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Compact – To learn immunology

Compact (To learn immunology)

The terms sought in the construction of another image of immunology should not be the same as those used in its fragmented current description, otherwise we will face the same questions and paradoxes. Over the past 50 years humanity has learned more than in its entire history and now has new means of accessing and managing what has been learned. In immunology, it was no different. The dominant theory for 60 years (Burnet, 1957) advocates a specific reactivity by expansions of lymphocyte clones. This idea was maintained although everything around it has changed, mainly because it is difficult to replace the stimulus-response-regulation framework by a historical-systemic way of seeing. Just before publishing his network theory, Jerne asked, “What precedes clonal selection?” (Jerne, 1971), He referred to conservative changes in the organism that happen before any intervention, changes that constitute the default state of the organism, and activity that does not require external “stimuli” to exist. There is an immunology of the healthy organism, an “immunology of peace” to which we want to refer. It is impossible to understand how ideas emerged in immunology without understanding immunology, and what follows is an ultra-short and biased script in another direction. Roughly, I divide the story into three periods, and I point to accidental misunderstandings and results that do not fit into the usual way of seeing.

Founding period

01 – The Smallpox Vaccine

02 – The hope of vaccines

03 – Antibodies against diseases – serum therapy

04 – Hemoglobunuria – immunological self-inflicted damage

05 – Oral tolerance – a forgotten model

Cellular immunology: second half of the 20th century

06 – Medawar and allo-tolerance; Jerne; Burnet

07 – Transplantation: graft versus host reactions

08 – The syngeneic barrier

09 – Alo-reactivity

10 – Hypercyclic Antibodies

Contemporaneity

11 – The native microbiota

12 – Poly-specific natural IgA

13 – Micro-chimerism

14 – Multiplicity of specific agents

15 – Re-wilded mice

Founding period

01 – The Smallpox Vaccine

The original text by Jenner (1798) states that exposure to vaccinia pus (cowpox, smallpox) protected from smallpox but did not protect from vaccinia itself (Jenner, 1798, see excerpt below). This observation is odd; the usual idea is that the vaccine generates a “memory”, reinforces the reactivity to the virus. How possibly can the vaccinia virus protect against smallpox and not against itself? To make things more difficult, the vaccinia virus has disappeared from nature and the mechanisms of protection generated by the vaccine remain ill-understood. None of this speaks against the enormous benefit brought by the smallpox vaccine, but it tell us that the lesson we may learn from it is more confusing than it seems.

The original quote:

“It is singular to observe that the Cow-pox virus, although it renders the constitution unsusceptible to the variolous, should, nevertheless, leave it unchanged with respect to its own action. I have already produced an instance to point  out this and shall now corroborate it with another. Elizabeth Wynne, who had the cow-pox in the year 1759, was inoculated with various matter, without effect, in  the year 1797, and again caught the cow-pox in the year 1798…”

(pag 124 in Brock, 1961)

Basic reference:

Jenner, E. (1798) (1961). An inquiry into the causes and effects of the variolae vaccinae, a disease discovered in some of the western counties of England, particularly Gloucestershire,and known by the name of The Cow Pox. Milestones in Microbiology. T. Brock. Washington, American Association of Microbiology: 121-126

02 – The hope of vaccines for all diseases

In the early twentieth century, a director of the Pasteur Institute exclaimed, “A disease, a germ, a vaccine” – hoping that soon vaccines for all diseases would be availbles. This did not happen; i inventing new vaccines proved to be a difficult endeavor. Inducing increased reactivity (antibodies etc.) to infectious agents or their products (immune memory) is relatively easy, but usually it does not result in protection. From the nineteenth century to the present, vaccines have emerged always as empirical successes. There is no standard procedure for producing vaccines, nor is it clear that there may be one. Infectious diseases are multiple and multiple are their pathogenic mechanisms; equally variable should be the protective mechanisms. A recent article points out eleven important variables in susceptibility to infectious diseases: microbioma, inoculum, sex, temperature, environment, age, chance, history, immunity, nutrition and genetics; with the initials of these terms the authors create the term MISTEACHING (Casadevall and Pirofski, 2018)

Basic reference:

Casadevall, A. and L. A. Pirofski (2018). “What Is a Host? Attributes of Individual Susceptibility.” Infect Immun 86(2): e00636-17.

