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• W1553576586 abstract "We were impelled to put together this volume on ‘Quantitative Modeling of Immune Responses’ to confront the fact that such studies have had little or no impact on the experimental development of the field. Yet, we remain convinced of the growing importance of such studies. We hope that the presentation of a collection of theoretical investigations in a variety of immunological areas would give the experimentalist a chance to appraise their value. In a previous volume of Immunological Reviews(1) a different tack was used, namely, to present one comprehensive theory of immune function and ask experimentalists to comment. While this engendered enthusiastic criticism, the most striking result was that no one felt that the effort to generalize was of value to them. Fifteen years have passed since that volume has appeared, so it is time to see whether and/or how thinking has changed. The central role of theoretical studies in genetics and evolutionary biology is well recognized. By contrast, in immunology, we remain crassly empirical. Even the theoretician has become a victim of this view, often equating theory to a tool to store or catalogue the vast amount of complex data being generated. Simulation, the extrapolation of which is called a prediction, is viewed as understanding. As theoreticians, we must face the fact that building a mathematical web around a random collection of observations does not in and of itself increase understanding. Theoreticians in this field believe that today’s experimentalists are not sufficiently adroit in the use of mathematics and computer modeling and, therefore, are not prepared to deal with immunology as it increases in complexity. Experimentalists believe that most theoretical studies are sterile meanderings into Neverland, either because they are too general to be useful or so specific that they become another way of describing what we know already. Clearly, interactive discussion is needed. The theorist conjures up the various ways that the system might work; the experimentalist determines which of those ways is actually used. We should look to the theorist to define clearly and make transparent the competing concepts, extrapolate them to possible mechanism, apply the extrapolations to existent data, suggest where new data are needed, and design experiments distinguishing validly competing concepts, theories, and models. But above all, the theorist should be a discerning critic bluntly evaluating the pool of experiments and putting them into a larger cohesive framework. The role of the theorist is to characterize and widen our understanding, not to review it. The conceptual foundation should precede any attempts at modeling. As for all biological systems, interactive natural selection (2) is the framework within which we eventually must operate. So let us illustrate this framework by stating the elements of one such conceptual foundation. It is based on the 10 postulates described here. The immune system is a protective mechanism with a biodestructive and ridding output. Therefore, it must have a way to rid the invader (‘pathogen’) without debilitating the host, and it must have a way to optimize the choice of the ridding effector mechanism without destroying innocent bystanders. The recognitive repertoire can be divided into two parts: germ line selected and somatically derived. The germ line-selected (‘innate’) repertoire distinguishes the components of the host species from the pathogen, whereas the somatically derived (‘adaptive’) repertoire distinguishes the components of the individual from the pathogen. The components of the individual that are not to be ridded are classically referred to as ‘Self’, while the to-be-ridded components (e.g. pathogens) are classically referred to as ‘Nonself’. The two terms are convenient because of their wide usage, but because of their nasty ambiguities, the reader should exercise taste when interpreting them in the present context. The innate repertoire was germ line selected to recognize slowly varying components common to as many different pathogens as possible. However, this repertoire became inadequate, because the prokaryotic pathogenic universe evolves to escape recognition more rapidly than the eukaryotic genome can track. The result is an innate repertoire that is blind to a significant portion of the to-be-ridded antigenic universe. To deal with this problem, evolution selected for a crafty solution, namely, to somatically generate a random recognitive repertoire that divides the antigenic universe into combinatorials of ligands or determinants (epitopes). An antigen is a combinatorial of epitopes. As a consequence, it became difficult for a pathogen to escape recognition but it created two new problems. First, the somatically generated (adaptive) repertoire had to be sorted into those specificities (anti-Self) which, if expressed, would debilitate the host by autoimmunity and those specificities (anti-Nonself), which if, not expressed, would result in the death of the host by infection. We refer to this sorting of the adaptive repertoire as decision 1. Decision 1 can properly be referred to as the Self–Nonself discrimination. Second, the sorted repertoire (anti-Nonself) had to be coupled to the appropriate effector function that destroys and rids the pathogen. We refer to this as the regulation of class or decision 2. Because the adaptive repertoire deals with a portion of the antigenic universe that the innate repertoire cannot see, these two decision processes must be mediated by a somatic mechanism that is dependent on the adaptive repertoire (3, 4). The necessity to make a Self–Nonself discrimination is the sole selection pressure for the specificity of the adaptive repertoire and, therefore, specificity should be defined by that necessity (5–7). The degree of specificity (referred to as the specificity index) of the recognitive site (paratope) is the probability that a change in its sequence that results in a new functional specificity will be anti-Self. This definition has many consequences, one of which is germane here. Specificity is to be distinguished from degeneracy (8). A single paratope that effectively recognizes a family of epitopes distinguishable by the immunologist treats that family as a single epitope. If one member of the family is Self, then it is a family of Self epitopes. A single epitope that is effectively recognized by a family of paratopes distinguishable by the immunologist treats that family as a single paratope. If