Tisler C, Dasilva D, Anklam K, Mikus LD, Rosenthal LA, Ober C, Gangnon R,. Lemanske RF, Effects of dog ownership and genotype on immune development ...
Medicina Evolucionista Aportaciones pluridisciplinares
Alvaro Daschner José-Luis Gómez Pérez Maria-José Trujillo Tiebas (Editores)
Volumen IV
Evolutionary plausibility of specific immunotherapy in Allergy Alvaro Daschner
This is a translation of the original Chapter text in Spanish: Daschner A: Plausibilidad evolutiva de la inmunoterapia específica en alergia. In Daschner A, Gómez-Pérez JL, Trujillo-Tiebas MJ (Editores): Medicina Evolucionista. Aportaciones pluridisciplinares Volumen IV, pp. 81-89. ISBN 978-1986667319
More information at www.medicinayevolucion.com
Book available at https://www.amazon.es/dp/1986667316/
Evolutionary plausibility of specific immunotherapy in Allergy Alvaro Daschner
Summary Specific immunotherapy, in its different forms of administration, has been established for decades for the therapeutic approach of allergic diseases. In this work we offer an evolutionary view of the immune response against antigens with which we usually have contact. It is described how tolerance to ubiquitous agents such as food is not simply an absence of reactivity, but rather an active regulatory response, in which the anti-inflammatory forces inhibit the specific effector response, which are also present. The theory of discontinuity proposes that an effector immune response makes more biological sense when there is an antigenic difference in a given temporal context, which would explain its biological usefulness in case of acute infections, in which contact with antigens is rapidly increasing. In the same way, it would explain the tolerance of antigens with which we have contact in a context of more prolonged temporality or if in time the exposure to antigens is maintained continuously, as in chronic infections. Applying these ideas for the treatment of allergies, differentiated dynamics of controlled exposure to allergens with specific dosages can be postulated. In this sense, immunological studies have shown the induction of a specific anti-inflammatory response when immunotherapy is administered in scenarios of very rapid administration of high doses or progressively increasing doses of allergen. Therefore, in a gradient, which includes a function of speed and intensity of exposure to the antigen, the anti-inflammatory characteristics seem to appear both at the beginning and at the end, while the effector responses are expected in an intermediate scenario.
Introduction: Fight or flight, stress and the immune response against possible dangers The concept of "fight or flight" was coined by Walter Bradford Cannon at the beginning of the last century and describes a reaction, in which catecholamines play an important role, such as adrenaline that prepares the individual to fight or run away. It is an emergency that is also called
acute stress response and is launched before the perception of damage or attack [1]. Previously Claude Bernard had introduced the idea of the "milieu interieur" (internal environment) and proposed the idea that the physiological functions or vital processes had as objective to maintain the milieu interieur through compensatory reactions before any change induced by external forces [2], which subsequently was called homeostasis by WB Cannon. While C. Bernard had his merit searching for the reason of the compensation reactions, it was W.B. Cannon who sought and explained the mechanisms. Hans Selye is the one who later popularized the concept of stress and described the General Adaptation Syndrome, in which the fight or flight reaction would correspond to the first of the stages described as "Alarm reaction". The second stage of adaptation corresponds to the resistance to the stressor, the agent that initially supposed a perception of danger and set in motion an alarm reaction. If this phase finally lasts too long, the adaptation system claudicates giving way to the third exhaustion stage [3]. In order to look for the role of tolerance mechanisms, it is necessary trying to understand the relationship between the stress reaction and the immune system. The general definition of immune system of Wikipedia says: the immune system is that set of structures and biological processes inside an organism that allow it to maintain the homeostasis or internal balance against external aggressions, either of biological (pathogenic agents) or physico-chemical (as contaminants or radiation), and internal nature (for example, cancer cells). Thus it is observed that in the fight or flight reaction, the neurological and endocrinological systems are studied and described dealing with possible external dangerous agents, while the immune system must protect from possible pathogens or smaller harmful agents and is involved in repair or wound healing and also has a certain role in tumor surveillance [4]. The relationship between stress and the immune response has been studied in different contexts. In the popular idea, stress in a bad press would be related mainly to the appearance of allergies, infections or cancer. However, it is important to differentiate acute stress and chronic stress. Today, two types of stress are considered: eustress and distress, the former being the one that evolutionarily is beneficial and of short duration and the latter the one that is pernicious because of its prolongation in time or because it occurs in the face of a truly non-
2
dangerous stimulus. F.S. Dhabhar argues that it makes no sense that in the face of acute stress, triggered by a potentially dangerous external agent, evolutionary history has allowed a decrease in immune capacity to be maintained. As an example, a possible aggression by an animal or a trauma by accident would be associated with a high probability of injury and risk of infection. Since the role of the immune system is not only protection against pathogens, but also the start-up of tissue reconstruction, an increase in immune defense capacity would be expected [5]. On the contrary, there is evidence that in the face of an allergic reaction already underway or a phenomenon of autoimmunity, these could be increased in intensity or prolonged [6, 7]. In this context it should be noted that there is already a basal inflammatory response that leads to the phenomena of allergy or autoimmunity.
