How do we know to differentiate between self and nonself? The genetic reductionist approach suggests that there is a single genetic criterion for identification of the self: a simple code, which is a genetic fingerprint that allows the immune system to differentiate between the self and the other (nonself). In other words, the reductionist perspective offers a simple correspondence between the immune self and a molecular component of the cell.
The MHC is the set of gene loci specifying major histocompatibility antigens. It first looked as though this genetic marker might provide us with the ultimate criterion for self-nonself differentiation. Rolston (1996, quoted in Howes, 1998, p. 3) expresses this idea clearly:
Recognition of the nonself is signaled by the molecules of the major histocompatibility complex (MHC). There are class I molecules on every nucleated cell in the body to identify the self. It is also important to determine which cells to kill, and this is done by T cells, using class II molecules located in macrophages, B cells and some T cells.
It should be noted that according to this suggestion the nonself is an empty slot. There is only a self, which is identified through the genetic marker of the MHC. Whereas the immune self corresponds to the MHC, the nonself corresponds to nothing. An entity is recognized as "nonself' if it lacks the sign of the self. In other words, the foreignness of the antigen is implicit in not having a self marker.
Identity markers such as the MHC or fingerprints may be very helpful in i dentifying a specific self. However, the advancement of our understanding of identity markers does not solve a problem inherent in identity markers: The map is not the territory and the identity marker should not be confused with the self it supposedly signifies. No simple coding exists between an emerging phenomenon on one scale of analysis (i.e. the immune self) and another phenomenon on a lower scale of analysis. For example, although my right thumbprint may serve to identify me, my right thumb is not my self. Similarly, the MHC may signify my immune self but it is not the self. The fallacy of identifying the identity marker with the self it signifies should always be avoided, but in practice some people make the mistake of identifying the sign with the signified, the identity marker with the self. The genetic-reductionist approach is a fertile ground for this fallacy since it clearly adheres to the referential theories of meaning. In semiotics this is taken to mean that the meaning of a sign is explained through a simple correspondence with a reference. If we adopt this perspective, then the MHC seems to be a sign that clearly corresponds to the "self," whatever that is.
Following the work of the philosopher Gottlob Frege, we should differentiate between "sense" (the semantic content of the sign) and its reference (what the sign refers to). The MHC does not seem to have a simple and concrete reference. It does not point to a concrete object. Nevertheless, it has a sense. It is a sign of the self. What is this self? Here we come to a blind alley. The genetic-reductionist approach does not explain what the immune self is. Our complete genome? The codable part of our genome? It just points to the MHC as a sign corresponding to the self.
The genetic-reductionist approach is not totally wrong, just as the referential theories of meaning are not totally wrong. Meaning can be interpreted to a certain extent and in certain contexts in terms of a correspondence between a sign and a signified. When a child learns to use language by pointing to a bird and saying "bird," a direct correspondence is established between the sign and the signified. The problem is that the meaning of a sign or the "immune self' cannot be exhausted by using simple means of direct correspondence between a sign and a signified. As summarized with regard to immunology: "Although an understanding of such immune behavior canonically begins with the major histocompatibility complex (MHC), its complete characterization appears to reside at levels of biological organization beyond the gene" (Tauber, 1998: p. 458, emphasis mine).
Let me support Tauber's argument by pointing out the theoretical and empirical difficulties with the genetic-reductionist approach to the immune self. The first theoretical problem is that, in nature, the "self' is a dynamic object. One does not have to be an orthodox Darwinist to recognize this fact. If the self is recognized by a single, strict genetic criterion, how can we explain the changes in organisms' identity through evolution? This question remains unanswered if we adopt a simplistic reductionist approach to the immune self. The same problem is evident in semiotics. Indeed, the sign "cat" may correspond to a member of the feline family. But the sign "cat" may also signify a jazz musician or may be used as a slang word for a sexy woman. The correspondence between a sign and a signified is not simple, static, and permanent.
When we examine the empirical evidence, things become even more problematic. To see why, let us consider tolerance and autoimmunity, two phenomena central to understanding the problems of the genetic-reductionist approach.
Autoimmunity is a process in which the immune system turns against constituents of the host that it is supposed to defend, that is: against the self. Autoimmunity is usually associated with disease; the body's attack on its own self is described as a kind of a pathological deviation. For example, lupus is an autoimmune disease in which antibodies identify host tissues as nonself and may cause arthritis and kidney damage. Autoimmunity is usually associated with disease. However, it has been found that autoimmunity is not necessarily a pathological process. For example, Schwartz et al. (1999, p. 295) argue that "Autoimmune T cells that are specific for a component of myelin can protect CNS neurons from the catastrophic secondary degeneration, which extends traumatic lesions to adjacent CNS areas that did not suffer direct damage."
