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Self, intentionality, and immunological explanation
seminars in IMMUNOLOGY, Vol. 12, 2000: pp. 249–256 doi: 10.1006/smim.2000.0238, available online at http://www.idealibrary.com on
Self, intentionality, and immunological explanation Moira Howes
ological and anthropomorphic sounding language may be neither possible nor desirable. There is more than one way to be teleological, and the kind that is pernicious in biology, the kind that involves conscious or intentional design, is only one of these ways. Second, examining a non-pernicious form of teleological explanation can help us to figure out how and why the self-concept is used in immunology and may help to clarify conflicts concerning its place in immunological reasoning. The debate in philosophy of biology concerning the place of teleology in biology has not been decided. So rather than offer a definitive verdict, my objective is to show what conceptual role teleology may serve and how it relates to the question of the immunological self. In this paper, I first argue that the use of intentional terms in immunology is not anthropomorphic. This opens the way for a different understanding of intentionality, one that is tied to a non-pernicious form of teleological explanation. Second, I argue this non-pernicious teleology is needed if immune function is to be understood. This in turn suggests, I claim, that the self-concept is a non-expendable component of immunological explanation, generally speaking. Finally, assuming for the sake of argument that immunologists wish to retain the self-concept, I will set forth what I think is the best way to conceptualize this self.
In this paper I propose that there are a number of conceptual reasons to preserve self-concepts in immunology. First, I contend that immunological language, including self-terminology, is neither genuinely anthropomorphic, nor perniciously teleological. Furthermore, although teleology associated with future-directed purposive intent is clearly inappropriate in biological contexts, a special type of teleology, intentionality-as-aboutness, needs to be present if there is to be functional explanation in immunology. Second, based on an analogy with the human self, a self comprised of both non-specific innate functions and somatic self-representation, I claim that self-terminology is very appropriate in immunological contexts. Finally, given the appropriateness of self-concepts in immunology, I suggest that the most satisfactory conceptual structure for self-nonself discrimination probably includes both innate and somatic mechanisms. Key words: explanation / function / immunology / intentionality / teleology c 2000 Academic Press
Introduction Silverstein and Rose claim that some of the terminology used in immunology concerning self-nonself discrimination, immunity, and immunopathology is either impermissibly teleological or involves unwarranted anthropomorphism.1 Both of these claims need to be looked at more closely for two reasons. First, the issue of teleology and anthropomorphism in immunology is more complex than represented by Silverstein and Rose, and the elimination of tele-
Intentional terms and anthropomorphism Intentional terms used to talk about immune function, like those of ‘recognize’ and ‘discriminate’ are terms that seem to ascribe some kind of intermediary subjective state to the immune system, a state which exists prior to the immune system’s action. Clearly, to ascribe subjective states to the immune system is anthropomorphic: it suggests that the immune system is somehow conscious of what it is doing. It is equally clear that this is a view no one should hold and the truth of this is not likely to be disputed by anyone.
From the Department of Philosophy, University at Buffalo, The State University of New York, Buffalo, NY 14260, USA. c
2000 Academic Press 1044–5323 / 00 / 030249+ 08 / $35.00 / 0
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glance, there seem to be two reasons for this. First, Rosenberg says that it is so obvious that these terms are not meant literally, scientists do not bother to draw attention to their non-literal nature. Second, scientists generally feel confident that a purely biochemical mechanism can be substituted for the term, if not now, then in the future. The reason the term is used is to avoid literal, complicated and unmanageable mechanistic explanations. As Rosenberg points out, biologists are well aware that by ‘selfish gene’ Richard Dawkins is not saying that genes literally have a subjective state of selfishness. Rather, ‘selfishness’ is implicitly redefined to refer to a behavioral state and behavioral states need not involve a subjective state, or as Dawkins says, a ‘psychology of motives’, at all (Reference 5, pp. 4–5). Mohan Matthen and Edwin Levy put the point the following way:
The question, then, might be whether or not the use of intentional terminology entails the ascription, unwittingly perhaps, of conscious states, beliefs, and desires to the immune system. In other words, are immunologists just being imprudent, from the standpoint of biology, is using these terms and risking these connotations? Some argue that intentional terminology may be useful when the biochemical interactions involved are not fully understood or known. Thus, immunologists are not really ascribing conscious states when they use the terms, but rather using them as shorthand ways of saying ‘we do not quite know what is going on here yet’. Once a biochemical mechanism is fully known, a non-intentional account can be supplied. This view is supported by philosophers such as Melander who says that, ‘immunology has already taken the first steps towards a purely chemical and non-intentional characterization of the immune system’s capacity to distinguish self from nonself’ (Reference 2, p. 239). Presumably, then, the intentional terms used are just metaphors. They may have heuristic value insofar as they ‘stimulate’ scientific reasoning, or confuse matters insofar as they do not (Reference 3, pp. 199–200). If these terms or metaphors have only heuristic value, and are not otherwise involved in immunological explanations, we can omit them as soon as purely chemical formulations come along. As a philosopher, however, I am quite interested in the question of why all of the metaphors used in immunology are intentional terms. Possibly, immunologists could find other metaphors to use, ones that are non-intentional. I have a hard time imagining what these metaphors would be: even lock-and-key interactions seem to imply some kind of intention. Nonetheless, there may be some. The line I wish to investigate here concerns whether there might be a third way of understanding the use of intentional terms in immunology, one that neither views intentional terms as attributing consciousness to the immune system, nor holds that they are expendable. Rosenberg argues that in dismissing intentional terminology as mere metaphor, aspects of scientific theory that are natural to science are ignored. Intentional terminology comes very naturally to scientists and appears to be ‘inevitable and unavoidable’ (Reference 4, p. 66). This, he claims, stands in need of explanation. As Rosenberg points out, intentional terminology is generally used by biologists without any ‘precaution of definition, nor with any caveat against taking it literally’ (Reference 4, p. 69). At first
the view that attributing intentional structures to non-sentient entities is anthropomorphic rests, we think, on the misconception that such structures are somehow connected to consciousness— that postulating intentionality in nonsentient entities rests on a metaphorical assimilation of these entities to sentient entities (Reference 6, p. 371). What is eliminated in the implicit redefinition of intentional terms in science, then, is mentalistic, or conscious, intentionality. In the immune system there are no conscious beliefs, desires, goals or motives and when immunologists use these terms they implicitly empty them of intentionality. So far this description of what occurs when biologists use intentional terms fits quite well with the view that these terms are expendable metaphors. Rosenberg, however, makes a further claim, one that suggests to me that intentional terms are neither expendable nor do they require an imprudent belief in a psychology of motives. Rosenberg says of intentional terms that suitably redefined, it is no surprise that these terms function naturally and inevitably in the description of molecular interactions. They have been implicitly tailored to this purpose. Intentional vocabulary, when pressed into biochemical service retains its teleological, functional implications for behavior, and this together with the intricacy, the plasticity, and the variability of the biochemical interactions 250
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causal processes.7 Teleology is introduced into the equation because of the need to explain biological processes in terms of what they are for. However, this teleology is not the kind one finds when sentient purposive agents set about achieving their goals. This point can be illustrated by looking at the claim that evolutionary history is what makes biological systems teleological. Consider Ruth Millikan’s wellknown notion of a proper function, a notion which is intended to naturalize teleology and reduce it to evolutionary explanation. Adapting an example put forth by Mohan Matthen, a proper function can be described in the following manner. The immune system has defense against pathogenic bacteria as a proper function because:
is what makes for its appropriateness in this context (Reference 4, p. 73). What does it mean to say that stripped of mentalistic intentionality, intentional terms retain their teleological, functional implications for behavior? It can mean only this: there is a way of thinking teleologically in biology that involves neither subjective, conscious, psychological goals or desires to achieve some given end, nor the notion of conscious intentional design. The task, then, is to determine what is happening when we posit intentional structures in non-sentient entities. How is intentionality in non-sentient entities different from that in sentient ones? To answer this question I will now turn to a brief examination of the notion of teleology. Teleology, properly construed in a biological context, need not violate precepts of evolutionary theory concerning the absence of conscious design. I argue that it is this kind of teleology that explains why intentional terms are doing more than acting as shorthand descriptions of biochemical mechanisms, but less than teleological accounts which violate evolutionary precepts. It explains why ridding immunology of ‘self’ and ‘danger’ terminology, for example, in order to avoid an impermissible teleology is an oversimplification that obscures matters. Finally, the need for teleological frameworks for functional explanation provides a strong reason for retaining intentional terminology, although not, of course, uncritically.
