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About theories and the integrative function of the immune system
Abstract
In recent years, dendritic cells have been placed centrally in starting and shaping the immune response, and a number of complex theories have been proposed to explain the immune response to antigen, Here, Zlatko Dembic overviews the Danger, Stranger and Integrity theories among others, and provides a broad look at early immune responses.
... Thus, 'pattern recognition receptor' model holds that the dendritic cells detect the exogenous, infectious agents through Toll-like receptors [10][11][12], while 'danger' model [13], predicts that the immune system additionally reacts on any process that causes cell disruption, damage or necrotic death, providing an endogenous alarm signal, which subsequently upregulate the costimulatory molecules on antigen-presenting cells (APCs). Similarly, the most recent 'integrity' model, enlarging the previous hypotheses, introduces the 'strength' control of innate immunity, proposing the existence of an additional coactivation signal for the activation of APCs, which depends on the degree of disruption of the surrounding tissue [14]. ...
... In syngeneic pregnancy, therefore, it could be speculated that they are related with greater quantity of self-antigens released from maternal-fetal interface during the process of placentation [6,20,21], or with the presence of fetal nucleated cells, transferred into maternal circulation [46,47]. The hypothesis is consistent with the 'danger' and 'integrity' models, which hold that immune response might be triggered by endogenous alarm signals, coming from the stressed or injured tissue [13,14] as well as with recent knowledge about the function of heat-shock protein (HSP)-chaperoned peptides derived from damaged tissue [48]. HSP-peptide complexes bind to CD91 and other receptors on dendritic cells, mediate endocytosis and dendritic cell maturation, and chaperon internalized peptides into MHC class I and class II of the APCs, resulting in consequent stimulation of CD8 þ and CD4 þ T cells. ...
... Interestingly, we also noticed that these activities might be additionally enhanced with peptidoglycan monomer, derived from gram(þ) bacteria (unpublished data), which in nonpregnant mice significantly increased the proportion of NKT cells in the liver [50]. The intensity of extrathymic T-cell production in the liver depends, however, not only on the induction of additional costimulatory molecules by microbial constituents on dendritic cells [10][11][12][13][14]49] but also on the sympathetic nerve activation [51], concentration of estrogens [52] and other neuroendocrine influences [40][41][42], pointing to the possibilities that different mechanisms might contribute to the dysregulation of NKT cells generated in the maternal liver, resulting in abortion. Moreover, the activation of hepatic NKT cells and simultaneous autoantibody production seems to depend also on the quantity of damaged hepatocytes, induced by the exposure of the liver to denaturated syngeneic tissue [53]. ...
... Thus, 'pattern recognition receptor' model holds that the dendritic cells detect the exogenous, infectious agents through Toll-like receptors [10][11][12], while 'danger' model [13], predicts that the immune system additionally reacts on any process that causes cell disruption, damage or necrotic death, providing an endogenous alarm signal, which subsequently upregulate the costimulatory molecules on antigen-presenting cells (APCs). Similarly, the most recent 'integrity' model, enlarging the previous hypotheses, introduces the 'strength' control of innate immunity, proposing the existence of an additional coactivation signal for the activation of APCs, which depends on the degree of disruption of the surrounding tissue [14]. ...
... In syngeneic pregnancy, therefore, it could be speculated that they are related with greater quantity of self-antigens released from maternal-fetal interface during the process of placentation [6,20,21], or with the presence of fetal nucleated cells, transferred into maternal circulation [46,47]. The hypothesis is consistent with the 'danger' and 'integrity' models, which hold that immune response might be triggered by endogenous alarm signals, coming from the stressed or injured tissue [13,14] as well as with recent knowledge about the function of heat-shock protein (HSP)-chaperoned peptides derived from damaged tissue [48]. HSP-peptide complexes bind to CD91 and other receptors on dendritic cells, mediate endocytosis and dendritic cell maturation, and chaperon internalized peptides into MHC class I and class II of the APCs, resulting in consequent stimulation of CD8 þ and CD4 þ T cells. ...