Immunodominance.

One of the important human epidemic diseases is influenza, for which a different vaccine must be manufactured each year, given the high mutability of the virus. There are recent indications that antibodies that arise after vaccination are not the same as those arising in natural infection (Chen et al., 2018). At the frontier of the research is the search for a “universal” vaccine that protects against all strains of influenza viruses. The immune response to “dominant” (salient) antigenic details of the virus (hemagglutinins) blocks responses to other antigens (neuraminidase) that would provide broader protection (Corti et al., 2011). And there is still the problem of “original antigenic sin,” that is, the organism tends to repeat previous responses to similar antigens (Henry et al., 2018).

Basic References:

Chen, Y. Q., et al. (2018). “Influenza Infection in Humans Induces Broadly Cross-Reactive and Protective Neuraminidase-Reactive Antibodies.” Cell 173(2): 417-429 e410.

Corti, D., et al. (2011). “A Neutralizing Antibody Selected from Plasma Cells That Binds to Group 1 and Group 2 Influenza A Hemagglutinins.” Science 333(6044): 850-856.

Henry, C., et al. (2018). “From Original Antigenic Sin to the Universal Influenza Virus Vaccine.” Trends Immunol 39(1): 70-79.

How vaccines work.

In the nineteenth century, Pasteur believed that immunization resulted from the depletion of an essential nutritional element (a micro-element, perhaps) by the attenuated germ (weakened in the laboratory); this would make the body unfit for the growth of the same germ in future contacts. But soon effective vaccines with dead germs were produced (Smith, 2012) which invalidated Pasteur’s hypothesis. Half a century later, the characterization of antibodies and lymphocytes led to the belief that these are the components responsible for immuno-protection, but the examples that clearly demonstrate this are rare.

claramente são raros.

Basic reference:

Smith, K. A. (2012). “Louis Pasteur, the father of immunology?”

Frontiers in Immunology 3(Article 68): 1-10.

The lack of knowledge about attenuation.

In virus vaccines, which are entities with a small number of genes, successive passages by tissue culture or by infection in other species, may eventually generate mutants suitable for use in human vaccines. This was what apparently happened with the yellow fever vaccine (Tany & Deprés, 2014). But this mutation was not deliberately provoked; there is no way to direct the mutations to the desired course. As in other cases, the case of yellow fever was a stroke of luck. To date, it is impossible to define a time frame for obtaining, say, an effective vaccine against the Zika-virus. Decades of research at the frontier of knowledge have been unable to generate effective vaccines against, for example, AIDS, malaria or tuberculosis.

Basic References:

Beck, A., et al. (2014). “Comparison of the live attenuated yellow fever vaccine 17D-204 strain to its virulent parental strain Asibi by deep sequencing.” J Infect Dis 209(3): 334-344.

Tangy, F. and P. Desprès (2014). “Yellow Fever Vaccine Attenuation Revealed: Loss of Diversity.” J.Inf.Dis. 209: 318-320.

Walker, L. M. and D. R. Burton (2018). “Passive immunotherapy of viral infections: ‘super- antibodies’ enter the fray.” Nature Reviews Immunology.

03 – Antibodies against diseases: serum therapy

After the great success in the treatment of children with diphtheria by diphtheria antitoxin (anti-diphtheria serum) obtained in animals, it was hoped that the transfer of preformed antibodies (serum therapy, passive immunization) would be able to treat most infectious diseases. These experiments failed. Serum therapy works by “neutralization”, that is, when antibodies spatially block the binding of toxins (diphtheria), or viruses (those that make a phase of viremia, as in polio) to their receptors in the body. Extensive unsuccessful attempts with multiple infectious diseases suggest that antibodies alone do not cure bacterial infectious diseases (there are exceptions, such as pneumococcal pneumonia). This applies both to conventional antibodies (polyclonal “antisera”) and more recently attempted monoclonal antibodies. In the last decades the use of intravenous high doses of IgG (IVIg) isolated from mixtures of thousands of donors in the treatment of diseases of unknown origin, such as autoimmune diseases, has been developed empirically (without an explanation). The efficacy of the treatment is erratic.