1. This defense is a reproduction of some prior process that defended against pathogens. 2. We now have an immune system because that prior process defended against pathogens.8 An example first introduced by A. G. Cairns-Smith is used by Mark Bedau, to illustrate that the above analysis of function is not sufficient to explain how we normally think of function.9 That is, as Matthen contends, proper functions do not properly align with vernacular functions. Suppose there is a type of crystal, one variant of which will crystallize more rapidly and to a greater extent if it is exposed to water. If the water-sensitive and non-sensitive variants are both present in a river, the water-sensitive variants will come to dominate the population. Suppose also that given enough time, the water-sensitive variants will proliferate to such an extent that a dam will be created. According to Bedau, on Millikan’s account we can say that the water- sensitive variant was selected for dam-making, and therefore dam-making would be a proper function of the crystal. Crystals have dam-making as a proper function because:
Function, teleology and intentionality-as-aboutness The somewhat awkward phrase ‘intentionality-asaboutness’ serves to label a kind of intentionality at work in biological explanations. This intentionality has no mentalistic component: in a sense, intentionality is here implicitly redefined much in the way that ‘selfish gene’ and ‘immune recognition’ are. The reason for keeping the notion of intentionality, even though it has no mentalistic component, rests on the idea that unless a biological mechanism can be understood to be about something, it is not understood. If the biological mechanism you are studying cannot be understood as being about something, what you have is a collection of molecules, reactions and relations and no way of telling what they are doing in any overall sense. Without knowing what a system is about, it is difficult to distinguish between functional processes and other concurrent, but non-functional,
1. This dam-making is a reproduction of some prior process that led to dam-making. 2. We now have this dam-making process because that prior process led to dam-making. It seems reasonable to say that the function of crystals here stated is not a function as we normally think of it; that is, it is a proper function, not a vernacular one. There just seems to be something wrong with the statement ‘crystals are selected for dam making’, if by this we mean that dam-making is a function of these 251
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the individuals we are interested in are not just whatever units that science decides it can most conveniently understand the world in terms of: we already have an antecedent sense of what units we want to focus on. This is the ‘evaluative’ aspect of individuation. In the case of the immune system, whether something does or does not count as ‘self’ is partly an evaluative issue: there are good reasons, for example, to regard a cancerous growth as ‘nonself’ rather than self, even though in some respects its development is an outcome of the organism’s ‘own’ evolution (Reference 10, p. 205).
crystals. Rather, dam-making seems to be something that just happens: it is not a function of the crystals. Matthen says, vernacular functions depend on how something is used, and not on causal aetiology. Function attributions seem to be dependent on user, role, mode of use, and the utility that the ‘user’ realizes from the outcome. Further, function attributions seem to be a matter of degree in such a way that the perspective of the observer is relevant to how an absolute attribution is made. This also indicates that a program of reducing teleology to a scheme of causality present in the objective phenomena is misguided (Reference 8, p. 31).
Silverstein and Rose wish to rid immunology of an impermissible teleology and unwarranted anthropomorphism. I argue that the teleology found in conscious design is not the kind that makes its way into explanations of immune function and further, that the anthropomorphism found in immunology is not really anthropomorphism. Silverstein and Rose themselves use intentional terminology and non-pernicious teleology in trying to explain their view of immune function. They use it when speaking of the law of unintended consequences and when claiming that a balance will be struck between the benefit and cost at each step of the immune process (Reference 1, p. 3, 9). These claims depend on there being a user and a mode of use, and this in turn introduces an evaluative component regarding that user. What captures the interest of a philosopher of biology is how teleological concepts involving ‘users’ and ‘modes of use’ in biological explanation can be understood naturalistically, that is, without incorporating notions of consciously intended design. Millikan’s account might not be satisfactory, but this does not preclude the possibility of there being other accounts, such as Matthen’s, which are.
In reducing teleology to mechanical causality, Matthen argues that what appears to be lost is a level of description or analysis that is epistemologically necessary. We seem to need the notion of teleology, the notion that functions are about something, to understand those functions. Instead of naturalizing teleology, Millikan’s account simply uncouples selection and teleology and teleology drops out of the equation. When teleology drops out of the equation, we are left with a type of functional explanation that cannot fully capture what is going on in living systems. The idea that the function of an immune response is to protect the organism cannot be captured in purely chemical terms. What is different about crystals and living organisms and the functional explanations or analyses that apply to them is two-fold. First, living organisms bring in the notion of a user and with it teleology. Second, an evaluative component is introduced insofar as the perspective of the observer is relevant to the functional attribution made. As Ronald de Sousa says, functional explanations that do not incorporate teleology only work
What does this say about self-nonself discrimination?
insofar as we are not interested in the issue of what counts as an individual. As soon as that issue is broached we cannot altogether escape evaluative issues. Cases where such references to individuals seem inescapable include the case of the immune system as well as the case of mentality (Reference 10, fn. p. 187).
