Home > Hypothesis: The origins of the adaptive immune system and the ulitieis of induced pathogenous of commensals by hosts upon comp

Hypothesis: The origins of the adaptive immune system and the ulitieis of induced pathogenous of commensals by hosts upon comp


Direct and indirect utilities of commensals and adaptive immunity. 

John Skoyles 

Abstract: The adaptive immune system first arose in jawed vertebrates. The symbiotic management of commensals rather than pathogen defense has been proposed as its original function. But what advantages did commensals originally offer ancient jawed vertebrates? And how did these utilities lead to the evolution of the adaptive immune system? Here I argue that the adaptive immune system manages its resident commensals through the antigenic partitioning of its anatomical compartments. This partitioning is aided by the physiological sensing and control abilities of the enteric nervous system and the entero-endocrine cells. Such partitioning: (1) greatly increases the utility of symbiosis to a host as it allows it to harvest from the different commensals in each of these partitions many small (but in total large) direct benefits. (2) Such partitioning allows a host to engage in interhost conflict through commensals that transfer from them to their resource and sexual conspecies rivals. In one scenario, transferred pathogens create an advantage to a primary host related to a handicap principle process. In another, this management allows hosts to select commensals for which the host is an asymptomatic ‘silent carrier’ but which are to other hosts pathogenic. In a further scenario, allelic polymorphisms that provide immunity in the host, self-select through the commensals’ elimination of competing individuals lacking such alleles. As a result of this interhost competition, I argue that the adaptive immune system and pathogens have undergone a three-way coevolution (primary host, secondary host and pathogen) rather than a two way coevolution (host and pathogen). This three-way coevolution led to a byzantine complexity in cytokines, and pathogens engineered to subvert them. What circumstances allowed for adaptive immunity to arise to exploit commensals? I show that these circumstances can be directly linked to the predatory lifestyle of the first jawed vertebrates.  

The adaptive immune system: why did it arise? 

Jawed vertebrates possess two immune systems: innate and adaptive. Adaptive immunity first arose in extinct gnathostomes around 450 million years ago in an evolutionary time span estimated to be less than 20 million years (Marchalonis & Schluter, 1998). This happened due to a horizontal transposon insertion of genes into the vertebrate genome from a bacteria (Agrawal, Eastman & Schatz, 1998). This insertion placed the recombinase activating genes RAG1 and RAG2 into an already existing non-rearranging V-like exon of an Ig-domain-containing gene that was regulating cell mediated cytotoxicity or phagocytosis (Kaufman, 2002; van den Berg, Yoder & Litman, 2004). The result was a method of rearranging genes to create molecules that had a greater structural diversity than those supplied by the genome for the rest of the vertebrate body. This event for these reasons is so radical and unprecedented that it has been described as a biological ‘Big Bang’ (Schluter, Bernstein, Bernstein & Marchalonis, 1999). While there has been evolutionary modifications in mammals, even the most basal group of living gnathostomes, the elasmobranchii or cartilaginous fish, contain all its basic elements: MHC class I and class II, Ig, TCR chains α, β, γ and δ (Rast, Anderson, Strong, Luer, Litman, & Litman, 1997), and RAG1 and RAG2 (Agrawal, Eastman & Schatz, 1998; Laird, De Tomaso, Cooper & Weissman, 2000). In spite of extensive search, none of these elements have been found in the phylogenically earlier cyclostome vertebrates (such as lampreys and hagfish), even though other elements have been detected that became coopted into the adaptive immune system such as lymphocyte-like cells (Mayer, Ulnuk-ool, Tichy, Klein & Cooper, 2002).  

The adaptive immune system of mammals has well researched abilities to defend against intra- and extracellular pathogens and engage in the surveillance of genetically altered cells (neoplasms). Even so, the adaptive immune system only adds to an unknown degree upon the pathogen control abilities that already are provided by innate immunity. Adaptive immune activation can compromise survival: one study found a two-fold greater one year survival in animals that had not activated their adaptive immune system compared to those that had mounted an immune response (Hanssen, Hasselquist, Folstad & Erikstad, 2004). The adaptive immune system is slow: it takes about a week to react to an infection whereas innate immunity starts immediately. Adaptive immunity has iatric costs upon the body: it is responsible for around 70 varieties of autoimmune illness. To manage and inhibit inappropriate activation, the adaptive immune system has had to add upon itself a complex system of regulatory cells (Nagler-Anderson, Bhan, Podolsky & Terhorst, 2004). The role of the adaptive immune system in nonmammalian vertebrates in protecting against pathogens is even less clear with it being argued in regard to elasmobranchii that the “elements of the adaptive immune system do not essentially contribute to protection of this species from pathogens. These taxons seem to use predominantly protective factors of innate immunity” (Klimovich 2002). There is also the continued puzzle why invertebrates manage to survive so well without any equivalent to adaptive immunity.  