... Interestingly, we also noticed that these activities might be additionally enhanced with peptidoglycan monomer, derived from gram(þ) bacteria (unpublished data), which in nonpregnant mice significantly increased the proportion of NKT cells in the liver [50]. The intensity of extrathymic T-cell production in the liver depends, however, not only on the induction of additional costimulatory molecules by microbial constituents on dendritic cells [10][11][12][13][14]49] but also on the sympathetic nerve activation [51], concentration of estrogens [52] and other neuroendocrine influences [40][41][42], pointing to the possibilities that different mechanisms might contribute to the dysregulation of NKT cells generated in the maternal liver, resulting in abortion. Moreover, the activation of hepatic NKT cells and simultaneous autoantibody production seems to depend also on the quantity of damaged hepatocytes, induced by the exposure of the liver to denaturated syngeneic tissue [53]. ...
Conditions such as stress, infection, autoimmune disease, etc. elevate the number and function of extrathymic T cells that are generated mainly in the liver. As primitive, self-reactive clones of T cells that coexpress receptors of the natural killer (NK) lineage, they mediate cytotoxicity against altered self, malignant and infected cells and have the unique potential to rapidly secrete large amount of T helper 1 (Th1) or Th2 cytokines.
To elucidate whether some of these changes occur even during the syngeneic pregnancy, we made phenotypic and functional characterization of mononuclear lymphatic cells (MNLCs) isolated from the liver and spleen of pregnant C57BL/6 mice, testing their cytotoxicity against syngeneic thymocytes as well as against NK- and lymphokine-activated killer (LAK)-sensitive targets. The data have shown that on the sixteenth day of syngeneic pregnancy TCRint, NK1.1+ and IL-2Rβ+ cells were accumulated in the liver, while the quantities of CD4+ and CD8+ T cells and total number classical NK (NK1.1+CD3– or IL-2Rβ+CD3–) cells were increased in the spleen. Pregnancy-activated hepatic and splenic MNLCs were more cytotoxic against syngeneic thymocytes, YAC-1 and P815 targets, suggesting that the maternal liver is a main producer of autoreactive NKT clones, which subsequently augment NK- and LAK cell-mediated cytotoxicity in the liver and spleen.
... It has exposed considerable difference of opinion [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17]. Three of the contributors have, at some time, cited my morphostasis papers [6,[17][18][19][20][21] so, perhaps, the time is ripe for me to comment. In developing new explanatory models, we depend heavily upon social language and we resort to metaphor and analogy; immunology is rife with these already. ...
... Matzinger's [7] purpose is to respond to danger with adaptive immune system aggression (damaging stimuli leading to aggression contrasted with efficient apoptosis leading to tolerance). Dembic's [18,19] purpose is the maintenance of tissue integrity (and homeostasis) by the deployment of various cytokines. Zinkernagel and Hengartner [13] are more empirical and circumspect. ...
This article continues the ongoing debate around models of the immune system. Earlier contributors have paid much attention to the various processes that lead to adaptive immune system aggression or tolerance. They have often based their discussions around facts that have been established by experimental investigation. However, both the observation and interpretation of these facts have been influenced by the function--or system goal--that is believed to have generated them. The perception of this function (of all or part of the immune system) is influenced by long established theories in immunology (e.g. horror autotoxicus, clonal deletion in utero, pathogen elimination, clonal selection, auto-immunity and so on) which, for many, have become enshrined as facts. One function that has had less consideration and has not been extensively investigated is the maintenance of tissue homeostasis. When the immune system is viewed from this perspective, the facts invite alternative interpretations. Whilst this perspective may not necessarily be the only valid one, let alone a correct one, viewing things this way--at least briefly--might help to expose hidden assumptions. It also emphasizes that the immune system is a system and, as such, it can by analysed through the principles of general systems theory.