My argument thus far provides some justification for the continued use of teleological frameworks for the analysis of the immune function. It also suggests that intentional terms like ‘discriminates’ are non-mentalistic and that they are important, integral and acceptable components of immunological theorizing. It seems clear that one must consider the
And, furthermore: 252
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organism in order to adequately analyze and describe the immune function. What is still problematic is the use of the term ‘self’. The working definition for self-nonself discrimination outlined in the introduction to this seminar is that biodestructive activity has to be regulated so that the host is not destroyed and the pathogen is. Others in this seminar are clearly concerned with the organism when structuring their explanations of what the immune system is doing. António Coutinho says that because natural selection concerns whole organism behaviour, only observations pertaining to whole individuals, and not just those of isolated cells or molecules, should be considered with respect to self-nonself discrimination. In vitro studies are thought to be lacking because the meaning of effector functions, for example, can only be ‘read-out through the organism itself’ (Reference 11, p. 3). Rolf Zinkernagel points to the importance of asking whether observations and their interpretations make evolutionary sense, ‘since the driving evolutionary force of the immune system is protection of the host against pathology caused by infections’ (Reference 12, p. 4). Zinkernagel also says that self-nonself discrimination is obligatory for antigens in lymphoid systems. Here, the terms ‘self’ and ‘host’ are used interchangeably. Rod Langman and Melvin Cohn also use ‘host’ and ‘self’ interchangeably.13 The question that needs to be answered here is why ‘self’ need be used at all; perhaps the user needed in functional explanations is simply the host. Why not just talk about hostpathogen discrimination? Is not ‘self’ just implicitly redefined to mean ‘host’ anyway? I claim that there are two reasons why using ‘self’ may be preferable. The first reason is the weaker of the two. Consider the function of the liver, which contributes to the well being of the organism through its metabolic activities. The function of the immune system is also to contribute to the well being of the organism, at least insofar as it increases reproductive fitness. However, unlike the liver, its function is specifically concerned with the organism-pathogen relationship. Because the immune system has a special function set up to deal directly with the organism-environment relationship, it is more akin in this respect to the nervous system than any other organ system in the body. Self-terminology may be a way of implicitly acknowledging the specific functions of the immune system that concern the relevant differences between an organism and its environment. However, one could still use the terms ‘host’ and ‘pathogen’ to describe this function specific to the
immune system. It may be that germline mechanisms which serve to protect the host from pathogens can be discussed in the context of organism-environment relations, and self-nonself relations need not be considered. Even so, Ruslan Medzhitov and Charles Janeway say that the ‘innate immune response to pathogen-associated molecular patterns (PAMPs) distinguishes non-infectious self from infectious nonself, and does so with great accuracy’ (Reference 14, p. 6). This first reason, then, suggests (although not in the most convincing manner) that self terminology is appropriate at the innate level. A stronger reason for the retention of self terminology rests on the existence of somatic immunological mechanisms peculiar to certain organisms. The somatic mechanisms contributing to immune-system function introduce a higher level of individuality and this is where the use of self-terminology is most appropriate. If an organism’s immune system has a specific mechanism of self-representation, it seems appropriate to describe this system using self terminology. Organisms that have only an innate immune system, such as invertebrates, may not have such systems of representation; this being the case, the self term would not be appropriate in accounts of invertebrate immunology. Vertebrates, on the other hand, might have varying degrees of representation, and so varying degrees of immunological self. If the vertebrate immune system does engage in self-representation, and it seems that it does, this maps nicely onto the way we divide up the animate world according to conscious self-representation. We do not say that worms have selves. We might say cats have some kind of proto-self, if we like them. We are comfortable with the idea that human beings have selves. Where the human self and the human organism begin and end remains a matter of controversy: what seems clear is that many different functions and systems go into the making of human selfhood, right down to the more reptilian aspects of our brains. What is distinctive about the human self is that a higher system of self-representation is an integral part of our individuality, even though it is not solely responsible for that individuality. It is in virtue of somatic functions that are directed towards self-representation that ‘self’, as opposed to ‘host’ or ‘organism’, is an appropriate term in psychology and neuroscience. The same could be said of the immune system. Whether the immune system actually engages in self-representation is, of course, an empirical matter to be decided by immunologists. The question I address next concerns how the self 253
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to do this here, I claim that a modified self identity can be maintained in virtue of overlapping sets of criteria, none of which are necessary and sufficient in themselves to account for the self. Because the criteria overlap via functional relationships, a modified form of identity over time can be maintained. Such a self must be dynamic, not static. And, at any given moment, the discreteness of the self is not possible, both because an unclear boundary exists between self and other, functional relationships drawing upon both as they do, and because evaluative considerations concerning individuality are inescapable. Gaining acceptance for an indiscrete view of the self is not a simple task. The assumption that any real self must be discrete is a difficult one to dislodge. Nonetheless, an indiscrete view of the self has its merits, some of which are relevant to the situation in immunology. A view of the human self as overlapping and multi-factorial makes the most sense given our actual experience of self in the world. Psychological features closely overlap with physical features. Although innate biological factors may not themselves be sufficient grounds from human selfhood, they certainly inform and shape the self. Also, because of functional inter-relationships, it may be difficult to tease germline contributions from the higher specific functions directly responsible for self-representation and self-definition in human beings. To show how the multi-factorial and overlapping nature of the self is relevant to immunology I will consider examples taken from Irun Cohen, and Langman and Cohn respectively. Cohen says,
is to be conceptualized in immunology, assuming for the sake of argument that immunologists wish to retain self-concepts in their explanations of immune function.
Conceptualizing selfhood One of the assumptions that most derailed accounts of self-identity in analytic philosophy is the assumption that there must be one necessary and sufficient criterion capable of accounting for the identity of the self over time. Such a criterion would actually define the real self, a self that is persistent through time. Coupled with this assumption is another, one that is often concealed from view. This is the assumption that the real self must be discrete; that is, the real self must be definite, clearly bounded, distinctly separate from nonself, and it must be resistant to change. The real self, in this view, is like an anchor: it grounds and maintains the self while physical and psychological properties change. Both psychological and physical criteria have been proposed for such an anchor; however, these different criteria fail to pick out the same entity as the real self, that is, the criteria fail to coincide. This would be unproblematic if either psychological or physical criteria could be shown to be superior. The trouble is that these different criteria are, generally speaking, equally compelling. They are also equally problematic. One might think an obvious solution to the failure of criteria to coincide would be to develop a criterion complexing both psychological and physical features of self. However, this cannot be done while still satisfying yet another requirement for self-identity over time. This is the transitivity requirement of identity and it holds that if X is Y, and Y is Z, then X is Z. The transitivity requirement explains why philosophers have focused on developing criteria that are either exclusively psychological or exclusively physical. A complexed criterion, where X is psychological and Z is physical would violate transitivity. A solution to the problem of the self in philosophy presents itself, as I have argued elsewhere, if we reject the following four assumptions. First, that the real self is discrete and unchanging. Second, that there must be a necessary and sufficient criterion for the real self. Third, that transitivity must be satisfied. Fourth, that psychological and physical criteria must pick out precisely the same entity as the real self.15 Next it has to be shown how there can be a self in spite of the rejection of these assumptions. While there is no room
the healthy immune system recognizes both self-antigens and foreign antigens, without class discrimination. Contrary to the assertion of Langman and Cohn, the job of the immune system is not to produce a verdict distinguishing ‘that which is destroyed’ from ‘that which is not to be destroyed’. The data suggest that the immune system, in both its germline and somatic (adaptive) arms, is continuously busy recognizing the states of tissues and responding to them with corrective inflammation. Self-nonself discrimination is not what the immune system is about. The immune system is about fitness (Reference 16, p. 6). Self-nonself discrimination may not be what the immune system is about in its entirety, but it is hard to think it is irrelevant. Consider, for example, Jeffrey 254
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or whether the fetus creates a privileged boundary for its relatively short but important invasion of the mother (Reference 13, p. 11).