This raises the question whether pathogen defense was indeed the primary function that led to the evolution of adaptive immunity (Klimovich, 2002; Marchalonis & Schluter, 1998; Marchalonis, Kaveri, Lacroix-Desmazes, & Kazatchkine, 2002; Stewart, 1992). Macfarlane Burnet, the founder of the clonal theory of acquired immunity, noted that ‘there is a growing tendency to regard the evolutionary origin of adaptive immunity as being related to something other than defense against pathogenic microorganisms’ (Burnet, 1959, cited in Rinkevich, 2004). Alternative explanations for its origin have been proposed including that it was only a “stochastic event” (Marchalonis & Schluter, 1998), that it provided “additional control mechanisms for processes of the internal milieu” (Marchalonis, Kaveri, Lacroix-Desmazes, & Kazatchkine, 2002), that it aided the integrity of the environmental milieu within the body (Stewart, 1992), that it preserved host individuality from invading conspecific cells (Rinevich, 1999; 2004), and that it aided the management of symbiosis with commensals (Klimovich, 2002; McFall-Ngai, in preparation).  

The idea that adaptive immunity arose to enhance the management of commensals is made plausible by the different nature of the relationship between invertebrates and vertebrates to commensals. Invertebrates tend to have one type of commensal relationship per host but, in contrast, vertebrates host many hundreds of types in complex hierarchical symbiotic consortia (Xu & Gordon, 2003; Hooper, Bry, Falk & Gordon, 1998). Exquisite adaptations exist in the host to coexist with commensals (McFall-Ngai, 2002; Ruby, Henderson & McFall-Ngai, 2004). These adaptations include the adaptive immune system which actively samples and tolerates nonpathogenic microbes. For example, the adaptive immunity indirectly through M cells, and directly through dendrite cells actively extract commensals and antigens present in the lumen (Gewirtz & Madara, 2001; Kraehenbuhl & Corbett, 2004; Macpherson & Therese, 2004). Following this commensal sampling, cellular processes ensure adaptive immune tolerance to symbiotic and nonpathogenic commensals (Beg, 2004; Nagler-Anderson, Bhan, Podolsky & Terhorst, 2004; Sakaguchi, 2003). As a result of these systems, consortia commensals ‘educate our immune system so we become tolerant of a wide variety of microbial immunodeterminant’ (Xu & Gordon, 2003: p. 10453). What factors drove the evolution of this capacity to manage consortia relationships?  

Here I examine several questions.  

(1) How does the adaptive immune system aid the host’s management of its relationships with commensal consortia? The circumstances and economic factors that shape the development and management of these symbiotic relationships have largely gone unexamined. I argue here that an important aspect of such management is the creation of antigenically defined partitions within the anatomical compartments (such as skin, gills, mouth, lower intestine, colon, cloacae, reproductive tract) in which such commensals reside. To these antigenic defined ‘spaces’ is added physiological information and control provided by the enteric nervous system (Furness, Jones, Nurgali & Clerc, 2004), and entero-endocrine cells. The enteric nervous system provides information about such factors as the movement of the villi, distortion of the mucosa, contraction of intestinal muscle, and changes in the chemistry of the gut lumen. Such partitions enable the host to manage the densities, entry and exclusion of selected commensals into symbiosis with the host in regard to their benefits and costs. The economics of commensals is radically changed by such partitioning in that it allows the spreading of fixed physiological ‘costs’ over a large number of symbiotic relationships. 