The challenges of the immune system The defense The knowledge on the mechanisms of immune defense against harmful agents has increased rapidly in recent decades, however the riddle has been maintained for a longer time on what would be the mechanism by which the immune system would be able to simultaneously combat dangerous agents and permit tolerance of innocuous antigens of all kinds, including food or microbiota. Recently, even the possible active role of the adaptive immune system in the promotion of beneficial micro-organisms in the host organism has been postulated [8, 9]. The hypotheses about the method used for this purpose have been changing during the last half century. We had initially learned that the immune system differentiates between the self and the non-self [10]. The set of skin surface, gastro-intestinal, genitourinary and respiratory mucosa separates us from the external world with large surfaces. This idea seemed initially intuitive, when the microbes and parasites were generally considered as "danger" and had to be attacked. However, antigens such as food or microbiota must be tolerated or ignored and not initially considered "own". In a second model attempt it was proposed that the immune system should differentiate the "non-infectious", equivalent to the pathogens, and the "non-infectious" self, so that the microbiota should be considered as its own in order to tolerate, ignore or promote [11].
3
This scheme, however, would not explain the autoimmune phenomena, in which the immune system attacks its own non-infectious cells or proteins. In this way, a new concept emerged, called the danger model, according to which an effector immune response would be triggered when the receptors of the innate immune system are stimulated by danger ligands, either in response to infections or trauma [12]. This means that the priority recognition is not a specific molecule of the pathogen or the harmful agent, but the damage that it produces and that would be associated with the production of damage associated molecular patterns (DAMPs). A more advanced proposal that derives from this idea is described as the effector-triggered immunity. As the name implies, immune surveillance would include sensors that would be triggered by the recognition of cellular perturbation induced by bacterial toxins or other effectors, rather than by the direct presence of these toxins [13]. Inflammation and regulation Another challenge of the immune system is to achieve a good temporal coordination of the active inflammatory response and its termination at the appropriate time. The concept that the termination of the immune response is not simply a cessation of its pro-inflammatory activity is relatively new. Rather, an active mechanism is observed [6]. Faced with a danger such as the presence of pathogens or a wound, which in turn is frequently associated with the presence of micro-organisms or internal danger signals, the immune system starts up. Through the mechanism of inflammation, resulting from the accumulation and activation of a series of effector and mediator cells, not only does the elimination of hazards get better, it is also necessary to start the restoration of the system to the previous stage, equivalent to homeostasis, and this includes the cessation of inflammatory activity. If the inflammation is too long or too intense in order to combat the danger, it will cause the immune system itself to perpetuate and cause the disease, such as allergy, autoimmunity, etc. With this information in mind, it is clear that there must be not only a balance, but also a temporary coordination between the pro-and anti-inflammatory forces, or at cellular level between the effector cells and regulatory cells. Immune tolerance Immune tolerance is defined as the absence of a (specific) effector response of the immune system against an antigen. This is necessary, since we cannot allow beneficial antigens in the food or the microbiota itself to be attacked by the immune system. A second function is further
4
the avoidance of tissue damage when inflammation is prolonged and the regulatory mechanism helps in the termination of the same. Figure 1: Equilibrium between effector and regulatory response
The "naïve" T cells can generally be differentiated into effector cells (elimination of noxious agents, pathogens, inflammation, etc.) or regulatory cells (inhibition of the effector response, antiinflammatory effect, etc.). In allergy, effector T cells induce B cells to produce immunoglobulin E (effector), whereas regulatory T cells induce the production of immunoglobulin IgG4.