Stewart’s hypothesis that systemic lupus erythematosus is related to female X-inactivation mosaicism.17 Clonal descendants of late blastula cells in females will have the same X-inactivation as their progenitors and this results in patches of tissue in which the cells have the same X-inactivation. Stewart points to the lines of Blaschko in human beings and the color variation found in calico cats as examples of patches of cells having the same X-inactivation. Because the selfproteins expressed by these cells will also differ (because the X-encoded genes will either be from the mother or the father), Stewart reasons that if these two-cell classes extend to the tolerizing cells of the thymus, some lymphocytes may only be rendered tolerant to one of these two classes. The lymphocytes may then be autoreactive to self-antigens of the other cell class. This might help explain why lupus disproportionately affects females. Stewart also points out that linear scleroderma has been found, in some cases to follow the lines of Blaschko.18 Stewart’s view here highlights why a mechanism resulting in the differential treatment of self tissues may be important. Cohen points to scleroderma as an example of how the immune system may be concerned with inflammation and healing and not self-nonself discrimination, scleroderma involving the inappropriate formation of scar tissue. In this instance, Cohen says that disease ‘can result from unregulated processes associated with healing, and not only from the first killing of self-target cells’ (Reference 16, p. 5). It is unclear to me why unregulated processes associated with healing need exclude self-nonself- discrimination. If X-inactivation affects tolerization, this could be enough to upset the regulation of natural autoimmunity, and consequently, self-maintenance. Why cannot all of these factors be involved in the immunological maintenance of selfnonself discrimination? There may be many routes, independent or otherwise, to scleroderma. However, perhaps Cohen’s view is more akin to the idea that killing self-target cells is not all that is involved, and that the immune system will sort the situation out via some sort of flexible self dialogue. The benefits of a multi-factorial and overlapping approach to selfhood in immunology might also be demonstrated by looking more closely at the immunology of pregnancy. Langman and Cohn say that
This view seems to rest on there being two discrete selves: those of the mother and the fetus. But this discreteness has been challenged. Elizabeth Bonney and Polly Matzinger, for example, found that ‘the mother is not continuously exposed to circulating fetal cells and, in fact, has the capacity to eliminate them without eliminating the fetus’ (Reference 19, p. 40). Others suggest that maternal recognition for fetal antigens may be beneficial or necessary for a normal pregnancy (Reference 20, p. 383). Such findings cannot be accommodated if a strict self-nonself boundary is thought necessary to prevent the rejection of the fetus. If maternal immune cells and fetal cells do come into contact, on the discrete view, one would think the fetus would be rejected. Given that selfhood in general is not, as far as I am concerned, a matter of discrete boundaries, I am suspicious of attempts to use discreteness in determining relationships between biological organisms. This is particularly the case in pregnancy, where our usual assumptions about selfhood in general are challenged. This does not mean that tolerance and special boundaries are not involved in pregnancy, but that such mechanisms may be only part of the story. It may be that the fetus is not rejected because it is not dangerous to the mother, as Matzinger claims. It is possible that there are several routes to the maintenance of self in both mother and fetus during pregnancy, some germline-encoded, and some somatic. What might have to be given up is the idea that discriminating self from nonself in a discrete fashion is necessary and sufficient to account for the immune self. I think Anderson and Matzinger provide the most explicit statement of the problem regarding the self in immunology, and this accords with what I claim is the best way to conceptualize selfhood in general. The key to the problem seems to involve the claim that the immunological decision about whether to respond is separate from the question of how the immune system is to avoid destroying the tissues it is meant to protect when it responds. Anderson and Matzinger contend that, the most important distinction between SNS models and the Danger model is whether this definition is used to determine whether a response will occur. In the Danger model, endogenous alarm
it remains an open question whether the fetus induces unresponsiveness in the mother of the same type as the mother develops toward her own self-antigens, 255
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and Rod Langman, Salk Institute, for their helpful comments and criticisms regarding earlier work. I have taken these comments into consideration here; however, it should not be assumed they would support the claims made in this paper.
signals govern that decision. Thus, self need not be ignored and non-self need not always be fought. This distinction allows for all of the following. First, the definition of self can change as the body changes, matures, procreates and grows old. Second, the definition is never final (Reference 21, p. 6).
References
This does not mean that tolerance to self is unimportant. It does mean that a discrete separation of self from nonself in immune function is not the entire basis of immunological self. As Anderson and Matzinger say,
1. Silverstein A, Rose N (2000) There is only one immune system! The view from immunopathology. Semin Immunol 2. Melander P (1993) How not to explain the errors of the immune system. Phil Sci 60:223–241 3. Tauber AI (1994) The Immune Self: Theory or Metaphor, Cambridge University Press, Cambridge 4. Rosenberg A (1986) Intention and action among the macromolecules, Current Issues in Teleology (Rescher N, ed.) pp. 65–76. University Press of America, Lanham 5. Dawkins R (1976) The Selfish Gene, Oxford University Press, Oxford 6. Matthen M, Levy E (1984) Teleology, error, and the human immune system. J Phil 81:351–371 7. Bechtel W (1986) Teleological functional analyses and the hierarchical organization of nature, Current Issues in Teleology (Rescher N, ed.) pp. 26–48. University Press of America, Lanham 8. Matthen M (1997) Teleology and the product analogy. Aust J Phil 75:21–37 9. Bedau M (1991) Can biological teleology be naturalized? J Phil 88:647–655 10. De Sousa R (1994) Individualism and Local Control, Biology and Society (Matthen M, Ware R, eds) pp. 185–206. University of Calgary Press, Calgary, Alberta 11. Coutinho A (2000) Germ-line selection ensures embryonic autoreactivity and a positive discrimination of self mediated by supraclonal mechanisms. Semin Immunol 12. Zinkernagel R (2000) Localization dose and time of antigens determine immune reactivity. Semin Immunol 13. Langman R, Cohn M (2000) A minimal model for the selfnonself discrimination: a return to the basics. Semin Immunol 14. Medzhitov R, Janeway C (2000) How does the immune system distinguish self from non-self? Semin Immunol 15. Howes M (1999) Immunology and the Indiscrete Self. PhD Thesis, The University of Western Ontario, London, Ontario 16. Cohen I (2000) Discrimination and dialogue in the immune system 17. Stewart J (1998) The female X-inactivation mosaic in systemic lupus erythematosus. Immunol Today 19:352–357 18. Taieb A, el Youbi A, Grosshans E, Maleville J (1991) J Am Acad Dermatol 25:637–642; Kennedy D, Rogers M (1996) Pediatr Dermatol 13:95–99 19. Bonney EA, Matzinger P (1997) The maternal immune system’s interaction with circulating fetal cells. J Immunol 158:40–47 20. Heyborne K, Silver RM (1996) Reproductive Immunology (Bronson RN, Alexander D, Anderson D, Branch D, Kutteh W, eds) p. 383. Blackwell Science, Cambridge, Mass Inc 21. Anderson C, Matzinger P (2000) Danger: the view from the bottom of the cliff. Semin Immunol
the Danger model allows for a definition of self that is dynamic and non-exclusive: a living, changing definition that allows us to come out of the cold war attitude of ‘us versus them’ to a new view of global interrelationships (Reference 21, p. 14). Langman and Cohn’s view sets up a discrete sorting of the world into self and nonself from the outset. However, if the on/off switch is not based on a discrete sorting (and perhaps even if it is), it seems unlikely that the immune function can be conceptualized under the rubric of discrete selfhood. This, however, does not mean there is no specific immune function relating to self- representation and self-definition. As with the personal self, higher functions involving self-representation and self-definition can do the job without generating or relying upon a discrete boundary between self and nonself. It can also do the job in concert with other functions that contribute to and shape selfhood, even though these latter functions may make no representative distinction between self and nonself at all. The role of intentional terminology and non-pernicious teleology in immunology indicates that immunological explanations are well-served by self-concepts. Self-concepts may even be necessary to those explanations. The remaining question appears to be the empirical one: is there a system of self-representation in the immune system or not?