... In 1997, a very interesting, long and vivid debate took place among immunologists, some more classical and others proposing alternative views such as the "danger" model (Matzinger [14]), the "integrity" one (Dembic [10]), together with models around the idiotypic networks (Varela, Coutinho, Stewart [21] [24]) (this debate is available on the Web at http://www.cig.salk.edu/BICD_140_W99/debate/). Among other issues, one very warmly discussed was the classical self-nonself distinction and the importance given by immunologists to "detection and recognition" processes. ...
The response to the title would simply be that the state of the organism has changed between the first and the seventh glass
and that, before the seventh, this state was much closer to some kind of “homeostatic limit”. Although the external impact
i.e. the glass of wine is identical in both cases, the reaction of the receptive organism might be different, depending on
its current state: accept the first glass then reject the seventh. It is the couple “wine and current state of the organism”
which is important here and not just the wine. Introducing this paper, I will attempt to clarify the famous self-nonself controversy
by referring attentively to the debate which took place in 1997 between more traditional immunologists (Langman) and less
ones (Dembic, Coutinho), and by proposing a very simple and illustrative computer simulation allowing a beginning of “formalization”
of the self-assertion perspective. I will conclude by discussing the practical impact that such a perspective should have
on the conception of “intrusion detectors” for vulnerable systems such as computers, and why a growing number of immunologists,
like Varela twenty years ago, plead for going beyond this too narrow vision of immune system as “intrusions detector” to rather
privilege its “homeostatic character”.
... There is a model in which the immune system has three decisions to make and is helped by a three-signal cellular activation mechanism that operates for communication purposes among the cells [1][2][3][4]. The concept involves the immune system as a guardian of tissue integrity. ...
The immune system is seen as a guardian of tissue integrity. It would analyse the extent and quality of damage and respond adequately. If no ill effects were found, the system would ignore disturbance, but if beneficial effects were found, it could protect certain microorganisms (establishing commensalism), perhaps via regulatory cells. The Integrity hypothesis proposes three basic groups of intercellular signals for cells of all tissues and assumes that they govern communication between dendritic cells, T cells and B cells. Signal-1 would be the main information source resulting with generation of intracellular mediators that are bound to travel into the nucleus to achieve reaction. Signal-2 represents the generation of additional signal transducers representing a modifier at the level of cytosol. And, signal-3 would be a modifier at nuclear level, perhaps guarding accessibility to chromosome or genetic locus.
The Toll family of receptors comprises numerous related proteins implicated in the development and defense of plants and animals.
Toll was first discovered in Drosophila melanogaster as a gene that controlled the dorsal-ventral axis of the developing embryo. Elements of its molecular structure; the extracellular
leucine-rich repeat domain (LRR), short cysteine rich patches, a transmembrane portion, and an intracellular domain homologous
to that of the human interleukin-1 receptor (IL-IR) are discussed in detail in other chapters. Here we are principally concerned
with the role of the Toll like receptors (TLRs) and their signaling pathways in the immune system.
In Credo 2004, Zinkernagel and Hengartner (Z&H) have continued their challenge to the immunological community to reconsider assumptions regarding the most fundamental aspects of adaptive immunity. They have appropriately championed the role of persistent, widely distributed antigen in tolerance induction, parameters that do not figure prominently in most other models. The global theory of immunity they have developed is predominantly based on observations from studies with viruses and tumours. I suggest here that a more successful approach to generating a theory of the default rules of immunity can be obtained through the study of immunity versus tolerance in the setting of transplantation. Transplantation studies lack the confounding variable of competing evolution present in responses to specific infectious agents and tumours and, therefore, more clearly elucidate default rules of immunity. The geographical model in Credo 2004, primarily a one-signal model regulated by antigen, is contrasted with (1) Cohn's time-based two-signal model and (2) a development-context model that postulates distinct central and peripheral tolerance mechanisms.
