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Immunology, culture and nature

Immunology, culture and nature

Vaccines and antibodies

Two historically important pillars of thinking in immunology are vaccines and antibodies. I will discuss whether immunological practices as well as the ideas guiding these practices and scientific research in immunology on vaccines and antibodies derive from accurate knowledge of how to divert natural processes to our benefit, or whether they depend on our cultural practices and have obscure aspects. In other words, whether we can consider anti-infectious vaccination as based on a “natural” process as usually interpreted, or whether this depends on the particular way of viewing the world adopted by Western culture.

We are still far from understanding why some anti-infectious vaccines work so well and provide lifelong protection, and many others still fail in the process of inventing them. The yellow fever vaccine is very effective and derived from a point mutation in the virus, but vaccines for other flaviviruses, such as dengue, chikungunya and zika-virus, are not yet available despite much research. It is not known when we can dispose of these new vaccines, and other highly sought after. In fact, we do not even understand exactly how most vaccines currently in human and veterinary use work, and as in other situations, the issue will become more complex before it becomes intelligible.

Vaccines

The most widespread belief is that vaccines protect us from infectious diseases because they mimic a natural process. Certain diseases only occur once in a lifetime; the individual becomes “immune” after  the first infection, as in the so-called “childhood viruses”: measles, rubella and mumps. This is called “natural immunity.” At vaccination, the body is deliberately exposed to an infectious agent (microbe, virus), or its products, previously attenuated (weakened) in the laboratory. As a result of this exposure, the body increases its specific resistance – its immunity. That is, the vaccine would artificially create a simulacrum of the infectious disease, and this would result in immunity.

The practice of vaccination (not by this name) was initiated by Jenner (1798) with the deliberate inoculation with bovine pox pus (cowpox) to protect against smallpox. At that time, “variolation” was already practiced, the deliberate inoculation of pus from benign cases of human smallpox, a much more risky procedure. About a century later, Pasteur generalized this procedure as part of his Germ Theory (Pasteur, 1878), by proposing that infectious diseases depend on the contagion with specific germs. Pasteur created several vaccines by “attenuating” (artificially weakening) their specific germs. The term “vaccine” was created by Pasteur in honor of Jenner, because “vaccuna” in Latin means “”young cow”.

Antibodies

The term “antitoxin” was invented in 1890, a dozen years after the publication of the Germ Theory, to designate substances (later called “antibodies”) that appear in the blood of animals that survived injections of the diphtheria “toxin” because these substances  “neutralize“ the effects of the toxin. The neutralizing action of these anti-toxins (antibodies) is specific for the injected immunizing toxin, they do not neutralize other toxins. Antitoxins were understood as special antidotes produced by the body in its own defense.

When transferred (transfused) to other animals, anti-toxins collected from immunized animals (repeatedly “vaccinated”) passively transfer this protective effect to the recipient organism an this is called serum therapy. Serum therapy with diphtheria anti-toxin produced in large animals (cattle, horses) was used with great success in the treatment of children with severe cases of diphtheria in the 19th century. This was the most important example to date of the “translation” of knowledge obtained in scientific research for public health, with medicine as an intermediary, and inaugurated the idea of a “scientific medicine” based on the protective role of antibodies.

The Schick test

The Schlick test makes it possible to know whether or not a child is immune to diphtheria. The test consists of the intradermal injection of a small dose of diphtheria toxin; in a few hours, a small hemorrhagic lesion develops on the spot through the action of the toxin. If the child is naturally immune or has been artificially immunized (vaccinated), and has specific antibodies against the toxin, the lesion does not develop. The presence of diphtheria anti-toxin in the circulation, therefore, can be pointed as the molecular substrate of the immunity to diphtheria, its molecular explanation.

An improper generalization

Both serum therapy and the Schick test suggest that immunity actively developed by the use of vaccines generally results from the induction of specific antibodies. This is a mistake because situations in which the lesions found in an infectious disease result from the action of toxins that act at a distance (exotoxins) such as those involved in diphtheria, tetanus and some other diseases, are very rare. In general, infectious diseases do not depend on the secretion of powerful toxins by the infectious agent, and immunity does not depend on the production of antibodies that act as anti-toxins. This disappointing finding stems from years of failed attempts to treat human diseases with animal sera containing antibodies (serum therapy); with the exception of diphtheria, tetanus and a few more examples, serum therapy does not work, has no protective effect whatsoever. The presence of specific antibodies in the circulation, therefore, can not be generalized as the explanation of anti-infective immunity.