Acknowledgements I would like to thank Wayne Myrvold, Department of Philosophy, The University of Western Ontario
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Self, intentionality, and immunological explanation Moira Howes
ological and anthropomorphic sounding language may be neither possible nor desirable. There is more than one way to be teleological, and the kind that is pernicious in biology, the kind that involves conscious or intentional design, is only one of these ways. Second, examining a non-pernicious form of teleological explanation can help us to figure out how and why the self-concept is used in immunology and may help to clarify conflicts concerning its place in immunological reasoning. The debate in philosophy of biology concerning the place of teleology in biology has not been decided. So rather than offer a definitive verdict, my objective is to show what conceptual role teleology may serve and how it relates to the question of the immunological self. In this paper, I first argue that the use of intentional terms in immunology is not anthropomorphic. This opens the way for a different understanding of intentionality, one that is tied to a non-pernicious form of teleological explanation. Second, I argue this non-pernicious teleology is needed if immune function is to be understood. This in turn suggests, I claim, that the self-concept is a non-expendable component of immunological explanation, generally speaking. Finally, assuming for the sake of argument that immunologists wish to retain the self-concept, I will set forth what I think is the best way to conceptualize this self.
In this paper I propose that there are a number of conceptual reasons to preserve self-concepts in immunology. First, I contend that immunological language, including self-terminology, is neither genuinely anthropomorphic, nor perniciously teleological. Furthermore, although teleology associated with future-directed purposive intent is clearly inappropriate in biological contexts, a special type of teleology, intentionality-as-aboutness, needs to be present if there is to be functional explanation in immunology. Second, based on an analogy with the human self, a self comprised of both non-specific innate functions and somatic self-representation, I claim that self-terminology is very appropriate in immunological contexts. Finally, given the appropriateness of self-concepts in immunology, I suggest that the most satisfactory conceptual structure for self-nonself discrimination probably includes both innate and somatic mechanisms. Key words: explanation / function / immunology / intentionality / teleology c 2000 Academic Press
Introduction Silverstein and Rose claim that some of the terminology used in immunology concerning self-nonself discrimination, immunity, and immunopathology is either impermissibly teleological or involves unwarranted anthropomorphism.1 Both of these claims need to be looked at more closely for two reasons. First, the issue of teleology and anthropomorphism in immunology is more complex than represented by Silverstein and Rose, and the elimination of tele-
Intentional terms and anthropomorphism Intentional terms used to talk about immune function, like those of ‘recognize’ and ‘discriminate’ are terms that seem to ascribe some kind of intermediary subjective state to the immune system, a state which exists prior to the immune system’s action. Clearly, to ascribe subjective states to the immune system is anthropomorphic: it suggests that the immune system is somehow conscious of what it is doing. It is equally clear that this is a view no one should hold and the truth of this is not likely to be disputed by anyone.
From the Department of Philosophy, University at Buffalo, The State University of New York, Buffalo, NY 14260, USA. c
2000 Academic Press 1044–5323 / 00 / 030249+ 08 / $35.00 / 0
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glance, there seem to be two reasons for this. First, Rosenberg says that it is so obvious that these terms are not meant literally, scientists do not bother to draw attention to their non-literal nature. Second, scientists generally feel confident that a purely biochemical mechanism can be substituted for the term, if not now, then in the future. The reason the term is used is to avoid literal, complicated and unmanageable mechanistic explanations. As Rosenberg points out, biologists are well aware that by ‘selfish gene’ Richard Dawkins is not saying that genes literally have a subjective state of selfishness. Rather, ‘selfishness’ is implicitly redefined to refer to a behavioral state and behavioral states need not involve a subjective state, or as Dawkins says, a ‘psychology of motives’, at all (Reference 5, pp. 4–5). Mohan Matthen and Edwin Levy put the point the following way:
The question, then, might be whether or not the use of intentional terminology entails the ascription, unwittingly perhaps, of conscious states, beliefs, and desires to the immune system. In other words, are immunologists just being imprudent, from the standpoint of biology, is using these terms and risking these connotations? Some argue that intentional terminology may be useful when the biochemical interactions involved are not fully understood or known. Thus, immunologists are not really ascribing conscious states when they use the terms, but rather using them as shorthand ways of saying ‘we do not quite know what is going on here yet’. Once a biochemical mechanism is fully known, a non-intentional account can be supplied. This view is supported by philosophers such as Melander who says that, ‘immunology has already taken the first steps towards a purely chemical and non-intentional characterization of the immune system’s capacity to distinguish self from nonself’ (Reference 2, p. 239). Presumably, then, the intentional terms used are just metaphors. They may have heuristic value insofar as they ‘stimulate’ scientific reasoning, or confuse matters insofar as they do not (Reference 3, pp. 199–200). If these terms or metaphors have only heuristic value, and are not otherwise involved in immunological explanations, we can omit them as soon as purely chemical formulations come along. As a philosopher, however, I am quite interested in the question of why all of the metaphors used in immunology are intentional terms. Possibly, immunologists could find other metaphors to use, ones that are non-intentional. I have a hard time imagining what these metaphors would be: even lock-and-key interactions seem to imply some kind of intention. Nonetheless, there may be some. The line I wish to investigate here concerns whether there might be a third way of understanding the use of intentional terms in immunology, one that neither views intentional terms as attributing consciousness to the immune system, nor holds that they are expendable. Rosenberg argues that in dismissing intentional terminology as mere metaphor, aspects of scientific theory that are natural to science are ignored. Intentional terminology comes very naturally to scientists and appears to be ‘inevitable and unavoidable’ (Reference 4, p. 66). This, he claims, stands in need of explanation. As Rosenberg points out, intentional terminology is generally used by biologists without any ‘precaution of definition, nor with any caveat against taking it literally’ (Reference 4, p. 69). At first
the view that attributing intentional structures to non-sentient entities is anthropomorphic rests, we think, on the misconception that such structures are somehow connected to consciousness— that postulating intentionality in nonsentient entities rests on a metaphorical assimilation of these entities to sentient entities (Reference 6, p. 371). What is eliminated in the implicit redefinition of intentional terms in science, then, is mentalistic, or conscious, intentionality. In the immune system there are no conscious beliefs, desires, goals or motives and when immunologists use these terms they implicitly empty them of intentionality. So far this description of what occurs when biologists use intentional terms fits quite well with the view that these terms are expendable metaphors. Rosenberg, however, makes a further claim, one that suggests to me that intentional terms are neither expendable nor do they require an imprudent belief in a psychology of motives. Rosenberg says of intentional terms that suitably redefined, it is no surprise that these terms function naturally and inevitably in the description of molecular interactions. They have been implicitly tailored to this purpose. Intentional vocabulary, when pressed into biochemical service retains its teleological, functional implications for behavior, and this together with the intricacy, the plasticity, and the variability of the biochemical interactions 250
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causal processes.7 Teleology is introduced into the equation because of the need to explain biological processes in terms of what they are for. However, this teleology is not the kind one finds when sentient purposive agents set about achieving their goals. This point can be illustrated by looking at the claim that evolutionary history is what makes biological systems teleological. Consider Ruth Millikan’s wellknown notion of a proper function, a notion which is intended to naturalize teleology and reduce it to evolutionary explanation. Adapting an example put forth by Mohan Matthen, a proper function can be described in the following manner. The immune system has defense against pathogenic bacteria as a proper function because:
is what makes for its appropriateness in this context (Reference 4, p. 73). What does it mean to say that stripped of mentalistic intentionality, intentional terms retain their teleological, functional implications for behavior? It can mean only this: there is a way of thinking teleologically in biology that involves neither subjective, conscious, psychological goals or desires to achieve some given end, nor the notion of conscious intentional design. The task, then, is to determine what is happening when we posit intentional structures in non-sentient entities. How is intentionality in non-sentient entities different from that in sentient ones? To answer this question I will now turn to a brief examination of the notion of teleology. Teleology, properly construed in a biological context, need not violate precepts of evolutionary theory concerning the absence of conscious design. I argue that it is this kind of teleology that explains why intentional terms are doing more than acting as shorthand descriptions of biochemical mechanisms, but less than teleological accounts which violate evolutionary precepts. It explains why ridding immunology of ‘self’ and ‘danger’ terminology, for example, in order to avoid an impermissible teleology is an oversimplification that obscures matters. Finally, the need for teleological frameworks for functional explanation provides a strong reason for retaining intentional terminology, although not, of course, uncritically.