Basic references:

Galeotti, C., Kaveri, S. V. & Bayry, J. (2017). “IVIG-mediated effector functions in autoimmune and inflammatory diseases.” Int Immunol. 29(11): 491-498

Graham, B. S. and D. M. Ambrosino (2015). “History of passive antibody administration for prevention and treatment of infectious diseases.” Curr Opin HIV AIDS 10(3): 129-134

Hey, A. (2015). “History and Practice: Antibodies in Infectious Diseases.”

Microbiol Spectr 3(2): AID-0026-2014

Hifumi, T., et al. (2017). “Clinical Serum Therapy: Benefits, Cautions, and Potential Applications.” Keio J Med 66(4): 57-64.

João, C., et al. (2018). “Passive Serum Therapy to Immunomodulation by IVIG: A Fascinating Journey of Antibodies.” J Immunol 200(6): 1957-1963.

Marston, H. D., et al. (2018). “Monoclonal Antibodies for Emerging Infectious Diseases – Borrowing from History.” N Engl J Med.

Sofia, M. A. and D. T. Rubin (2017). “The Impact of Therapeutic Antibodies on the Management of Digestive Diseases: History, Current Practice, and Future Directions.” Dig Dis Sci 62(4): 833-842.

Walker, L. M. and D. R. Burton (2018). “Passive immunotherapy of viral infections: ‘super- antibodies’ enter the fray.” Nature Reviews Immunology.

04 – Immunological Self-Aggression

In the nineteenth century, paroxysmal nocturnal hemoglobinuria (PNH) was the first example of “autoimmune” episodes, in which antibodies produced by the body itself participate in tissue damage. The serum of PNH patients contains antibodies (hemolysins) that react with their own red blood cells (autoantibodies) and when the patient is exposed to cold (they are cryoglobulins) they aggregate, activate the complement system and destroy the red blood cells. The patient then “urinate blood” (hemoglobin in the urine). Besredka (1901) stated that PNH does not depend on this auto-hemolysin, since this antibody is also present in the serum of healthy human beings; hemoglobinuria depends on the absence of an neutralizing anti-hemolysin that healthy individuals also produce, but patients with hemoglobinuria do not. Silverstein (1986) discusses this apparent contradiction that the body does not form antibodies to its own components (horror autotoxicus) according to Paul Ehrlich’s “inexorable logic.”

A second more recent example is that all humans, whatever their blood groups, have antibodies (IgG and IgM) that react with A + red blood cells; i.e. individuals of groups A and AB have anti-A antibodies, but do not lyse their own red blood cells because they also have anti-anti-A (Spalter et al., 1999) antibodies (anti-idiotypic).

Basic references:

Besredka, A. (1901). “Les autohémolysines naturelles.”

Ann Inst Pasteur 15: 785-807.

Silverstein, A. M. (1986). “Anti-antibodies and anti-idiotype immunoregulation, 1899-1904: The inexorable logic of Paul Ehrlich.” Cell.Immunol. 99(2): 507-522.

Spalter, S. H., Kaveri, S. V., Bonnin, E., Mani, J. C., Cartron, J. P., Kazatchkine, M. D (1999). “Normal human serum contains natural antibodies reactive with autologous ABO blood group antigens.” Blood 93(12): 4418-4424.

05 – Oral Tolerance

Early in the twentieth century, the phenomenon presently known as “oral tolerance” was  described over and over again, but it has not attracted much attention. The term “tolerance” refers to an inhibition of the specific immunological reaction, somewhat like an underside of the immunological memory triggered by vaccines. In “tolerance,” contact with an antigen, rather than increasing, reduces the readiness of responses when contact with an antigen repeats. The term “oral” means that tolerance has been induced by ingestion of the antigen as a food, but there are more recent indications that contact by other mucosal pathways and even through the skin, can generate phenomena similar to “oral tolerance.