Contagion and disease

Another, even more serious, disappointment is that infection with a given infectious agent does not necessarily lead to infectious disease: there is great variation in individual susceptibility to the disease, and there are individuals who establish a transient or permanent association with microbes, viruses or parasites which are pathogenic to other individuals of the same species. They are called “healthy carriers.” This contradicts the initial simplicity of the problem. By substituting divine demons and punishments, the Germ Theory of infectious diseases was a major advance in medical thinking, but it does not explain why contagion does not directly lead to infectious disease. We now also know that, in isolation, antibodies are not the substrate for anti-infective immunity.

Two watersheds

These two watersheds – memory and tolerance – suggest symmetrical changes in the body as a consequence of a first contact with an antigenic material, respectively, an increase or a decrease in the specific reactivity to subsequent contacts. Since the 1950s, when it was concluded that lymphocytes are the central cells in immunological activity, “memory” is thought to depend on an increase in the frequency of lymphocytes reactive to a given antigen, while “tolerance” would depend, reciprocally,  on a decrease or total elimination of these reactive lymphocytes – for example, in the case of lymphocytes reactive to components of the body itself. The dominant theory in immunology – Clonal Selection Theory (Burnett, 1959; Hodgkin et al., 2007) – is based on this dichotomy, the separation between memory and tolerance, known in immunology as “self-nonself” discrimination . In its early versions, clonal theory proposed that there is no self-reactive lymphocyte in healthy organisms and that the appearance of lymphocytes would result in diseases called “autoimmune.”

The third option

The memory-tolerance dichotomy (self-nonself) hides a third possibility. This third option is not immediately evident because the view of the default state of the organism is a state of rest (stasis) in which it remains until it is “stimulated” to “respond.” But between increasing (memory) or decreasing (tolerance) the “response to stimulation” with antigens, is the possibility of maintaining an “internal” physiology of lymphocytes and antibodies dynamically  stable, that is, a conservative physiology that preserves certain patterns of activity of lymphocytes that is generated autonomously, and does not require external stimulation.

In proposing the horror autotoxicus, Ehrlich’s idea was that the immunologists of the future would have to explain this lacuna in immune reactivity, a “loathing” of the body to self-destruct, something Ehrlich regarded as highly senseless (dystelelological). But the idea of horror autotoxicus, or self-tolerance, does not necessarily mean the absence of an internal immune activity of the organism. Even in the absence of “immune responses” there may be an internal activity that preserves certain patterns, keeps certain referential invariant. This involves a much-needed idea not yet included in immunology: the idea of a conservative immune physiology, the idea that lymphocytes and antibodies also act in the healthy organism and that even without stimulation, the body is not inert and expresses a stable activity.

A natural activity

This view – the characterization of an internal immune activity – is supported by many experimental demonstrations. For example, some aspects of immunological activity – such as the production of antibodies of the IgM class, and activation of T lymphocytes – remain unchanged in animals raised and maintained and “antigen free” environments, that is, they are indistinguishable from those found in animals raised under more conventional (SPF) conditions. Lymphocyte activation and antibody production are part of the construction and maintenance of the vertebrate organism, and are not episodes that arise only in response to contact with foreign materials as invading agents.

A genuine immune system

The term “immune system” as commonly used in immunology does not refer genuinely to a “system”, but to a cluster of lymphocytes and lymphocyte products independent of each other. But in a genuine system all components are directly or indirectly interconnected and affect each other. Therefore, to speak of an immune system, it would be necessary to describe an entity that, although it continually replaces its cellular and molecular components with others (change of structure), does not transform into something else, it remains, does not change its organization. This is the fundamental characteristic of systems in general: their conservative nature. As Jorge Mpodozis says: “systems change without becoming something else.”

In the immune system, this conservation is expressed, for example, in the robust maintenance patterns of reactivity of natural antibodies (immunoglobulins) found in healthy animals (Haury et al., 1997; Nóbrega et al., 2002). Lymphocytes and antibodies that result from immunological activity are being continually replaced by others, but they are replaced by others that  are equivalent to them and reproduce the same patterns (profiles) of reactivity; they are not the same lymphocytes, but they function as if they were.

Vaccines as biochemical impositions

A vaccine can be seen as a biochemical imposition or command that is given to the body and determines the production of antibodies and the activation of specific lymphocytes, which then protect the organism. But this idea is incompatible with the concept of “systems” as entities that hold invariant aspects of their structure that define their class identity (their organization). Systems are structurally dtermined, they do not change “from the outside in”, their organization is preserved; the immune system continually changes its cellular and molecular structure, guided by its own activity, and by its interactions with the organism, even with invading materials eventually present in the body at that moment. The system changes its structure but does not change its organization; there are no instructive interactions in the immune system. But in the usual medical view, the immune system and the organism obey what is apparently imposed on them by vaccination. Antigens can not teach the body to produce antibodies; they disturb an already ongoing production of antibodies (immunoglobulins); and the organism compensates for these disturbances and maintains its stability (its organization) which is at all times supported by the exchange of components – a characteristic of living systems in general.