Specific immune responses are controlled by two counterbalancing mechanisms-co-stimulation and co-inhibition. Antigen receptors determine specificity, activate co-stimulation and/or co-inhibition, and interact with these co-stimulatory/co-inhibitory mechanisms to dictate the direction of the immune response, either positive or negative. Co-stimulatory or co-inhibitory ligands interact with their specific receptors and may indicate the context in which antigen is perceived by lymphocytes. Ligation of antigen receptors may activate only co-stimulatory or co-inhibitory mechanisms, and thus may influence secondarily the direction of the immune response. Furthermore, the activity of a given co-stimulator or co-inhibitory receptor is modified depending on signalling via the antigen receptor. If neither co-stimulators nor co-inhibitors are present, lymphocytes, activated in response to antigen receptor signalling, produce low levels of effector elements and then revert to inactivity. Co-inhibitors are defective in autoimmune disease.
The hypothesis of immunologic surveillance of neoplasia is predicated on the theory that the immune system is capable of discriminating self from foreign antigens, and that tumor-specific antigens are regarded by the immune system as nonself. We propose here an alternate view, that the immune system has evolved to detect danger by employing 'professional' antigen-presenting cells as sentinels of tissue distress. In this model, cancers do not appear dangerous to the immune system, so that the default response of T cells to tumors is to be turned off. We discuss the implications for immunotherapy of malignancy.
The authors propose to evaluate the competing theories of induction and paralysis. Their analysis has been evoked by Coutinho & Moller's perceptive discussion of this question. The first step in the Coutinho Moller analysis consisted of reducing all formulations of the self nonself discrimination to two competing theories that they term the one and two signal models of induction and paralysis. Their second step was to provide a precisely stated one signal model. Thus they gave us a framework within which to discuss the self nonself discrimination problem in a way that should not permit misinterpretation of the argument. The progression of the argument will be opposite that of Coutinho & Moller. Their one signal model is derived essentially from an attempt to understand polyclonal induction (Section VIII), which of course is explained with admirable simplicity. However, they ignore what is known about the way in which the decision between induction and paralysis is made by the normal immune system. It is this key distinction that the one signal model cannot account for and which led to the postulation of the two signal model. The authors, therefore, open by developing the reasoning that leads to one and two signal models before showing why all one signal models are untenable. The authors close by arguing that the available data on polyclonal induction can be explained in many ways compatible with a two signal model and for this reason present no challenge to it.
Allogeneic reactions have conventionally been considered as typical immune responses by one population of cells to antigens present on the other. This view is inadequate, since it does not explain many features of these reactions, among which are: (1) reactivity is much higher between different strains within a species than between species, in spite of the much greater antigenic disparity in the second case; (2) a very high proportion of cells may respond to allogeneic stimuli; (3) major histocompatibility differences are not essential for vigorous allogeneic reactions; (4) the responding population need not be immunologically competent to respond to antigens of the stimulating population; (5) the stimulating population must be both metabolically active and immunocompetent.
According to a classical, antigen-driven view of the immune system, autoimmunity is due to the presence of self-reactive lymphocyte clones which have not been eliminated. However, computer simulations of the immune network show that the greater the degree of connectivity of a clone, the greater its degree of tolerance to chronic antigenic stimulation. This tolerance does not correspond to an absence of response on the part of the system as a whole. On the contrary, stimulation by a 'tolerogenic antigen' results in widespread modification and overall activation of the whole network. This suggests that on an autopoietic network view of the immune system, autoimmunity arises not because of the presence of self-reactive clones, which is completely normal, but because such clones are inadequately connected to the network. This amounts to a complete reversal in perspective, whose significance for the clinical treatment of autoimmunity and the future of immunology is discussed.
1) Induction of humoral antibody formation involves the obligatory recognition of two determinants on an antigen, one by the receptor antibody of the antigen-sensitive cell and the other by carrier antibody (associative interaction).