Besredka (1909) showed that the previous intake of cow’s milk blocked the possibility of sensitizing guinea pigs to anaphylactic shock by the injection of milk; Well and Osborne (1911) have shown something similar with zein, a corn protein. Thirty years later, Chase studied “contact dermatitis” in guinea pigs by repeatedly brushing the skin with highly reactive protein compounds, such as dinitrochloro-benzene, when eczema is generated. Perhaps in an attempt to induce “contact enteritis”, Chase introduced the compounds through the digestive tract and, to his surprise, not only did the digestive lesions not occur, as the subsequent sensitization of the skin was inhibited (Chase, 1946). As with the previous findings, the data were placed in the drawer of curious phenomena, for later analysis.

In the 1970s, independently, in several laboratories, evidenceof “oral tolerance” emerged (Vaz et al., 1977; 1997). This time, the phenomenon, with the current denomination, sometimes extended to “mucosal tolerance” (mucosal tolerance) was greatly expanded and had its cellular and molecular bases investigated. A society for the study of mucosal immunology was created, with an independent congress that precedes the world immunology congress, as well as periodicals dedicated to the subject (Weiner et al., 2011; Pabst and Mowat, 2012). Despite this, the idea that we are “tolerant” to everything we eat as food, and also products of our native microbiota, is not yet on the front pages of immunology textbooks and is ignored by most students and non-specialists. More recent experiments show that tolerance is more a locking (buffering) of the specific level of response than an inhibition (Verdolin et al., 2001); the induction of “oral tolerance” involves lymphocyte activation and changes in the class of active immunoglobulins (Castro Jr et al., 2012).     

Basic references:

Besredka, A. (1909). “De l’anaphylaxie. Sixiéme memoire de l’anapjylaxie lactique.” Ann.Inst.Pasteur 23: 166-174.

Castro-Junior, A. B., , Horta, B.C., Gomes Santos, A.C., Cunha, A.P., Da Silva, R.S., Do Nascimento, R.S., Faria, A.M.C. and Vaz, N.M. (2012). “Oral Tolerance correlates with high levels of lymphocyte activity.” Cellular Immunology 280: 171-181.

Chase, M. (1946). “Inhibition of experimental drug allergy by prior feeding of sensitizing agents.” Proc.Soc.Exp.Biol.&Med. 61: 257-262.

Faria, A. M. C. and H. L. Weiner (2005). “Oral tolerance.”

Immunological Reviews 206: 232–259.

Pabst, O. and A. M. Mowat (2012). “Oral tolerance to food protein.”

Mucosal Immunol 5(3): 232-239.

Vaz, N. M., et al. (1977). “Inhibition of homocitotropic antibody response in adult mice by previous feeding of the specific antigen.” J. Allergy Clin. Immunol. 60: 110.

Vaz, N. M., et al. (1997). “Immaturity, ageing and oral tolerance.”

Scand. J. Immunol. 46: 225-229.

Verdolin, B. A., Ficker, S.M., Faria, A.M.C., Vaz, N.M., Carvalho, C.R (2001) “Stabilization of serum antibody responses triggered by initial mucosal contact with the antigen independently of oral tolerance induction.” Braz. J. Biol. Med. Res. 34(2): 211-219.

Weiner, H. L., da Cunha, A. P., Quintana, F. and Wu, H. (2011).

“Oral tolerance.” Immunol Rev 241(1): 241-259.

Wells, H. G. and T. B. Osborne (1911). “The biological reaction to vegetable proteins.”

J.Inf.Dis. 8: 66-78

Second half of the twentieth century

The experiments and the theoretical proposals that formed the skeleton of the current immunology were created in the period 1951-1961: (a) lymphocytes were seen as the central cells in the immunological activity; (b) immune tolerance was invented, centered on self-tolerance (natural tolerance) interpreted as the absence of body reactivity to its own components; (c) lymphocyte activation was seen as a “selective” process, replacing previous ideas that proposed the “molding” of antibodies on antigen molecules (Jerne, 1955; Burnet, 1957); and (d) the participation of thymus and T lymphocytes in immunological activity was characterized.

