances harm humans seem to constitute a selective disadvantage and the immune response seems tailored to overcome this disadvantage. The contemporary social, disruption following the emergence and depredations made on the human species of the SARS-CoV-2 virus which can give rise to the Covid-19 severe respiratory disease, and the apparent failure of the immune mechanisms always to act protectively, underlines the importance of this manner of thinking. The standard way of getting round the problem is to evoke prophylactic vaccination, a process known in outline for centuries. Edward Jenner is often given great credit for showing, in 1798, that vaccination, in humans, using a form of small pox ‘vaccinia’ virus derived from cattle, could offer protection from the great harm that the wild type human pox virus could wreak [15]. That it took till October 1977 to extirpate the disease from human populations [16], by a combination of vaccination and contact identification using the immunisation technology invented by Jenner, inter alia, shows that highly beneficial changes in medical practice can take considerable time to become established but, nevertheless, vaccination worked. The immune response is certainly in part protective but it will be proposed that there are other aspects of its functioning. It is useful to amplify such a statement by reference to the information given in the American Public Health Association Manual of Control of Communicable Diseases which aims to review nearly all the presently known such diseases with attention to the kind of information needed by Public Health practitioners to reduce their effects when they harm humans.

The Evolutionary Perspective of the Immune Apparatus

Humans live in an increasingly sanitised world in which as far as possible micro-organisms are given short shrift as they are believed to be potentially dangerous and to be capable of causing disease. There is no doubt that there is a sound basis for such a belief in that there are some such organisms that can be pathogenic i.e. capable of causing harm in human populations. It is, nevertheless, worthwhile noting, using an evolutionary perspective, that the selective mechanisms by which the human body effects an immune response were probably put in place more than five hundred millions of years ago when vertebrates were first found in the fossil record. This is well before the advent of what we now know as the medical profession. The point about the medical profession is that the mores of the present age regard all human life to be valuable and that in those circumstances, where for medical reasons it seems to be threatened, it is the duty of the profession to do their best to reduce harm due to infection and where possible save lives. No such remediable measures were available at the time that Homo sapiens or his earlier progenitors roamed the earth. Life then, for the extant humans, was much as it is now for wild animals and plants. It can reasonably be argued that if we wish to estimate the biological significance of immune mechanisms in an evolutionary perspective it is to the ‘wild’ situation that we should look. This in no sense to argue that the medical profession are not doing a good job or that their mores are to be changed but simply to assert that the medical profession and the public health experts have moved the demographic structure of human populations massively in the last hundred or so years and that this demographic change can distort the way we think about an ancient interface system, between man and his complex environment, such as that constituted by the various facets of the immune response.

The Adaptive and the Innate Immune Responses

For historical reasons our thinking about immunity in recent years has been almost totally dominated by our pre-occupation with what immunologists call adaptive immunity. This property is possessed only by vertebrates [17] and its pursuit has largely led us to ignore the fact that the innate immune response is also an integral part of the total mechanisms of immunity. Innate immunity is not only a property of vertebrates but also functions in multicellular invertebrates [18] many of which have, in their adult forms, an exoskeleton, an alimentary canal and three basic blast layers in the early stages of their ontogenesis – so called triploblasts. The innate immune response in all such organisms has a system of cells that can become phagocytic and which, operating inside the body which contains them, in part if not exclusively, using a system of toll receptors [19], can find, ingest and destroy living invaders and act, in circumstances in which cells have been damaged or killed in the body, not necessarily as consequence of infection, to perform a clean- up operation.

The differences between adaptive and innate immunity in terms of their mechanisms and overall purpose have been dealt with extensively elsewhere [20]. Here it only needs to be said that the adaptive immune response is specific and capable of tailoring an immune response to relate to the inducing antigenic stimulus by the production of antibodies which have specific binding sites for the inducing antigen. In addition it is widely argued that specifically cytotoxic cells are produced. It must also be noted that adaptive immunity depends to a great extent on the existence and activities of two populations of lymphocytes terms T and B cells, the former of Thymic origin [21] the latter from Bone marrow. In vertebrates T-cells have a variety of ascribed functions of which one of the first to be discovered was to work synergistically to facilitate the production of antibodies by B cells [22]. These two populations of lymphocytes are often credited with a potentially long term memory of past activities perhaps comparable to memory possessed by organisms with a brain. This notion of immunological memory will be queried not as necessarily wrong but one which should be argued about.