2) Paralysis of antibody formation involves the obligatory recognition of only one determinant by the receptor antibody of the antigen-sensitive cell; that is, a nonimmunogenic molecule (a hapten) can paralyze antigen-sensitive cells.
3) There is competition between paralysis and induction at the level of the antigen-sensitive cell.
4) The mechanisms of low- and high-zone paralysis, and maintenance of the unresponsive state, are identical.
5) High-zone paralysis occurs when both the carrier antibody and the receptor antibody are saturated, so that associated interactions cannot take place.
6) The mechanisms of paralysis and induction for the carrier-antigen-sensitive cell are identical to those for the humoral-antigen-sensitive cell.
7) The formation of carrier-antigen-sensitive cells is thymus-dependent, whereas humoral-antigen-sensitive cells are derived from bone marrow. Since carrier antibody is required for induction, all antigens are thymus-dependent.
8) The interaction of antigen with the receptor antibody on an antigen-sensitive cell results in a conformational change in an invariant region of the receptor and consequently paralyzes the cell. As the receptor is probably identical to the induced antibody, all antibody molecules are expected to be able to undergo a conformational change on binding a hapten. The obligatory associated recognition by way of carrier antibody (inductive signal) involves a conformational change in the carrier antibody, leading to a second signal to the antigen-sensitive cell.
9) The foregoing requirements provide an explanation for self-nonself discrimination. Tolerance to self-antigens involves a specific deletion in the activity of both the humoral- and the carrier-antigen-sensitive cells.
Scientists have traditionally been resistant to fundamental changes in perspective. New ideas are rejected if they challenge essential, accepted paradigms. Here I present a concept that, I believe, represents a paradigm shift in the way self/non-self discrimination is perceived. Traditional opinion has it that lymphocytes carry out this discrimination. I propose an alternative view. Self/non-self discrimination is driven by mechanisms closely related to those that lead to cell sorting in disaggregated embryos. Lymphocytes are only used to classify cells according to their mode of death (apoptosis or necrosis). The hypothesis outlines the process of morphostasis (tissue homeostasis). It fills in much detail about the gradual evolution of the mammalian immune system. Earlier versions of this hypothesis have been reflexly rejected by numerous journals. Until recently, I too was unsure of the validity of the core concept. Recent publications have dispelled this doubt from my mind. A paradigm shift is due.
The network theory was proposed 21 years ago, attracting then much interest as applied to the regulation of (clonal) immune responses. The first 10 years of 'idiotypic network' research have thus addressed questions that were already appropriately solved by the clonal selection theory, leading to a justifiable loss of its impact. In contrast, 'second generation networks', concentrate on systemic properties that emerge from a network organization, thus providing a framework for several major questions that seem to supersede clonal solutions: the developmental 'learning' of self antigenic composition and the maintenance of the respective 'memory' (self-tolerance), repertoire selection and the homeostatic regulation of lymphocyte numbers, natural immune activities that are independent of external antigens, the physiology of autoreactivity. The immune network may well contribute solutions to autoimmune diseases, where clonal approaches, classical and modern alike, have failed.
Complexity in the activation/regulatory apparatus and the variable nature of the antigen-binding site dictate that B and T cells establish and select, during their development, appropriate activation and control mechanisms beyond simple antigen-binding specificity. These mechanisms are established partly by fixed interactions dictated by genetically defined structures, but they are also attained by calibration during ontogeny. This calibration depends on the ordered expression of early components (each of which is invariant), on their interaction with specific ligands, and on the receipt of invariant signals for calibration. Lymphocytes calibrate themselves by expressing various cell surface components, such as restricted heavy chain D-regions and pseudo-light chains. These are expressed in association with elements that will make up the antigen-receptor complex of mature lymphocytes. Calibration by invariant signals results in the establishment, selection and active maintenance of cellular activities which serve to control lymphocyte function. Since these cellular activities are one of a number of possible conditions, they are referred to as variant controls. Effectively calibrated basic cellular functions, specialized responses and cellular interactions allow lymphocytes to attain self-nonself discrimination. If calibration fails, lymphocytes will develop abnormalities, such as immunodeficiency and autoimmunity.