In the 1970s, the study of the genetic control of immunological activity led to the characterization of Ir (Immune-response) genes linked to MHC (Major Histocompatibility Complex); also in the 1970s, Jerne proposed the theory of the idiotype network, a systemic theory about immunological activity. In the 1980s, the role of Ir genes was clarified and led to the description of peptide processing / presentation in T lymphocyte activation.

Items 07-10 mention articles that radically contradict the usual way of thinking.

06 – Medawar and alo-tolerance (1953)

07 – Heteroclytic Antibodies (Makela, 1965)

08 – The syngeneic barrier (Celada 1967)

09 – allo-reactivity (Wilson, 1976)

10 – IgM generates IgM (hypercyclic antibodies) (Forni et al., 1980)

06 – Medawar and alo-tolerance (1953)

In 1953, Medawar and colleagues experimentally produced a tolerance status to allogeneic skin transplants (among mouse inbred lines) by injecting allogeneic cells into neonatal recipient animals (Billingham, Brent and Medawar, 1953). Based on these results (and also in Jerne’s theory of natural selection of antibody production, 1955), Burnet created the clonal selection theory of immunity (Burnet, 1957, 1959) that dominates immunological thinking to this day. Medawar and Burnet won the first Nobel prize in 1960 for the invention of the concept of immune tolerance.

Medawar’s experiments with neonatal tolerance were repeated almost 40 years later (Bandeira et al., 1989) and showed that the neonatal exposure to allogeneic lymphocytes activates and increases allo-reactive cells, rather than inhibit or destroy them. This is a conclusion opposite to Medawar’s and Burnet’s earlier conclusions. In addition, host-to-host (GvH) reactions should have occurred in neonatal mice injected with lymphocytes from another lineage (GvH, see Simonsen, 1967); in the Medawar experiments they did not occur by sheer luck in choosing the pair of lines (CBA-> A / J). The theoretical bases of Burnet’s proposed clonal selection (self-tolerance, autoimmune diseases, etc.) are false: autoantibodies and lymphocytes (Coutinho, Kazatchkine and Avrameas, 1995). common in healthy organisms.

Basic references:

Bandeira, A., et al. (1989). “Transplantation tolerance correlates with high levels of T and B lymphocyte activity.” Proc.Natl.Acad.Sci. 86: 272-276.

Billingham, R. E., et al. (1953). “Actively acquired tolerance of foreign cells.”

Nature 172: 603-606.

Burnet, F. M. (1957). “A modification of Jerne’s theory of antibody production using the concept of clonal selection.” Austr.J.Sci. 20: 67-69.

Burnet, M. F. (1959). The clonal selection theory of immunity.

Nashville/London, The Vandrbilt and Cambridge University Presses.

Coutinho, A., et al. (1995). “Natural autoantibodies.”

Curr Opin Immunol 7(6): 812-818.

Simonsen, M. (1967). “The clonal selection hypothesis evaluated by grafted cells reacting against their hosts.” Cold Spring Harbor Symp. 32: 517-524.

Silverstein, A. M. (2016). “The curious case of the 1960 Nobel Prize to Burnet and Medawar.” Immunology 147(3): 269-274.

Simpson, E. (2015). “Medawar’s legacy to cellular immunology and clinical transplantation: a commentary on Billingham, Brent and Medawar (1956) ‘Quantitative studies on tissue transplantation immunity. III. Actively acquired tolerance’. .” Phil. Trans. R. Soc. B 370(20140382).

07 – Heterocytic Antibodies (Makela, 1965)

Heterocytic antibodies are those that react best with an antigen other than the one that induced its formation. This phenomenon indicates that the organism “has reasons that reason does not know”

Basic reference:

Makela, O. (1965). “Single lymph node cells producing heteroclitic bacteriophage antibody.”

J. Immunol. 95(2): 378-386.

08 – The syngeneic barrier (Celada 1967)

The transfer of lymphocytes between histocompatible (syngeneic) animals is common in experimental immunology. In these experiments, the recipient animal is irradiated to inhibit (destroy) its lymphocytes, under the claim that this allows for the exclusive analysis of the reaction of the transferred lymphocytes. Celada shows that if the recipient animal is not irradiated, its specific reactivity (the formation of antibodies) is strongly inhibited, i.e. there is a “syngeneic barrier” to lymphocyte transplantation. The barrier is radio-sensitive and dependent on the age of the recipient animal. This is a serious observation because adoptive transfer experiments (for irradiated receptors) form the basis of theoretical immunology.