1. This defense is a reproduction of some prior process that defended against pathogens. 2. We now have an immune system because that prior process defended against pathogens.8 An example first introduced by A. G. Cairns-Smith is used by Mark Bedau, to illustrate that the above analysis of function is not sufficient to explain how we normally think of function.9 That is, as Matthen contends, proper functions do not properly align with vernacular functions. Suppose there is a type of crystal, one variant of which will crystallize more rapidly and to a greater extent if it is exposed to water. If the water-sensitive and non-sensitive variants are both present in a river, the water-sensitive variants will come to dominate the population. Suppose also that given enough time, the water-sensitive variants will proliferate to such an extent that a dam will be created. According to Bedau, on Millikan’s account we can say that the water- sensitive variant was selected for dam-making, and therefore dam-making would be a proper function of the crystal. Crystals have dam-making as a proper function because:
Function, teleology and intentionality-as-aboutness The somewhat awkward phrase ‘intentionality-asaboutness’ serves to label a kind of intentionality at work in biological explanations. This intentionality has no mentalistic component: in a sense, intentionality is here implicitly redefined much in the way that ‘selfish gene’ and ‘immune recognition’ are. The reason for keeping the notion of intentionality, even though it has no mentalistic component, rests on the idea that unless a biological mechanism can be understood to be about something, it is not understood. If the biological mechanism you are studying cannot be understood as being about something, what you have is a collection of molecules, reactions and relations and no way of telling what they are doing in any overall sense. Without knowing what a system is about, it is difficult to distinguish between functional processes and other concurrent, but non-functional,
1. This dam-making is a reproduction of some prior process that led to dam-making. 2. We now have this dam-making process because that prior process led to dam-making. It seems reasonable to say that the function of crystals here stated is not a function as we normally think of it; that is, it is a proper function, not a vernacular one. There just seems to be something wrong with the statement ‘crystals are selected for dam making’, if by this we mean that dam-making is a function of these 251
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the individuals we are interested in are not just whatever units that science decides it can most conveniently understand the world in terms of: we already have an antecedent sense of what units we want to focus on. This is the ‘evaluative’ aspect of individuation. In the case of the immune system, whether something does or does not count as ‘self’ is partly an evaluative issue: there are good reasons, for example, to regard a cancerous growth as ‘nonself’ rather than self, even though in some respects its development is an outcome of the organism’s ‘own’ evolution (Reference 10, p. 205).
crystals. Rather, dam-making seems to be something that just happens: it is not a function of the crystals. Matthen says, vernacular functions depend on how something is used, and not on causal aetiology. Function attributions seem to be dependent on user, role, mode of use, and the utility that the ‘user’ realizes from the outcome. Further, function attributions seem to be a matter of degree in such a way that the perspective of the observer is relevant to how an absolute attribution is made. This also indicates that a program of reducing teleology to a scheme of causality present in the objective phenomena is misguided (Reference 8, p. 31).
Silverstein and Rose wish to rid immunology of an impermissible teleology and unwarranted anthropomorphism. I argue that the teleology found in conscious design is not the kind that makes its way into explanations of immune function and further, that the anthropomorphism found in immunology is not really anthropomorphism. Silverstein and Rose themselves use intentional terminology and non-pernicious teleology in trying to explain their view of immune function. They use it when speaking of the law of unintended consequences and when claiming that a balance will be struck between the benefit and cost at each step of the immune process (Reference 1, p. 3, 9). These claims depend on there being a user and a mode of use, and this in turn introduces an evaluative component regarding that user. What captures the interest of a philosopher of biology is how teleological concepts involving ‘users’ and ‘modes of use’ in biological explanation can be understood naturalistically, that is, without incorporating notions of consciously intended design. Millikan’s account might not be satisfactory, but this does not preclude the possibility of there being other accounts, such as Matthen’s, which are.
In reducing teleology to mechanical causality, Matthen argues that what appears to be lost is a level of description or analysis that is epistemologically necessary. We seem to need the notion of teleology, the notion that functions are about something, to understand those functions. Instead of naturalizing teleology, Millikan’s account simply uncouples selection and teleology and teleology drops out of the equation. When teleology drops out of the equation, we are left with a type of functional explanation that cannot fully capture what is going on in living systems. The idea that the function of an immune response is to protect the organism cannot be captured in purely chemical terms. What is different about crystals and living organisms and the functional explanations or analyses that apply to them is two-fold. First, living organisms bring in the notion of a user and with it teleology. Second, an evaluative component is introduced insofar as the perspective of the observer is relevant to the functional attribution made. As Ronald de Sousa says, functional explanations that do not incorporate teleology only work
What does this say about self-nonself discrimination?
insofar as we are not interested in the issue of what counts as an individual. As soon as that issue is broached we cannot altogether escape evaluative issues. Cases where such references to individuals seem inescapable include the case of the immune system as well as the case of mentality (Reference 10, fn. p. 187).