From experimental observations on induction of transplantation tolerance, we discuss a model that accounts for tissue-specific tolerance to antigens not expressed inside the thymus. It is postulated that antigens presented to differentiating T cells by thymic epithelium (or at large within the thymic environment) positively select and activate self-reactive T cells. A developmental program and/or prevalent conditions in the thymic environment restrict the proliferative potential and the class of effector functions that can be exerted by differentiating T cells activated in the thymus. These do not mediate inflammatory or cytolytic activities, but instead will produce the appropriate mediators to inhibit aggressive effector activities by other T cells activated in their proximity. Such "regulatory" functions will be locally expressed at the periphery upon recognition of tissue antigens shared with the thymus, towards newly formed thymic emigrants directed at tissue-specific antigens expressed by the same "target" cells. This mechanism imposes "dominant tolerance", based on specific self-recognition and predominantly established in the embryonic and neonatal period. Throughout life, the process of thymic positive selection results in all newly-formed T cells being susceptible to such suppressive mechanisms, but becoming increasingly refractory with time in the resting, post-differentiative stage. Absence of antigen (nonself) in the embryonic and neonatal life therefore allows for the accumulation of such "suppression-resistant" antigen-reactive T cells that will mount aggressive responses upon antigenic exposure. Tolerance or immunity thus represent two classes of specific immune responses, the relative predominance of which is determined by the frequency of each type of effector T cell, representing the antigenic overlap between thymic and peripheral tissues, as well as the frequency of tissue-specific T-cell generation, and the kinetics of peripheral antigenic exposure. Tolerance induced by hemopoietic cells to all other tissues is also "dominant" and based on thymic colonization and persistence of antigenic cells, with the consequent positive selection of regulatory T cells and peripheral conditions for the establishment of suppression. Upon this simple model, that ensures "interclonal class regulation" by "bridging" regulatory and effector T cells through the recognition of different antigens on the same target cell, other mechanisms which are based on V-region interactions among T cells (Ben-Nun et al. 1981, Pereira et al. 1989, Webb & Sprent 1990, Gaur et al. 1993) might well operate to ensure "dominant tolerance" by self-reactivity and class regulation.(ABSTRACT TRUNCATED AT 400 WORDS)
The survival of viruses depends on the survival of susceptible hosts. The vertebrate immune system and viruses have therefore coevolved complementary facets. Evidence from various balanced virus-host relationships illustrates that immunological specificity and memory may best be defined biologically and that the mature immune system does not discriminate between "self" and "nonself." Rather, B cells distinguish antigen patterns, whereas T cell responses depend on localization, transport, and kinetics of antigen within lymphatic organs.
Self-tolerance is acquired in the embryonic/perinatal period, but new lymphocytes (that will have to distinguish between self and nonself) continue to be produced throughout life, after both self and nonself are present. This makes it impossible for natural tolerance to rely on recessive mechanisms. Recent observations on “dominant tolerance” have led to the hypothesis that natural tolerance is established as a consequence of simple developmental programs for gene expression and cellular composition of primary lymphoid organs.
The destructive effector functions of the immune system pose a problem that has aptly been described as 'horror autotoxicus'. This problem demands a solution that offers an effective self-nonself discrimination mechanism. Unlike all other defence mechanisms, the immune system makes the self-nonself discrimination somatically, and not at the germline level. This discrimination requires a way of separating self from nonself. Two proposals to accomplish this are based on separation in time or in space. In this paper the authors show that separation in time remains the only viable solution. A generally accepted solution to the mechanism of the self-nonself discrimination is overdue as it strongly influences the way in which much of immune regulation is interpreted.