There are three basic forms of tolerance to antigens. If an effector cell has been produced that recognizes an antigen, it can undergo deletion by apoptosis and then there would be no effector cell. Another mechanism, especially of the B cells producing immunoglobulins, is receptor editing, here the receptor would change so that it no longer recognizes the antigen that has to be tolerated. T cells can also undergo receptor editing of T cell epitopes. The third form of tolerance is anergy and corresponds to a functional inactivation of the effector cells. This has been studied above all at the level of recognition of self-antigens, in the context of central tolerance.
5
Here, very early lymphocytes are subjected in the thymus to mechanisms of central tolerance by these three mechanisms. However, effector T cells that eventually reach the circulation may undergo regulation or inhibition mechanisms later in the periphery. Then peripheral mechanisms are responsible for compensating the previous central regulation to avoid autoimmunity and in another scenario promote the tolerance of new antigens as indicated above. Given that specific cells are found in the circulation, the active suppression of these lymphocytes is of particular interest, which is started when a subset of specific T cells that are produced and called Treg cells will exert various suppressive functions on the activation of a specific effector immune response. Due to the continuous contact with food and the microbiota that must be tolerated in the intestine, this organ has been postulated as tolerogenic, so that it will be easier to tolerate an antigen with which we have contact through the intestine. This will result in the concept called oral tolerance [14, 15]. According to experimental studies, it seems that the antigen dose will be determinant to achieve this oral tolerance: single and high doses of antigen most frequently produce anergy or clonal deletion. On the contrary, low and repeated doses more likely produce a suppression mediated by T cells. However, as in other scientific scenarios, the relevance of each of these mechanisms in real life or different situations has to be determined (see Figure 1) . Regulatory T cells and pro-and anti-inflammatory balance We have observed that in the context of a non-allergic subject exposed to aeroallergens and also to food, tolerance to them is produced by an active dynamic of immune response against external antigens. The regulation or suppression mechanisms of the effector immune responses include Treg cells, whose effect has been studied and recognized at different levels of the immune or inflammatory response. With experimental studies it has been possible to differentiate several types of cells classified as regulatory T (T reg), which include the nTreg (natural Treg) produced at the central level, the FOX p 3 negative cells, which secrete the anti-inflammatory cytokine IL-10 , as well as those of most interest in the context of this chapter, the FOX P 3 positive T reg. Those that occur at the central level (nTreg of the thymus) are more stable over time, while those that are induced in the periphery (iTreg) can be redifferentiated in an inflammatory environment to effector cells. From the presented data it is concluded that in order to achieve a good functioning of the organism and its immune system, a balance between pro- and anti-inflammatory forces must prevail, which at the level of the T
6
cells corresponds to a balance between effector cells on the one hand and Treg cells those on the other, in order not to produce an immunopathology, but to maintain a line of defense against possible harmful agents [16]. When this is not the case, there is a risk for the onset of autoimmune disease. In an example such as inflammatory bowel disease, there is also a vicious cycle, in which under a local inflammatory environment it becomes very difficult to establish tolerance. Another important example derived from an imbalance between pro-and anti-inflammatory forces with predominance of effector cells over Treg cells, is allergic disease.
Box 1: Regulatory actions of regulatory T cells in the temporal order of their activity
Suppressing inflammatory dendritic cells Suppressing Th1 or Th2 effector cells Suppressing IgE production Inducing the production of other immunoglobulin isotypes Suppressing mast cells, basophils or eosinophils Role in remodeling (healing)
It is now worth highlighting two fundamental and unintuitive aspects of the findings: the process of tolerance to antigens with which we have contact, such as food, is an active process, not simply an absence of reactivity. Similarly, the cessation of a process of inflammation does not occur simply by a passive cessation, but by an active mechanism of regulation of inflammation.
However, tolerance to antigens in our environment may cease if regulatory mechanisms fail. To understand inflammatory diseases, in which these mechanisms fail, we must investigate the mechanisms of loss of tolerance in order to design treatment strategies.