My argument thus far provides some justification for the continued use of teleological frameworks for the analysis of the immune function. It also suggests that intentional terms like ‘discriminates’ are non-mentalistic and that they are important, integral and acceptable components of immunological theorizing. It seems clear that one must consider the
And, furthermore: 252
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organism in order to adequately analyze and describe the immune function. What is still problematic is the use of the term ‘self’. The working definition for self-nonself discrimination outlined in the introduction to this seminar is that biodestructive activity has to be regulated so that the host is not destroyed and the pathogen is. Others in this seminar are clearly concerned with the organism when structuring their explanations of what the immune system is doing. António Coutinho says that because natural selection concerns whole organism behaviour, only observations pertaining to whole individuals, and not just those of isolated cells or molecules, should be considered with respect to self-nonself discrimination. In vitro studies are thought to be lacking because the meaning of effector functions, for example, can only be ‘read-out through the organism itself’ (Reference 11, p. 3). Rolf Zinkernagel points to the importance of asking whether observations and their interpretations make evolutionary sense, ‘since the driving evolutionary force of the immune system is protection of the host against pathology caused by infections’ (Reference 12, p. 4). Zinkernagel also says that self-nonself discrimination is obligatory for antigens in lymphoid systems. Here, the terms ‘self’ and ‘host’ are used interchangeably. Rod Langman and Melvin Cohn also use ‘host’ and ‘self’ interchangeably.13 The question that needs to be answered here is why ‘self’ need be used at all; perhaps the user needed in functional explanations is simply the host. Why not just talk about hostpathogen discrimination? Is not ‘self’ just implicitly redefined to mean ‘host’ anyway? I claim that there are two reasons why using ‘self’ may be preferable. The first reason is the weaker of the two. Consider the function of the liver, which contributes to the well being of the organism through its metabolic activities. The function of the immune system is also to contribute to the well being of the organism, at least insofar as it increases reproductive fitness. However, unlike the liver, its function is specifically concerned with the organism-pathogen relationship. Because the immune system has a special function set up to deal directly with the organism-environment relationship, it is more akin in this respect to the nervous system than any other organ system in the body. Self-terminology may be a way of implicitly acknowledging the specific functions of the immune system that concern the relevant differences between an organism and its environment. However, one could still use the terms ‘host’ and ‘pathogen’ to describe this function specific to the
immune system. It may be that germline mechanisms which serve to protect the host from pathogens can be discussed in the context of organism-environment relations, and self-nonself relations need not be considered. Even so, Ruslan Medzhitov and Charles Janeway say that the ‘innate immune response to pathogen-associated molecular patterns (PAMPs) distinguishes non-infectious self from infectious nonself, and does so with great accuracy’ (Reference 14, p. 6). This first reason, then, suggests (although not in the most convincing manner) that self terminology is appropriate at the innate level. A stronger reason for the retention of self terminology rests on the existence of somatic immunological mechanisms peculiar to certain organisms. The somatic mechanisms contributing to immune-system function introduce a higher level of individuality and this is where the use of self-terminology is most appropriate. If an organism’s immune system has a specific mechanism of self-representation, it seems appropriate to describe this system using self terminology. Organisms that have only an innate immune system, such as invertebrates, may not have such systems of representation; this being the case, the self term would not be appropriate in accounts of invertebrate immunology. Vertebrates, on the other hand, might have varying degrees of representation, and so varying degrees of immunological self. If the vertebrate immune system does engage in self-representation, and it seems that it does, this maps nicely onto the way we divide up the animate world according to conscious self-representation. We do not say that worms have selves. We might say cats have some kind of proto-self, if we like them. We are comfortable with the idea that human beings have selves. Where the human self and the human organism begin and end remains a matter of controversy: what seems clear is that many different functions and systems go into the making of human selfhood, right down to the more reptilian aspects of our brains. What is distinctive about the human self is that a higher system of self-representation is an integral part of our individuality, even though it is not solely responsible for that individuality. It is in virtue of somatic functions that are directed towards self-representation that ‘self’, as opposed to ‘host’ or ‘organism’, is an appropriate term in psychology and neuroscience. The same could be said of the immune system. Whether the immune system actually engages in self-representation is, of course, an empirical matter to be decided by immunologists. The question I address next concerns how the self 253
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to do this here, I claim that a modified self identity can be maintained in virtue of overlapping sets of criteria, none of which are necessary and sufficient in themselves to account for the self. Because the criteria overlap via functional relationships, a modified form of identity over time can be maintained. Such a self must be dynamic, not static. And, at any given moment, the discreteness of the self is not possible, both because an unclear boundary exists between self and other, functional relationships drawing upon both as they do, and because evaluative considerations concerning individuality are inescapable. Gaining acceptance for an indiscrete view of the self is not a simple task. The assumption that any real self must be discrete is a difficult one to dislodge. Nonetheless, an indiscrete view of the self has its merits, some of which are relevant to the situation in immunology. A view of the human self as overlapping and multi-factorial makes the most sense given our actual experience of self in the world. Psychological features closely overlap with physical features. Although innate biological factors may not themselves be sufficient grounds from human selfhood, they certainly inform and shape the self. Also, because of functional inter-relationships, it may be difficult to tease germline contributions from the higher specific functions directly responsible for self-representation and self-definition in human beings. To show how the multi-factorial and overlapping nature of the self is relevant to immunology I will consider examples taken from Irun Cohen, and Langman and Cohn respectively. Cohen says,
is to be conceptualized in immunology, assuming for the sake of argument that immunologists wish to retain self-concepts in their explanations of immune function.
Conceptualizing selfhood One of the assumptions that most derailed accounts of self-identity in analytic philosophy is the assumption that there must be one necessary and sufficient criterion capable of accounting for the identity of the self over time. Such a criterion would actually define the real self, a self that is persistent through time. Coupled with this assumption is another, one that is often concealed from view. This is the assumption that the real self must be discrete; that is, the real self must be definite, clearly bounded, distinctly separate from nonself, and it must be resistant to change. The real self, in this view, is like an anchor: it grounds and maintains the self while physical and psychological properties change. Both psychological and physical criteria have been proposed for such an anchor; however, these different criteria fail to pick out the same entity as the real self, that is, the criteria fail to coincide. This would be unproblematic if either psychological or physical criteria could be shown to be superior. The trouble is that these different criteria are, generally speaking, equally compelling. They are also equally problematic. One might think an obvious solution to the failure of criteria to coincide would be to develop a criterion complexing both psychological and physical features of self. However, this cannot be done while still satisfying yet another requirement for self-identity over time. This is the transitivity requirement of identity and it holds that if X is Y, and Y is Z, then X is Z. The transitivity requirement explains why philosophers have focused on developing criteria that are either exclusively psychological or exclusively physical. A complexed criterion, where X is psychological and Z is physical would violate transitivity. A solution to the problem of the self in philosophy presents itself, as I have argued elsewhere, if we reject the following four assumptions. First, that the real self is discrete and unchanging. Second, that there must be a necessary and sufficient criterion for the real self. Third, that transitivity must be satisfied. Fourth, that psychological and physical criteria must pick out precisely the same entity as the real self.15 Next it has to be shown how there can be a self in spite of the rejection of these assumptions. While there is no room
the healthy immune system recognizes both self-antigens and foreign antigens, without class discrimination. Contrary to the assertion of Langman and Cohn, the job of the immune system is not to produce a verdict distinguishing ‘that which is destroyed’ from ‘that which is not to be destroyed’. The data suggest that the immune system, in both its germline and somatic (adaptive) arms, is continuously busy recognizing the states of tissues and responding to them with corrective inflammation. Self-nonself discrimination is not what the immune system is about. The immune system is about fitness (Reference 16, p. 6). Self-nonself discrimination may not be what the immune system is about in its entirety, but it is hard to think it is irrelevant. Consider, for example, Jeffrey 254
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or whether the fetus creates a privileged boundary for its relatively short but important invasion of the mother (Reference 13, p. 11).