The Adaptive Immune Response, Reject or Acceptor of Invaders

The adaptive immune response is seen by most medical practitioners, by many contemporary immunologists and often by parasitologists as primarily a defensive mechanism ideally capable of rejecting living invaders and dealing with foreign bodies of any kind. This view has been criticised [23-25] and the counter suggestion made that the adaptive immune response in evolutionary terms exists to assist accommodation of invaders. The name adaptive against this background can suggest either rejection or accommodation with, in the views of its protagonists, the latter being commonly possible and the former less often observed. These notions are not in general popular either with immunologists or parasitologists but nevertheless deserve consideration here. Probably the vertebrates appeared later in evolutionary time than the invertebrate organisms which are generally supposed to be their precursors. Accepting this view it is worth considering briefly why the adaptive immune response, characteristic of the vertebrates, was added, in response to a selective advantage, to the innate immune response of their precursors. The innate immune response has no specific memory such as is seen as a property of the adaptive response. It could be that the acquisition of a specific memory is a selective advantage. Equally as a consequence of the existence of the substantial array of isotypes of immunoglobulin antibody and their even greater array of idiotypic diversity associated with the adaptive immune response it could be seen as providing an all- purpose far more extensive protective reaction to invasion than the innate immune response alone. It seems to make good sense but it can be argued that if that were the case vertebrates would have been selected for their capacity to reject pathogenic organisms capable of reducing their viability. In fact a significant finding from the APHA manual is that humans and incidentally their domestic animals very often live for long periods of time asymptomatically with latent disease forming organisms. Also most disease causing organisms are found to be symptom free in species other than the target of interest. For example Theileria parva which can cause a disastrous and almost always lethal disease in humped cattle in East Africa is to be found in native species of asymptomatic [26] cattle (buffalo). That the great majority of viruses and bacteria do not cause disease in man could be attributed more to the organisms concerned not having a necessary biochemical affinity with hosts that they do not invade. The APHA manual makes it clear that susceptibility to the infections known to be capable of causing disease is almost universal. If such susceptibility were dangerous perhaps the all-purpose apparatus of the adaptive immune response will deal with the consequences of the ‘free’ entry of invaders. Of course there are many non-immunological barriers to entry such as mucosal membrane secretions with anti-microbial properties and physical barriers such as provided by sturdy keratinised skin but when these barriers, for whatever reason, have been by-passed successfully invasive organisms often do not cause disease symptoms or only those that can readily be dealt with by the various responsive systems possessed by the vertebrates, particularly the elements of the innate immune response which act as very effective sentries in locating and exterminating foreign organisms intent on immigration. Without doubt the adaptive immune response can control the scale of invasion which for various reasons has not been dealt with by the innate system [7] but it is not too difficult to show experimentally that long term persistence can be associated with the presence of circulating antibody specifically capable of binding to and inactivating, though not exterminating invaders [7]. It has even been argued in relation to eukaryotic single celled organisms that antibody bound by specific idiotypic ligands to their target cells could offer a high level nutritious proteinaceous diet [7]. Fie!

Recent studies on Covid-19 patients claimed that high antibody levels were present in seriously ill patients but far less frequently in the majority of infected individuals who were asymptomatic [27]. Is it totally ridiculous to argue that elements of the adaptive immune response contributed in some way to the sickness of the patients with severe disease but in those who were asymptomatic no such harmful effects were seen for the simple reason that the adaptive immune response was not so active? Alternatively the asymptomatic patients, using their adaptive system or their innate immune response, had restricted the prevalence of the invading virus and thus only a minor response in terms of inactivating circulating antibody was observed.

Invertebrate vectors which facilitate the introduction of potentially pathogenic invaders of vertebrates do not themselves seem to suffer disease symptoms or at least do not have sufficient restriction of their movements to prevent them being capable of gaining entry to the vertebrate host usually with the aim of getting a blood meal. Is the apparent general lack of suffering from disease in infected invertebrates because they do not have adaptive immune mechanisms? There are no easy ways of resolving these apparently conflicting interpretations of observations. The prevailing view is that pathogenic microbes exist to harm their hosts and must be avoided or killed. The terminology adopted by the human protagonists of this kind of approach is that used in waging wars and it is difficult not to be sympathetic but it must be pointed out that the possibility of mutual benefit as a consequence of infection should be considered. The benefit to the potential parasite is that it gets somewhere safe to live. The long term advantage to the host could be that it gains an indwelling source of genetic material. If this seems bizarre it should be remembered that two major steps in evolution, firstly the formation of eukaryotic organisms from fusion of a number of species of archaea and bacteria with subsequent simplification of the genomes involved as Lynn Margulis [28] has so elegantly pointed out, led to the emergence of the nucleated cells of which all the living organisms that not microbial are now composed. The mitochondria which are the relics of these long ago events but still retain a small fraction of genetic material known to be of microbial origin. The mitochondria are essential vital energy managing organelles of which the much simplified genetic material derived from what were initially free living organisms enacts the required energy managing function.