7
Tolerance or allergic reaction The mechanisms of the allergic reaction have parallels with other immunological responses. The first phase of the allergic response is sensitization and corresponds to the primary response, in which the allergen causes for the first time an immune recognition with production of specific IgE against the allergen. The second phase is the effector phase (corresponding to the secondary response), where in successive contacts of IgE molecules (circulating or present on the effector cells such as the mast cell or the basophil) with the allergens, these are recognized eliciting a cascade of molecular events that lead to the clinical allergic reaction. There are some models that help to clarify and understand how healthy subjects establish the mechanisms of tolerance to antigens that are not tolerated in allergic subjects. Hymenoptera, such as bees and wasps, are capable of producing an acute, sometimes severe, allergic reaction such as anaphylaxis or anaphylactic shock in subjects with allergic predisposition. More interesting is the long-known fact that beekeepers who are frequently stung are generally protected from allergic reactions. These subjects produce higher amounts of specific IgG4 against bee allergens, while allergic ones produce relevant amounts of IgE. One study has been able to reveal some of the immunological mechanisms associated with the beekeepers' tolerance to sting. It has been possible to associate the termination of the annual season with more bites to an increase in the proliferation of T cells after stimulation with an allergen. In parallel, cutaneous reactivity was decreased by subjecting patients to the allergen skin test [17]. In this way it has been possible to demonstrate that the clinical tolerance is associated to a state of anergy of peripheral effector T cells after high doses of allergen. It is interesting to note that beekeepers also produce IgE in many cases, but that IgG values, especially at the expense of IgG4, are up to 100 times higher. In this pathology, one of the oldest and most effective immunotherapies, for which immunological plausibility now exists, had been empirically inaugurated decades ago, since by means of the controlled administration of hymenoptera extracts we try to imitate in allergic patients the model of beekeepers tolerance. The epidemiological data in relation to animal ownership are not so clear. While living on a farm and having contact with livestock seems to have a protective effect against the appearance of allergies [18], there is some evidence that early contact (especially in first year of life) could prevent from pet allergy [19, 20]. In a cross-sectional study of children with asthma, domestic exposure to a major cat allergen was measured and, on the other hand, the presence of IgE antibodies and other immunoglobulin
8
isotypes. A correlation has been found between allergen exposure and serum IgG levels [21]. In other scenarios, the presence and levels of IgG is frequently associated to exposure levels. However, in the case of the IgE of the subgroup of allergic patients, the correlation curve was not linear, initially increasing in correlation with the exposure to the allergen, while at very high exposure the levels of IgE dropped again (inverted Ushaped curve). In another third scenario, those children were analyzed who, after a more or less long stage of food allergy, tolerated the foods involved. Regarding cow's milk protein allergy, children who had overcome the allergy were compared with those who maintained symptoms in a provocation test with milk. By means of a flow cytometry study, CD25 T cells (corresponding to the regulatory T cells) were separated, the percentage of them being higher in tolerant than allergic children before the challenge [22]. After provocation, this percentage increased even more, while it decreased slightly in the allergic ones at the expense of other effector CD4 T cells. From this it was possible to conclude that in tolerant children the relative number of effector T cells is suppressed and also that the provocation itself, that is, the antigenic stimulus, produced a proliferation of the T reg cells. Respiratory allergy is the most frequent manifestation of allergic diseases and it is interesting to compare the specific immune response in allergic and healthy individuals. While intuitively we might think that healthy subjects simply ignore antigens or allergens when they have contact with them, the reality is different: by studying specific T cells against two major allergens Der p 1 (from mite) and Bet v 1 (from birch pollen), it was possible to identify the specific T cells involved by measuring the production of cytokines. It was thus possible to observe that the specific response against both allergens was active and of antiinflammatory type (IL-10) in healthy individuals, but and pro-inflammatory and type Th2 (IL-4) in allergic [23].
Fight or flight in the allergic reaction Taking into account the definition of allergy as an IgE-mediated hypersensitivity reaction to generally harmless agents in subjects with predisposition, we observe that in contact with any antigen, the body's immune system should be cautious to consider potentially dangerous any of them until you check its harmlessness. The theory of clonal selection of Burnet predicts that after an initial central maturation of the immune system, those lymphocytes with auto-reactivity have been deleted, leaving a pool of peripheral lymphocytes with a broad
9
spectrum of specificities against possible antigens with which the organism could have contact throughout his life. Given the contact with a new antigen, there are two main possibilities: to attack or to tolerate, or to mount an effector response versus a regulatory response. Figure 2: Immunological theory of discontinuity. Modified according to Pradeu T el al. [29]
Several scenarios of exposure to an antigen dynamics are displayed, defined as a molecule not previously recognized. A: The sudden and acute appearance of an antigen in sufficient quantity as in an acute infection produces an acute and temporary effector response. B: The sudden, but persistent appearance of an antigen in sufficient quantity also induces an acute effector response that diminishes after a time, giving way to a regulatory response as in a chronic infection. C: The slow and gradual appearance of an antigen produces an effector response, but a greater persistent regulatory response, while the amount of antigens is constant. D: The intermittent appearance of antigen produces a persistent vigorous effector response. Examples include recurrent acute infection or seasonal pollen allergy.