Stewart’s hypothesis that systemic lupus erythematosus is related to female X-inactivation mosaicism.17 Clonal descendants of late blastula cells in females will have the same X-inactivation as their progenitors and this results in patches of tissue in which the cells have the same X-inactivation. Stewart points to the lines of Blaschko in human beings and the color variation found in calico cats as examples of patches of cells having the same X-inactivation. Because the selfproteins expressed by these cells will also differ (because the X-encoded genes will either be from the mother or the father), Stewart reasons that if these two-cell classes extend to the tolerizing cells of the thymus, some lymphocytes may only be rendered tolerant to one of these two classes. The lymphocytes may then be autoreactive to self-antigens of the other cell class. This might help explain why lupus disproportionately affects females. Stewart also points out that linear scleroderma has been found, in some cases to follow the lines of Blaschko.18 Stewart’s view here highlights why a mechanism resulting in the differential treatment of self tissues may be important. Cohen points to scleroderma as an example of how the immune system may be concerned with inflammation and healing and not self-nonself discrimination, scleroderma involving the inappropriate formation of scar tissue. In this instance, Cohen says that disease ‘can result from unregulated processes associated with healing, and not only from the first killing of self-target cells’ (Reference 16, p. 5). It is unclear to me why unregulated processes associated with healing need exclude self-nonself- discrimination. If X-inactivation affects tolerization, this could be enough to upset the regulation of natural autoimmunity, and consequently, self-maintenance. Why cannot all of these factors be involved in the immunological maintenance of selfnonself discrimination? There may be many routes, independent or otherwise, to scleroderma. However, perhaps Cohen’s view is more akin to the idea that killing self-target cells is not all that is involved, and that the immune system will sort the situation out via some sort of flexible self dialogue. The benefits of a multi-factorial and overlapping approach to selfhood in immunology might also be demonstrated by looking more closely at the immunology of pregnancy. Langman and Cohn say that
This view seems to rest on there being two discrete selves: those of the mother and the fetus. But this discreteness has been challenged. Elizabeth Bonney and Polly Matzinger, for example, found that ‘the mother is not continuously exposed to circulating fetal cells and, in fact, has the capacity to eliminate them without eliminating the fetus’ (Reference 19, p. 40). Others suggest that maternal recognition for fetal antigens may be beneficial or necessary for a normal pregnancy (Reference 20, p. 383). Such findings cannot be accommodated if a strict self-nonself boundary is thought necessary to prevent the rejection of the fetus. If maternal immune cells and fetal cells do come into contact, on the discrete view, one would think the fetus would be rejected. Given that selfhood in general is not, as far as I am concerned, a matter of discrete boundaries, I am suspicious of attempts to use discreteness in determining relationships between biological organisms. This is particularly the case in pregnancy, where our usual assumptions about selfhood in general are challenged. This does not mean that tolerance and special boundaries are not involved in pregnancy, but that such mechanisms may be only part of the story. It may be that the fetus is not rejected because it is not dangerous to the mother, as Matzinger claims. It is possible that there are several routes to the maintenance of self in both mother and fetus during pregnancy, some germline-encoded, and some somatic. What might have to be given up is the idea that discriminating self from nonself in a discrete fashion is necessary and sufficient to account for the immune self. I think Anderson and Matzinger provide the most explicit statement of the problem regarding the self in immunology, and this accords with what I claim is the best way to conceptualize selfhood in general. The key to the problem seems to involve the claim that the immunological decision about whether to respond is separate from the question of how the immune system is to avoid destroying the tissues it is meant to protect when it responds. Anderson and Matzinger contend that, the most important distinction between SNS models and the Danger model is whether this definition is used to determine whether a response will occur. In the Danger model, endogenous alarm
it remains an open question whether the fetus induces unresponsiveness in the mother of the same type as the mother develops toward her own self-antigens, 255
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and Rod Langman, Salk Institute, for their helpful comments and criticisms regarding earlier work. I have taken these comments into consideration here; however, it should not be assumed they would support the claims made in this paper.
signals govern that decision. Thus, self need not be ignored and non-self need not always be fought. This distinction allows for all of the following. First, the definition of self can change as the body changes, matures, procreates and grows old. Second, the definition is never final (Reference 21, p. 6).
References
This does not mean that tolerance to self is unimportant. It does mean that a discrete separation of self from nonself in immune function is not the entire basis of immunological self. As Anderson and Matzinger say,
1. Silverstein A, Rose N (2000) There is only one immune system! The view from immunopathology. Semin Immunol 2. Melander P (1993) How not to explain the errors of the immune system. Phil Sci 60:223–241 3. Tauber AI (1994) The Immune Self: Theory or Metaphor, Cambridge University Press, Cambridge 4. Rosenberg A (1986) Intention and action among the macromolecules, Current Issues in Teleology (Rescher N, ed.) pp. 65–76. University Press of America, Lanham 5. Dawkins R (1976) The Selfish Gene, Oxford University Press, Oxford 6. Matthen M, Levy E (1984) Teleology, error, and the human immune system. J Phil 81:351–371 7. Bechtel W (1986) Teleological functional analyses and the hierarchical organization of nature, Current Issues in Teleology (Rescher N, ed.) pp. 26–48. University Press of America, Lanham 8. Matthen M (1997) Teleology and the product analogy. Aust J Phil 75:21–37 9. Bedau M (1991) Can biological teleology be naturalized? J Phil 88:647–655 10. De Sousa R (1994) Individualism and Local Control, Biology and Society (Matthen M, Ware R, eds) pp. 185–206. University of Calgary Press, Calgary, Alberta 11. Coutinho A (2000) Germ-line selection ensures embryonic autoreactivity and a positive discrimination of self mediated by supraclonal mechanisms. Semin Immunol 12. Zinkernagel R (2000) Localization dose and time of antigens determine immune reactivity. Semin Immunol 13. Langman R, Cohn M (2000) A minimal model for the selfnonself discrimination: a return to the basics. Semin Immunol 14. Medzhitov R, Janeway C (2000) How does the immune system distinguish self from non-self? Semin Immunol 15. Howes M (1999) Immunology and the Indiscrete Self. PhD Thesis, The University of Western Ontario, London, Ontario 16. Cohen I (2000) Discrimination and dialogue in the immune system 17. Stewart J (1998) The female X-inactivation mosaic in systemic lupus erythematosus. Immunol Today 19:352–357 18. Taieb A, el Youbi A, Grosshans E, Maleville J (1991) J Am Acad Dermatol 25:637–642; Kennedy D, Rogers M (1996) Pediatr Dermatol 13:95–99 19. Bonney EA, Matzinger P (1997) The maternal immune system’s interaction with circulating fetal cells. J Immunol 158:40–47 20. Heyborne K, Silver RM (1996) Reproductive Immunology (Bronson RN, Alexander D, Anderson D, Branch D, Kutteh W, eds) p. 383. Blackwell Science, Cambridge, Mass Inc 21. Anderson C, Matzinger P (2000) Danger: the view from the bottom of the cliff. Semin Immunol
the Danger model allows for a definition of self that is dynamic and non-exclusive: a living, changing definition that allows us to come out of the cold war attitude of ‘us versus them’ to a new view of global interrelationships (Reference 21, p. 14). Langman and Cohn’s view sets up a discrete sorting of the world into self and nonself from the outset. However, if the on/off switch is not based on a discrete sorting (and perhaps even if it is), it seems unlikely that the immune function can be conceptualized under the rubric of discrete selfhood. This, however, does not mean there is no specific immune function relating to self- representation and self-definition. As with the personal self, higher functions involving self-representation and self-definition can do the job without generating or relying upon a discrete boundary between self and nonself. It can also do the job in concert with other functions that contribute to and shape selfhood, even though these latter functions may make no representative distinction between self and nonself at all. The role of intentional terminology and non-pernicious teleology in immunology indicates that immunological explanations are well-served by self-concepts. Self-concepts may even be necessary to those explanations. The remaining question appears to be the empirical one: is there a system of self-representation in the immune system or not?
Acknowledgements I would like to thank Wayne Myrvold, Department of Philosophy, The University of Western Ontario
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