one member of the family is anti-Self, it is a family of anti-Self paratopes. Specificity is characterized by the ability to distinguish between families, not between members of a family. Degeneracy is characterized by the inability of a paratope to distinguish between members of an epitopic family. The size of the repertoire is determined by specificity (i.e. the number of distinguishable families) not by degeneracy (i.e. the number of sequence-different or -distinguishable paratopes in a family). The specificity index of a paratope is roughly the probability that a family will be anti-Self. The functional signaling and effector outputs have sharp triggering thresholds of occupancy of their recognitive elements. The sorting of the somatically generated (adaptive) repertoire (decision 1) separates families of paratopes. The anti-Self families are subtracted, leaving the residue to function as anti-Nonself. The mechanism of the sorting depends on the prior sorting of the antigenic universe into Self and Nonself. The sorting of the antigenic universe is a somatic process dependent on developmental time. Only when the antigenic universe has been separated into Self and Nonself can the adaptive repertoire be sorted. As this repertoire is expressed as receptors on cells, it is the cells that must be sorted. The sorting of the cells expressing the somatic repertoire requires that they have three properties. They must be without effector function, express only one paratope, and have two pathways open to them, inactivation and activation. These cells are referred to as initial state cells or i-cells. The sorting of the repertoire is accomplished by inactivating cells interacting with Self. As paratopes recognize epitopes not antigens, inactivation occurs epitope-by-epitope and activation occurs antigen-by-antigen. Antigen-by-antigen activation requires associative (linked or coincidental) recognition of antigen (ARA) by a regulatory effector cell [known to be an effector T helper (eTh)] and an i-cell. The regulatory eTh cell tells every i-cell interacting with that antigen that its response should be ‘activation’. As the absence or presence of the eTh cell determines whether the i-cell is inactivated or activated, the signal by its expressed paratope (Signal[1]) must be inactivating and the signal delivered in ARA from the eTh (Signal[1]+[2]) must be activating. Activation is the first step of decision 2 on the pathway to effector. The choice between these two pathways, inactivation or activation, requires two signals. Decision 1 cannot be made by effector T suppressors (9, 10), because they would have to function in ARA. The consequence would be that the individual would be unresponsive to the Self of the species, which is contrary to fact. The adaptive immune system is characterized by the rejection of transplants between individuals. The central decision role of the eTh cell raises questions as to its origin, how it is sorted, how it communicates its signal, the role of the APC, etc. (11–13) These are largely questions of mechanism, but the proposals of mechanism are severely limited by the conceptual framework, in particular, the requirement for ARA. The regulation of class (decision 2) has a number of generalizations (14). There must be a relationship between what is to be ridded and what is to be induced. The unit to be eliminated (referred to as an Eliminon, e.g. a toxin, a virus, a bacterium, a protozoan, a piece of necrosing cell, etc.) must be taken up by antigen-presenting cells or B cells in such a way that i-cells and the regulatory T helper interacting with it communicate in ARA. The role of ARA in decision 2 is to assure that the response is coherent and independent for each Eliminon. There are for each Eliminon effective and ineffective classes. As the ineffective classes interfere with the functioning of the effective classes, they must be separated by induction or in space. Although no experimental hint has emerged, the regulation of class must involve a somatic learning process, as the innate system is blind to many pathogens. A good theory would be welcome. Such a theory should have proposals as to how the system determines the relationship between the efficiency of ridding and the choice of effector class, how only effective isotypes are expressed at the site where the effector mechanism is armed, how the response to each Eliminon is kept coherent and independent, and how the magnitude of the response is regulated. The size of the repertoire is dependent on functional considerations. The functional immune system can be reduced to a minimum unit that has all of the protective properties of the whole (5, 15). This is why a mouse and an elephant are equally protected against the pathogenic universe. This unit (referred to as a Protecton) has been estimated to be of the order of 107 cells at a concentration of 107 cells/ml. The key is that the repertoire cannot be larger than the number of i-cells per Protecton. However, even 107 is an overestimate of the size of the functional repertoire, as it must provide a sufficiently effective response in a short enough time. This places the size of the functional repertoire at roughly 5 × 104 specificities (5, 15). The repertoires of the three categories of cell, T helpers, T killers, and B cells, must each be of the same magnitude, as there would be no selection pressure to overstock one repertoire. Lastly, the sorted primary repertoire must be functional both in size and rate of response. Any individual unable to survive an initial encounter with a pathogen is unlikely to be a target of selection for a secondary encounter. This conceptual framework is one among several. Each one must be dissected until we arrive at a default framework. Among the competing frameworks are those based on Nonself markers, like pathogenicity (16) or danger (17), or on a role of the immune system in regulating the normal physiology of the individual like integrity (18), morphostasis (19), or healing (regulation of inflammation) (20). These are discriminatory regulatory models based on germ line-encoded not somatically learned mechanisms. As competing frameworks are essential to a clarifying discussion, we should either integrate them into the overall pathway of immune responsiveness or we should find reason to reject them. The various contributors to this volume have given us a very encompassing view of the present status of theoretical work. We will leave it to the reader to assess the value of these studies." @default.
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