Basic reference:

Celada, F. (1966). “Quantitative studies of the adoptive immunological memory in mice.

I. An age-dependent barrier to syngeneic transplantation. “J. Exp. Med. 124: 1-14.

09 – Allo-reactivity (Wilson, 1971)

Contrary to the expectation that the body reacts immunologically to what is most “foreign” to it, lymphocytes react more intensely (by transforming into activated lymphoblasts) to contact with allogeneic lymphocytes (cells of the same animal species) than xenogeneic lymphocytes from other animal species. Rat lymphocytes react more strongly to lymphocytes from other rat lineages than to lymphocytes from mice, hamsters, guinea pigs or humans. This difference becomes even clearer in germ-free mice (Wilson and Fox, 1971). These data favor the hypothesis that immunological activity is more linked to the detection of allogeneic cells (of the same animal species) than viruses, microbes and parasites (see Rinkevitch, 2004, 2011)

Basic references:

Wilson, D. B. and D. H. Fox (1971). “Quantitative studies on the mixed lymphocyte interaction in rats. VI. Reactivity of lymphocytes from conventional and germfree rats to allogeneic and xenogeneic cell surface antigens.” J Exp Med 134: 857-870.

Rinkevich, B. (2004). “Primitive immune systems: Are your ways my ways?”

Immunological Reviews 198(12): 25-35.

Rinkevich, B. (2011). “Quo vadis chimerism?”

Chimerism 2(1): 1-5.

Hypercyclic Antibodies (Forni et al., 1980)

Basic reference:

Forni, L., et al. (1980). “IgM antibodies induce the production of antibodies of the same specificity.” Proc.Natl.Acad.Sci.USA 77: 1125-1128.

Contemporaneity

11 – The native microbiota (McFall-Ngai, 2013, Gilbert, Sapp & Tauber, 2012; Dupré, 2012)

12 – Poly-specific natural IgA (Bunker et al., 2015; 2017)

13 – Micro-chimerism is the rule (Diershelius & Goulmy, 2012, Kinder, 2015, 2017)

14 – Multiple agents in each infection (Balmer, 2011; Méthot & Alizon, 2014)

15 – Re-wilded mice (Beans, 2018; Willyard, 2018)

11 – The native microbiota (McFall-Ngai, 2013, Gilbert, Sapp & Tauber, 2012; Dupré, 2012)

The radical modification in the way of seeing the “microbial world”in general, and the human native microbiota in particular, is the most significant change in current immunological thinking (Dupré, 2012). This is relevant not only as a new position in relation to the “natural world” but also because the historical origin of immunology has been in the study of infectious diseases. The immense diversity and ubiquity of microbes and viruses and the realization that only a small part of them can be involved in infectious diseases, forces another understanding. In another item (14), I comment on the recent finding that in these diseases, there are usually a plurality of forms of the infecting agent which also change during the infection. The complexity of these events relativizes the idea that contagion is a determinant of illness: several other factors linked to both the host and the infecting agent are determinants of the course of events. But there is no doubt that the native microbiota essentially affects all activities of the host, including its conduct, for example, in food consumption.

Basic References:

Dupré, J. (2012). Processes of Life. Essays in the Philosophy of Biology.

Oxford, Oxford University Press.

McFall-Ngai, M., et al. (2013). “Animals in a bacterial world, a new imperative for the life sciences.” PNAS 110 (9): 3229-3236.

Gilbert, S. F., et al. (2012). “Symbiotic View of Life: We Have Never Been Individuals.”

Quarterly Review of Biology 87: 326-341.

12 – Poly-specific natural IgA (Bunker et al., 2015; 2017)

A very recent addition to immunological thinking was the characterization of natural, poly-specific IgA with characteristics that contrast with all that was previously known about immunological reactivity.