In other words, autoimmunity is not necessarily a problem in self-nonself discrimination, and the meaning of the self turns out to be less simple than we might have thought. The implication of the above argument for the genetic-reductionist conception of the self is clear. The self is not a stable, well-defined entity protected from the nonself by the immune system but a contextual construct. In a certain context, the immune system may turn against host constituents, against the self, as a normative function of bodily maintenance. As Cohen (2000a,b, p. 215) argues with respect to inflammation: "The difference between autoimmune protection and autoimmune disease, it appears, is a matter of intensity and the timing of the autoimmune inflammation." The idea that the immune self is a contextual construct will be discussed below. For now, we should realize that no simple correspondence exists in the realm of the living, and that any correspondence is subject to regulation by environmental factors, i.e. context.
Tolerance is the other side of autoimmunity. It concerns the immune system's ability to ignore its own constituents. Interestingly, these constituents may be ignored even if they do not bear the genetic identity marker of the self. My example concerns the bacterium Escherichia coli When this bacterium is found in high concentrations in food, it is indicative of poor hygienic standards in the restaurant. However, this bacterium resides peacefully in our colon and mouth, without being aggressively attacked by our immune system. It is clearly not a part of the self as defined by the genetic-reductionist approach. How can we explain this tolerance?
Tolerance of parasites is not unusual in nature; E. coli is just a specific instance. Sometimes, like talented imposters, intruders in the host self develop a unique mechanism for hiding their identity. However, in many other cases they are simply tolerated by the host. Organisms, human beings, for example, host a variety of parasites that live in perfect symbiosis with them. These parasites are not part of the self in the genetic sense. However, during the evolution of mammals, a symbiotic relationship was established with E. coli, for instance, which produces vitamins B12 and K and aids in the digestion process. In sum, the immune system tolerates the presence of E. coli, a fact which the genetic-reductionist approach to the immune self may find difficult to explain.
Another simple example of immune tolerance to cells that clearly do not have the genetic marker of the self is that of a woman having sexual relations with a man. The woman hosts his sperm cells in her womb. Unless her partner is her twin brother, his sperm cells clearly do not carry the marker of her self. How is it that the host immune system does not destroy the sperm as nonself? And when the fertilized egg develops into a fetus, how does the immune system tolerate the fetus?
Medawar (quoted in Choudhury and Knapp, 2000) suggests that the fetus represents an immunologically foreign graft that is tolerated by the mother's body during pregnancy. He proposes three hypotheses to explain this (Mellor and Munn, 2000): (1) physical separation of mother and fetus; (2) antigenic immaturity of the fetus; and (3) immunological inertness of the mother. However, it is clear that no single mechanism resolves the quandary.
How the mother's immune system tolerates the fertilized egg is an interesting and largely unanswered question in the biology of reproduction. Another interesting finding should be mentioned in this context. According to a news article entitled "Sex Is Good for You" (Buckland, 2002), recreational sex - sex with no procreational purpose - can have a positive impact on pregnancy. But an important qualification should be added: sex with the same partner. Sex, early, often, and with the intended father, may help overcome the reluctance of the mother's immune system to accept a fetus that is producing foreign proteins from the father's genes. That is, the more accustomed the woman's immune system is to the man's sperm, the more habitual or conventional the encounter, the less likely her body will be to reject the fetus. From this study we learn two things. First, the Catholic Church was again found to misunderstand the nature of living organisms. If pregnancy should be encouraged, then sex with the same partner with no procreational purpose should be encouraged too. The second lesson is that the somatic aspect of the immune system is crucial for understanding a variety of immunological phenomena. Not everything can be reduced to genes and delivered to us by our parents through germline cells. There are things we have to learn by ourselves, such as conventions. Learning is built into every intelligent system, and the immune system is just a particular case of an intelligent system that learns conventions.
Another example along the same lines: Sperm proteins arise in the testes after the development of neonatal immune tolerance, that is, after immune tolerance has basically been established. It is known that crude sperm proteins are highly immunogenic in all species (McLachlan, 2002). How is it that these nonself cells are tolerated by the host? Why does not it usually attack them as nonself? In fact, some infertility problems in men are caused by the immune system's identifying the sperm cells as nonself by means of antibodies (i.e. sperm antibodies). However, tolerance to the emerging sperm cells is the norm. We do not really know how this tolerance is established, and although a lack of knowledge is usually not a proof, in this case the lack of knowledge concerning sperm tolerance or autoimmu-nity is an indication that the genetic-reductionist approach to the immune self is overly simplistic and cannot provide us with the answers we are looking for. I now move on to another perspective on the immune self.
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