In an earlier article, I proposed a pathway by which morphostasis (tissue homeostasis) may have evolved. It began in single-celled organisms and culminated in the mammalian immune system. This evolutionary path is now traced from its source--the intracellular surveillance within an isolated cell of its own internal health. Morphostasis sequentially incorporates heat shock proteins, apoptosis, cell adhesion molecules, complement components, gap junctions, phagocytes, natural killer cells, cytotoxic T-cells, helper cells and antibodies. I propose that the sequence leading to the insertion of gap junctions is an ancestor of the complement attack sequence. Although contentious, this deduction is intriguing, since numerous, minimal clues support the proposition. The broad hypothesis emphasizes a theme that may prove to be a useful framework on which to hang a better understanding of immunology and embryology. It highlights points where a concentrated research effort may rapidly advance our understanding of both.
The paradigm of an immune system presumes that a system arose specifically to combat infection -- hence its name. This paradigm gained credibility with the discovery of antibodies and anamnestic immunity, even though these are relatively late arrivals in evolution. Another presumption has been that thymus-dependent T cells are responsible for discriminating self from non-self. Subsequent opinion has crystallized around these presumptions. This paradigm is flawed. Transforming it into a morphostatic system resolves the problems. There is, arguably, no such thing as an immune system.
The Toll genes code for activation receptors for innate microbial defence in insects and have recently been found to code for the Lps receptor in murine B lymphocytes. In this study, I will present evidence to show that this family of receptors are responsible for induction of specific thymus-independent immune responses in mice. T cells do not possess these pattern-recognizing receptors, but they possess structures capable of delivering activation signals to these receptors on B cells.
The innate immune system is an evolutionarily ancient form of host defense found in most multicellular organisms. Inducible responses of the innate immune system are triggered upon pathogen recognition by a set of pattern recognition receptors. These receptors recognize conserved molecular patterns shared by large groups of microorganisms. Recognition of these patterns allows the innate immune system not only to detect the presence of an infectious microbe, but also to determine the type of the infecting pathogen. Pattern recognition receptors activate conserved host defense signaling pathways that control the expression of a variety of immune response genes.
An immune system is required in any host that evolves slowly relative to the pathogens that attack it. This immune system must somatically generate and regulate new specificities. We propose a mechanism that results in a self-nonself discrimination that is a one-time regulatory event, which occurs early in development when maternal protection ensures an environment that is free of nonself. Our proposed mechanism considers all T and B cells to arise in an i-state which is incapable of effector reactions. Uniquely in iTh (helpers) a prolonged absence of antigen permits their differentiation to eTh (only nonself antigens are absent). In all i-state cells antigen induces an anticipatory a-state which, in the presence of eTh and via associative recognition of antigen results in the e-state, and which in the absence of eTh results in cell death.
The activation of dendritic cells, necessary for the initiation of primary and secondary immune responses, can be induced by endogenous danger signals - released by tissues undergoing stress, damage or abnormal death - and also by exogenous danger signals elaborated by pathogens. Some endogenous danger signals that recently have been discovered are heat-shock proteins, nucleotides, reactive oxygen intermediates, extracellular-matrix breakdown products, neuromediators and cytokines like the IFNs. We propose that allergy may be initiated by the direct damage of dendritic or other cells by toxic chemicals and allergenic proteases, and suggest that the triggering of danger signal receptors by exogenous pathogen-derived molecules may be more to the advantage of the pathogen than to the host.
The immune system neither discriminates between "Self" and "Nonself", nor it acts when confronting "Danger", rather, it reacts to disruption of tissue integrity allowing its renewal. The "integrity" hypothesis proposes three groups of signals that coordinate actions of dendritic cells and immunocytes during the initiation of the specific immune response, and suggests explanations for tolerance, memory formation, and repertoire selection, including differences with other theories.