Is it too difficult to imagine a protracted evolutionary sequence involving contact between living organisms leading sometimes to invasion, the initial stages of which in evolutionary time could be tempestuous and dangerous, facultative parasitism it could be thought of, followed by period of accommodation, obligate parasitism, and perhaps in time genetic simplification of the invaders and total loss of their independence. The microbial flora which all triploblastic organisms possess, the acquisition of which was a major step in evolution, shows convincingly that organismal relationships can be mutually beneficial despite the massive differences in the life styles and genetic constitutions of the organisms concerned. Several billion years ago almost the first fossil organisms to be discovered, stromatolites, were complex symbiotic associations. Symbiosis is essentially a universal phenomenon and not one easily predicted by a theory of evolution only advancing by selection of advantageous point mutations. The disadvantage to host of harm or death as consequence of invasion of course exists but it can be argued that this is irrelevant in evolutionary terms however abhorrent it is to a species such as Homo sapiens which prides itself on being able to keep all the individuals of its species in good health. The innate immune response is swift and lethal. Impose on this assassin the mechanism for adoption and rehabilitation of immigrants and it can be argued that this potentially accelerates evolution by creating greater gene pools that have the capacity over time for responding to a greater degree of environmental vicissitudes than can be arrived at by monophyletic notions of evolution.

Non-Immunological Consequences of Activation of the Immune Apparatus – Inflammation

Over the years it has become apparent that immune cells of all kinds activated in vitro or in vivo produce a wide variety of proteins other than the specific antibodies, which are derived from B-cells transformed into plasma cells. The various cytokine products, in addition to antibodies, are exported into the surrounding medium whether this is a tissue culture dish or extracellular spaces. In this way activation can be, in addition to be concerned with the response to an antigenic stimulus , part of a signalling process having consequences on surrounding cells often in vivo on adjacent tissues and systemically. The secretions include what are called paracrine and autocrine hormones which by definition act locally. Wikipedia has this to say:

“When macrophages are exposed to inflammatory stimuli, they secrete cytokines such as tumor necrosis factor (TNF), IL-1, IL-6, IL-8, and IL-12. Although monocytes and macrophages are the main sources of these cytokines, they are also produced by activated lymphocytes, endothelial cells, and fibroblasts.”

The cytokine secretions from activated cells of the immunological apparatus, whilst they can also act locally in the paracrine sense, can also have systemic endocrine effects. The relationship between these cell products and the rather better known products of the endocrine organs, the thyroid, the adrenals, the pituitary and the sex organs, for example, is less well understood. There are other organs which secrete hormones such as the alimentary canal and again the relationship between these and the other secretions which can act hormonally in the sense that they have effects remote from their sites of production is far from clear though in the years to come research will sharpen up our knowledge. The cleaning operation after damage to cells in the previously whole body, referred to above, is an aspect of inflammation executed by elements of the innate immune response operating internally. This mopping up is comparable in some ways with the external debridement of wounds surfaces by the medical profession to expedite the commencement of the healing process. The clean- up operation can involve what are called pro-inflammatory constituents of the innate immune system. All being well they give way in time to anti-inflammatory components associated with the healing process. This transition often goes smoothly but if the pro-inflammatory influences do not give way in time to the next phase symptomatic problems can arise which, to those suffering from them, can be unpleasant, dangerous and potentially lethal. Presently we are not fully capable of easing the transition process but it seems likely that we can begin to identify the internal mechanisms involved. It must be made clear that the account given here is an oversimplification in that some of the cytokines identified as pro-inflammatory can be anti-inflammatory and vice versa. The whole array of inflammatory molecules is highly complex and perhaps for this reason the general analytic methods which will need to be applied to far to its control have not yet been fully discovered but a start has been made.