There are multiple known factors that facilitate sensitization, i.e. the production of clinically relevant specific IgE, such as genetic or
10
environmental predisposition, but also the own biochemical structure of the allergen, the route of administration (it must be remembered that contact through the digestive tract usually facilitates oral tolerance), the dose, concomitant factors such as stress, as well as probably the contact dynamics. These observations are relevant in that the production of IgE and allergic reactions could be considered as fight and tolerance as flight. This unusual comparison aims to describe how in both cases an active mechanism is set in motion, as in the fight or flight response.
Fight or flight in the treatment When a patient produces IgE that clinically manifests as allergy, we can conclude that the patient's immune system recognizes an antigen as harmful. One of the pillars of the allergological approach is the identification of responsible allergens in order to later offer useful advice, often avoidance. When faced with an allergy to a certain food, we will avoid its intake and, in case of an allergy to pets or environmental fungi, we will offer the appropriate avoidance advice. However, we have some problems. There are antigens that cannot be avoided at all, such as environmental pollen or dust mites, in certain climates and geographies. What will happen if we have a sporadic contact versus a regular contact? Will it increase or reduce reactivity? This is especially visible in pollen allergy, but also in the case of pets, whose airborne allergens can be found even in homes or schools, where these animals do not live. Looking for a therapeutic approach opposed to incomplete avoidance, the option of inducing tolerance in some way should be considered, which is being implanted more recently in food allergy [24], but which has been applied for decades by immunotherapy in the mentioned hymenoptera allergy as well as in respiratory allergy [See also: Ojeda Fernández I. Ojeda Fernández I. Inducción oral a la tolerancia alimentaria como nuevo paradigma alergológico. En Medicina Evolucionista. Aportaciones pluridisciplinares, Volumen III, pp. 127-135]. Immunotherapy Without going into the details of the different forms of immunotherapy, injected, sublingual, with modified antigens or not, with fast or slow patterns of dispensation, it can be summarized that in general, under correct indication and after an adequate study, the specific immunotherapy has demonstrated a highly favorable clinical effect not only in terms of significant reduction of symptoms, but also on the prevention of the appearance of new allergies [25-27].
11
As for the immunological mechanisms that have been demonstrated, the very early decline of the mast cell and basophilic reactivity, which is clinically relevant, is found first. After a few days the activation of T reg and Breg cells is stimulated, as well as the production of anti-inflammatory cytokines; after a few weeks specific IgA and IgG4 begins to be produced, while the production of specific IgE is reduced only after several months or years [28] (see also Box 1).
Effector versus regulatory response depending on the exposure dynamics
Figure 3: The scenarios described in figure 2 do not define what dose of antigens is high and what the rapid rate of appearance of the antigen is. The experience in immunotherapy with antigenic extracts has shown efficacy with slowly increasing patterns, but also with cluster patterns of dispensation, probably implying different mechanisms of immunological tolerance induction. This image shows how both scenarios are at the beginning and end of a curve that includes a function of speed and intensity, with predominating regulatory response, while the immune system would induce an effector response in an intermediate scenario.
Immune mechanisms show that tolerance to an antigen or its recognition as harmful depends on the specific anti-or pro-inflammatory response that
12
occurs in different scenarios of antigenic stimulation. Immunotherapy is able to reverse the anti-and pro-inflammatory balance by educating the immune system towards tolerance. The body must learn that the antigen does not cause harm and for this it is necessary to flood the body with its presence continuously and at certain doses. However, while this model is able to explain tolerance to generally harmless agents, it does not sufficiently explain the very appearance of allergic diseases (or autoimmunity phenomena). The model would be based on the fact that for some reason the organism identifies the disease-causing antigen as a "danger". Research in immunology has turned to research on a whole field of recognition patterns that are qualitative signals, which are associated with a "danger", but has left at a disadvantage the study of the dynamics of antigens to explain a danger model.