Differences in individual susceptibility

Immunology still does not explain the large differences in individual susceptibility to infectious diseases (and also to allergic or autoimmune diseases). Immediately, we are led to think that these differences come from genetics. In fact, the genome allows everything that occurs with the living being, but the genome, by itself, does not explain what occurs. There are very few examples where differences in susceptibility to diseases can be attributed to a small number of genes, or to a single gene (an allelic variation); the emblematic example is sickle cell anemia, a genetic variation (exchange of a single amino acid) in the hemoglobin structure, leading to increased resistance to malaria pathology. But even in these cases, the individual variety is enormous. More current views indicate that there are variations in susceptibility dependent on the entire genome, or a large part of the genome, studies by GWAS-Genome-Wide Association Studies (Ko & Urban, 2013). A hypothesis called Ominigenic (dependent on all genes) has proposed that not only some, but all the genes activated in an organism contribute to its susceptibility to infectious diseases (Boyle, Li & K. Pritchard, 2017). The general message, therefore, is that we can hardly reduce the explanation of anti-infectious immunity to a small number of elements, such as the production of specific antibodies, as in the case of diphtheria. And the use of genetic elements to explain individual differences does not help us much. I will propose another explanation that depends on the internal immunological decimation of the organism.

How do vaccines work?

Why there are vaccines that protect and others that do not protect? Vaccines are explained by immune memory. But there are no rules to attenuate infectious agents and this makes it very difficult to invent new vaccines. Pasteur used a different method of “attenuation” in each of the vaccines he invented, that is, he invented them by experience and error. Vaccine research has insisted on increasing specific reactivity, immune memory. However, although a secondary type (memory) reactivity can be easily induced for infectious agents and their products, this almost never results in a parallel increase in anti-infective immunity. A progressive reactivity does not explain protection. But then, how do vaccines that work effectively work? If they are not based on immune memory and do not depend directly on antibody formation, how do they work?

The immune system and its diversity

To see the immune system as a genuine system, we must see it as a multi-component articulated set that robustly conserves its patterns of activity, while changing cellular and molecular structure. If the immunological physiology, expressed in these patterns, depends on a complex set of connections that is harmonically articulated, the pathology in such a system may depend upon perturbations of these connections. Reductions in connectivity are capable of disrupting these connections by releasing certain unduly expanded components – something that in immunology is called “oligoclonal expansions” – the expansion of a small variety of lymphocyte clones.

There are numerous examples of pathology associated with these “oligoclonal expansions,” which are, after all, forms of abnormal simplification of the activity of the immune system. This has been reported both in infectious diseases, in allergic and autoimmune diseases, and even in various forms of congenital immunodeficiencies. In the mouse, experiments with schistosomiasis mansoni, for example, have shown that severe forms of the disease are associated with expansions of a particular type of T lymphocytes that react to a single detail (epitope) of a single protein secreted by Schistosoma mansoni eggs. When there is no reaction to this detail, the lymphocytes that expand are much more heterogeneous and the severe form of the disease does not occur (Finger, 2005). There are similar examples in allergic and autoimmune diseases.

Individual differences in internal connectivity

If the maintenance of a healthy immune system is disturbed by undue expansions of some components, possibly resulting from losses in internal connectivity, differences in susceptibility to disease may be correlated to differences in clonal diversity, not the intensity of expansion of specific clones mediated immunological memory. This is a much broader question than the understanding of how vaccines operate and has to do with one’s own understanding of healthy living and the nature of living systems, as discussed in Humberto Maturana’s Biology of Cognition and Language (2002).

A dangerous world

The dominant view in immunology is still Pasteurian, that we inhabit a dangerous world filled with microscopic invaders and that immunological activity is an important form of protection against these invasions. All this needs to be reviewed. There was a revolution in the view of the microbial world, its breadth, diversity and ubiquity; and also a change in our understanding of the role played by viruses in the origin of vertebrate organisms. In an alternative view, vaccines can not be and are not biochemical commands that guide how the body should behave.

It is possible that the available vaccines are exactly those that allow the pluralization of lymphocytic clones that would ensure the maintenance of important connectivity in the harmony of the immune system. If this is minimally true, the search for new vaccines would take an entirely different direction. And the worldview compatible with this change is not that of an immune system as opposed to a dangerous world but as an integrating element of the organism in its midst. The vast majority of the foreign materials to which the body comes into contact are not truly foreign since they consist of macro-molecules of the food and of products of the native microbiota.

Bibliography

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Finger, E., P. H. Brodeur, H. J. Hernandez and M. J. Stadecker1 (2005). “Expansion of CD4 T cells expressing a highly restricted TCR structure specific for a single parasite epitope correlates with high pathology in murine schistosomiasis.” Eur. J. Immunol. 35: 2659– 2669.

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