The Wikipedia entry summarises these issues and points particularly to a phenomenon, the secretion of TNF, tumour necrosis factor, which, as Ian Clark has pointed out for over forty years, [29] is vastly important in relation to disease symptoms including lethality. His argument based on an elegant series of experiments showed initially that the lethality of an infection of a species of Plasmodium in mice could be abolished prophylactically by reduction of the capacity of the recipient animals to produce TNF. Clark went on to show that TNF minus mice did not get sick and die, and if he injected normal animals with TNF, he could elicit disease symptoms. The issue is whether such a mechanism relates to the symptoms of some or all infectious diseases and whether it can be predicted which organisms will be most affected by the pathological effects which can derive from immune activation. Clark’s work with infection of various strains of mice with Babesia points a way forward in this respect. He found that the pathogenesis of Babesia could be predicted from a knowledge of the sensitivity of the species or subspecies strain of host animals to LPS, a bacterial product which has powerful physiological consequences due to its capacity to induce massive and dangerous inflammation [30]. Beyond such a finding if we could identify by some clinical biochemical markers those individuals most at risk from what is in fact immunopathology, lies the issue of how we can intervene to reduce such processes which, ex hypothesi, can be very harmful and should if possible be controlled.

Some of these issues are considered in a recent paper [31] summarising what I, an immunobiologist, believe is how we should think of infectious disease as a step in the evolution of a greater degree of genetic complexity. Such a message to those who die as a consequence of infection is not helpful and of course the medical profession should continue to strain to keep sick people alive but it is likely that some of their efforts are not mimicking the ways that over the ages man has emerged from the evolutionary swamp.

In summary:

1. Genetically based resistance to disease is uncommon compared with susceptibility to invasion by potential pathogens.
2. Immune activities are both helpful and potentially harmful to humans we should seek better to understand the mechanisms by which the harm element is brought about in addition to learning more about the general physiological benefits of immune processes.
3. Only to think of attacking and killing invaders is to disregard the immunopathological processes that often and probably always are involved in creating the symptoms of disease.
4. Inflammation arising from activation of immune cells occurs and it could often be better to attempt control of the host response than necessarily waging war on the invading organism. Most interaction between living systems are complex and involve activities which could be thought akin to playing table tennis i.e. the players change their activities according to the way that their partner in the game has played. An organism that can replicate in minutes rather than years and where the process of replication is prone to mutational error has a much better chance of creating advantageous genetic diversity.
5. It should be better recognised that both adaptive and innate immunity exist in humans and the roles that each of these mechanisms both in relation in the broad sense to infection and the maintenance of good health should be taken into account.
6. There are many problems susceptible to solution by active research by immunologists that arise from perusal of the APHA manual on Control of Communicable diseases in man.
7. The reasons why so many diseases are more severe in those who are said to immunosuppressed or physiologically at a disadvantage , diabetic say, should be better investigated than is presently the case. In balanced ecosystems predation occurs but the loss of life due to it is easily balanced in a number of ways. Man himself is a complex example of a whole series of ecosystems and their structure and maintenance might be facilitated by better recognition of this fact.
8. Particular attention should be given to the role that our microbiome friends play in the maintenance of health and how this property can be augmented and maintained perhaps by pro- and pre-biotics which have defined effects on the gut flora [32-34].

Acknowledgements

I wish first and foremost to thank my friend and erstwhile colleague Professor Page Faulk for bringing the APHA Manual to my attention. Over the years I was involved in active experimentation my colleagues and I published many papers and their contributions were recognized by joint authorship. I thank them here for their skill, support and enjoyment of the work we did together. As far as parasitic disease is concerned Professor Ian Clark offered an insight into the significance of Innate Immune mechanisms with his powerful studies of TNF and I thank him for his work and continued support. Prof Michael Doenhoff initiated me into the arcane world of Schistsome infections. I thank him for scientific discussions and the great fun we had together. I am grateful to Prof Lee Nelson who told me of the phenomenon of Microchimaerism which offers the possibility of all humans to have beneficial activity of immunological mechanisms they contain which they acquired following movement of cells from their mother during pregnancy. Cells acquired in this way offer generational continuity over and above the standard Weissman model of inheritance entirely through the genetic apparatus of the zygote. The importance of microchimaerism is probably presently understated. Professors Pierre Viens and Geoff Target produced results of experiments which revolutionised my understanding of adaptive immune responses and I thank them for their patience, friendship and collaboration. Professor Max Murray and his colleagues in the Veterinary College of Glasgow University led me gently into the world of parasite disease in cattle and from them I learned and continue to learn a great deal. More recently Dr Chris Owens and Professor Bruce Reid have had considerable influence on my way of thinking and I thank them for that. Dr Aamir Ahmed is a top rate physiologist with expertise in the electrophysiology of cell membranes, His regular discussions with me have both encouraged me to think and offered methodological insight which has been most valuable. My friend and wife, Agneta Lando has been unstinting in her support, checking manuscripts and offering encouragement to continue. She has been throughout invaluable.

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