Basic references:

Bunker, J. J., et al. (2015). “Innate and Adaptive Humoral Responses Coat Distinct Commensal Bacteria with Immunoglobulin A.” Immunity 43(3): 541-553.

Bunker, J. J., et al. (2017). “Natural polyreactive IgA antibodies coat the intestinal microbiota.” Science 358(6361).

13 – Micro-chimerism is the rule (Diershelius & Goulmy, 2012, Kinder, 2015, 2017)

Another recent addition to immunological thinking is the realization that, genetically, we are all “chimeras,” that is, we have active living cells that are originated in our mother and perhaps older sisters and siblings as a result of normal pregnancy. This finding refers to problems pointed out by Medawar (1953) as a sequel to his characterization of experimental allogeneic tolerance (Billingham, Brent and Medawar, 1953): if the fetus inso longer seen as an allogeneic transplant involving some kind of suppression of maternal responsiveness, an alternative understanding of the very nature of immunological activity is necessary.  In the United States, in 2006, in a paternity test for the dispute of the custody of a woman’s children by DNA gave astonishing results. DNA proved paternity in her husband, but denied mother’s motherhood (Lydia Fairchild)! The children were generated from the eggs of a sister of the woman who died still in the embryonic stage, so that the woman gave birth to nephews, instead of sons and daughters; Lydia is a chimera, genetic sister of herself.

Basic References:

Billingham, R. E., Brent, L. and Medawar, P.B. (1953). “Actively acquired tolerance of foreign cells.” Nature 172: 603-606.

Dierselhuis, M. P. and E. Goulmy (2012). “We are all born as microchimera.”

Chimerism 4(1): 18.

Kinder, J. M., et al. (2015). “Tolerance to noninherited maternal antigens, reproductive microchimerism and regulatory T cell memory: 60 years after ‘Evidence for actively acquired tolerance to Rh antigens’.” Chimerism 6(1-2): 8-20.

Kinder, J. M., et al. (2017). “Immunological implications of pregnancy-induced microchimerism.” Nat Rev Immunol 17(8): 483-494.

Medawar, P. B. (1953). “Some immunological and endocrinological problems raised by the evolution of viviparity in vertebrates.” Symp. Soc. Exp. Biol. 7: 320-338.

14 – Multiple agents in each infection (Balmer, 2011; Méthot & Alizon, 2014)

Equally surprising is the demonstration that, usually, infectious diseases do not involve a single variety (strain, lineage, mutant) of the infecting agent, but several of them (Balmer, 2018). Because of their reproductive rate (hours) vastly faster than that of their hosts, microbial and viral agents “evolve” during infection and this can have serious consequences, for example, in epidemics. Two scenarios in human history are likely to be examples of how this variation has had catastrophic effects on human populations: in the field of resettlement of multiple species in Mesopotamia in the Paleolithic (10-5 thousand years ago) (Scott, 2017); and in the interaction of the European conquerors with the native populations of the Americas in the sixteenth century (Black, 1972).

Referências básicas:

Balmer, O. and M. Tanner (2018). “Prevalence and implications of multiple-strain infections.”

The Lancet – Infectious Diseases 11(11): 868-878.

Dupré, J. (2012) “Processes of Life. Essays in the Philosophy of Biology”

Oxford, Oxford University Press

Methot, P. O. and S. Alizon (2014). “What is a pathogen? Toward a process view of host-parasite interactions.” Virulence 5(8): 775-785.

15 – Wild animals (Beans, 2018; Willyard, 2018)

Finally, current literature shows a growing number of experimental models that demonstrate very significant variations of experimental results when the maintenance conditions of experimental animals are changed – for example: size and quality of cages; contact with animals of other origins; etc.

Basic References:

Abolins, S., et al. (2018). “The ecology of immune status in a wild mammal, Mus musculus domesticus.” PLoS Biol 16 (4): e2003538.

Beans, C. (2018). “What happens when lab animals go wild.”

PNAS 115 (13): 3196-3199.

Viney, M., et al. (2015). “The laboratory mouse and wild immunology.”

Parasite Immunol 37 (5): 267-273.