Immunological theory of discontinuity A very interesting hypothesis proposed by T. Pradeu and collaborators (in an even more interesting collaboration between the disciplines of Philosophy and Immunology) can help to shed light on this last big question [29]. The key to the induction of an immune response (nontolerogenic effector reaction) would be the antigenic difference in a temporal context. To introduce the hypothesis they describe the following examples: NK cells (Natural Killer) have the ability to produce cytokines and cytolysis when they detect transformed stem cells. Through a series of interactions of receptors and ligands, they ignore or tolerate healthy cells, whereas if transformed cells appear by virus or by tumor alteration and further appear suddenly, the NK cells are activated and the target cells are eliminated. However, the key in this observation is that if these transformed cells appear chronically, the NK cells become hypo-reactive and are not activated, which leads to tolerance. In other examples they describe macrophages, which also adapt to chronically present motifs or the phenomena corresponding to anergy of B and T lymphocytes in certain cases of antigenic continuity. One goal of these hypo-response phenomena is the avoidance of harmful effects in a pro-inflammatory state. There is a greater potential for danger in the case of antigenic changes that progress rapidly, for example, in an acute infection. The hypothesis gains plausibility due to the fact that it is a biological principle to respond to variations in the environment.
13
Under this prism, we are now able to postulate focusing immunotherapy, induction of tolerance or other treatment possibilities with the idea of reversing a state of antigenic recognition with effector response towards a hypo-response. Perhaps the most suitable dynamics for the administration of extracts to which the patient is allergic would be a scenario with a phase of gradual increase of dose and prolonged maintenance, as would also correspond to the case of desensitization or induction of tolerance. This is what has been practiced for decades, but rather focusing on avoidance of specific side effects when dispensating allergens to which the patient is allergic. However, more recently, immunotherapy guidelines have established faster and safer protocols with similar efficacy. In Figure 2 several scenarios of antigenic continuity and the resulting proand / or anti-inflammatory response are described. The hypothesis leaves open what would be considered as "gradual", that is, if we speak of temporary spaces of hours, days, months, etc. or what in each case would correspond to high or low doses. Applying the accumulated experience in the field of immunotherapy, together with the evolutionary vision of the recognition and the effector or tolerogenic response against antigens, a research guide can be proposed to define the scenario of rapid, intermediate or slow antigenic administration, that may lead to different effects of antigen recognition in an inverted U shape (see figure 3). It would also be interesting to compare the long-term effect of these different scenarios. Undoubtedly it is clinical studies that should provide definitive answers for the specialist, but an evolutionary approach with biological plausibility should guide the design of the clinical studies.
14
References 1.
Cannon WB, Bodily changes in pain, hunger, fear and rage; an account of recent researches into the function of emotional excitement. 2d Edn. New York and London,: D. Appleton and company, 1929.
2.
Bernard C, Leçons de physiologie expérimentale appliquée à la médecine, faites au Collége de France. Paris,: Baillière, 1855.
3.
Selye H, The stress of life. Rev. Edn. New York: McGraw-Hill, 1976.
4.
Swiatczak B, Immune balance: the development of the idea and its applications. J Hist Biol 2014;47:411-42.
5.
Dhabhar FS, Effects of stress on immune function: the good, the bad, and the beautiful. Immunol Res 2014;58:193-210.
6.
Serhan CN, Brain SD, Buckley CD, Gilroy DW, Haslett C, O'Neill LA, Perretti M, Rossi AG, Wallace JL, Resolution of inflammation: state of the art, definitions and terms. FASEB J 2007;21:325-32.
7.
Bosma-den Boer MM, van Wetten ML, Pruimboom L, Chronic inflammatory diseases are stimulated by current lifestyle: how diet, stress levels and medication prevent our body from recovering. Nutr Metab (Lond) 2012;9:32.
8.
McFall-Ngai M, Adaptive immunity: care for the community. Nature 2007;445: 153.
9.
Lee YK, Mazmanian SK, Has the microbiota played a critical role in the evolution of the adaptive immune system? Science 2010;330:1768-73.
10. Burnet FM, Fenner F, The production of antibodies. 2d Edn. Melbourne,: Macmillan, 1949. 11. Janeway CA, Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb Symp Quant Biol 1989;54:1-13. 12. Matzinger P, Tolerance, danger, and the extended family. Annu Rev Immunol 1994;12:991-1045. 13. Stuart LM, Paquette N, Boyer L, Effector-triggered versus pattern-triggered immunity: how animals sense pathogens. Nat Rev Immunol 2013;13:199206. 14. Swiatczak B, Rescigno M, How the interplay between antigen presenting cells and microbiota tunes host immune responses in the gut. Semin Immunol 2012;24:43-9.
15
15. Abreu MT, Toll-like receptor signalling in the intestinal epithelium: how bacterial recognition shapes intestinal function. Nat Rev Immunol 2010;10: 131-44. 16. Nathan C, Ding A, Nonresolving inflammation. Cell 2010;140:871-82. 17. Meiler F, Zumkehr J, Klunker S, Rückert B, Akdis CA, Akdis M, In vivo switch to IL-10-secreting T regulatory cells in high dose allergen exposure. J Exp Med 2008;205:2887-98. 18. von Mutius E, Radon K, Living on a farm: impact on asthma induction and clinical course. Immunol Allergy Clin North Am 2008;28:631-47. 19. Gern JE, Reardon CL, Hoffjan S, Nicolae D, Li Z, Roberg KA, Neaville WA, Carlson-Dakes K, Adler K, Hamilton R, Anderson E, Gilbertson-White S, Tisler C, Dasilva D, Anklam K, Mikus LD, Rosenthal LA, Ober C, Gangnon R, Lemanske RF, Effects of dog ownership and genotype on immune development and atopy in infancy. J Allergy Clin Immunol 2004;113:307-14. 20. Platts-Mills TA, Vaughan JW, Blumenthal K, Woodfolk JA, Sporik RB, Decreased prevalence of asthma among children with high exposure to cat allergen: relevance of the modified Th2 response. Mediators Inflamm 2001;10:288-91. 21. Platts-Mills T, Vaughan J, Squillace S, Woodfolk J, Sporik R, Sensitisation, asthma, and a modified Th2 response in children exposed to cat allergen: a population-based cross-sectional study. Lancet 2001;357:752-6. 22. Karlsson MR, Rugtveit J, Brandtzaeg P, Allergen-responsive CD4+CD25+ regulatory T cells in children who have outgrown cow's milk allergy. J Exp Med 2004;199:1679-88. 23. Akdis M, Verhagen J, Taylor A, Karamloo F, Karagiannidis C, Crameri R, Thunberg S, Deniz G, Valenta R, Fiebig H, Kegel C, Disch R, Schmidt-Weber CB, Blaser K, Akdis CA, Immune responses in healthy and allergic individuals are characterized by a fine balance between allergen-specific T regulatory 1 and T helper 2 cells. J Exp Med 2004;199:1567-75. 24. Perezábad L, Reche M, Valbuena T, López-Fandiño R, Molina E, LópezExpósito I, Oral Food Desensitization in Children With IgE-Mediated Cow's Milk Allergy: Immunological Changes Underlying Desensitization. Allergy Asthma Immunol Res 2017;9:35-42. 25. Roberts G, Pfaar O, Akdis CA, et al., EAACI Guidelines on Allergen Immunotherapy: Allergic rhinoconjunctivitis. Allergy 2017; 26. Des Roches A, Paradis L, Menardo JL, Bouges S, Daurés JP, Bousquet J, Immunotherapy with a standardized Dermatophagoides pteronyssinus
16
extract. VI. Specific immunotherapy prevents the onset of new sensitizations in children. J Allergy Clin Immunol 1997;99:450-3. 27. Purello-D'Ambrosio F, Gangemi S, Merendino RA, Isola S, Puccinelli P, Parmiani S, Ricciardi L, Prevention of new sensitizations in monosensitized subjects submitted to specific immunotherapy or not. A retrospective study. Clin Exp Allergy 2001;31:1295-302. 28. Akdis CA, Akdis M, Mechanisms of allergen-specific immunotherapy. J Allergy Clin Immunol 2011;127:18-27. 29. Pradeu T, Jaeger S, Vivier E, The speed of change: towards a discontinuity theory of immunity? Nat Rev Immunol 2013;13:764-9.
17