(2) The advantages proposed so far for the management of symbiotic commensals are limited to those that directly occur between a host and its resident commensals such as nutrition and protection from pathogens (Xu & Gordon, 2003; Hooper, Bry, Falk & Gordon, 1998). But are these direct advantages the only ones? Here I argue that another kind of utility of an indirect nature exists. Hosts gain fitness not only in terms of their own physiological well being but in certain circumstances by the impairments suffered by their conspecies competitors. Since (a) commensals have effects upon their hosts from asymptomatic to death and infertility, and (b) commensals transfer between conspecies, a host might be able to impair its competitors by hosting commensals with a benign effect upon themselves, but that later infect their rivals to increase their morbidity, mortality or that reduce their fecundity.  

(3) The adaptive immune system arose with jawed – more accurately, jawed and toothed -- vertebrates. What was peculiar to the first jawed vertebrates rather than invertebrates that the above benefits resulted only in them evolving the adaptive immune system? One suggestion has been that it was due to jawed vertebrates being predators and the resulting increased exposure to pathogens following the ingestion of prey (Matsunag, & Rahman, 1998). This situation, however, is far from unique to vertebrates since many carnivorous invertebrates are similar in their predation though with beaks not jaws such as squid and octopuses. However, the existence of jaws with teeth does create peculiar circumstances that are (a) distinct from such carnivorous invertebrates, and (b) link to the above circumstances needed for the rise of managed relationships with commensals.  

(4) Why is the adaptive immune system so complex in its cytokines, and why pathogens show so many ingenious adaptations to defeat or exploit them? Present theory argues that pathogens evolved in a two way coevolution with the immune system. In this, hosts develop new means to fend off pathogens, and pathogens evolve in reply counter measures. The above suggestion of an interhost conflict through the use of commensals as vectors raises the possibility of a three-way coevolution. In this, primary hosts modify pathogens to impair secondary hosts in which they are in competition (see also Dower, 2000).  

The adaptive immunity and direct utilities.  

Attempts to understand the origins of the adaptive immune system in regard to commensals suffers a disadvantage that must be immediately acknowledged. Most of what is known about the adaptive immune system concerns that in mammals. This is unfortunate since in regard to the question of its evolution, the adaptive immune system of greatest theoretical importance is not the mammalian one but that of basal jawed vertebrates. Nonmammalian vertebrates are known to possess a less sophisticated adaptive immunity than mammals (and possibly birds). Specifically, they lack germinal centers in which somatic hypermutation and antigen selection occurs. In mammals, such processes result in increased antigen affinity after repeated immunizations and the class switching of Ig from IgM to IgG (Marchalonis, Kaveri, Lacroix-Desmazes, & Kazatchkine, 2002). It is claimed in consequence that the antibodies of nonmammals (other than birds) is low affinity and shows no memory. How far this is true of antigens in the gastrointestinal tract has not been researched. Further there are claims for hypermutation in sharks (Lee, Tranchian, Ohta, Flajnik and Hsu, 2002; and Diaz, Greenberg, & Flajnik, 1998). Moreover, the production of low affinity antibodies, does not necessarily entail less antigen discrimination (Van Regenmortel, 1998). Another issue is that our knowledge about the immune system concerns one existing in homothermic mammals. Homothermy could effect in subtle and unappreciated ways its functioning related to (a) the rate of the physiological processes involved, and (b), speed with which the host needs to react to pathogens and commensals.  

This having been observed, the adaptive immune system of sharks and other elasmobranchii is remarkably like that of later mammals as it possesses MHC class I and MHC class II, Ig, TCR (chains α, β, γ and δ), and RAG1 and RAG2. The key innovation was RAG genes (recombinase activating genes) since they enable the splicing of DNA of V, D, and J genetic elements that are combinationally rearranged during lymphocyte development for Ig and TCR. MHC genes show marked inheritable allelic polymorphism, as do other components of the adaptive immune system, that determine its ability to identify and target antigens.  

The combinational rearrangement of TCR and Ig allows a vertebrate in effect to create a “cognitive system” for recognizing (TCR) and targeting (Ig) antigenic epitopes. Combinational rearrangements that match self antigens can be deleted leaving a residual subset that detects nonself antigens. If such antigens are detected (through MHC presentation), not only can a response specific to them be made (by antigen targeted Ig M antibodies) but a memory of them can be made enabling modified responses. Antigen detection and antigen targeting provide a host with a sophisticated means to control commensals.  

Control requires both afferent and efferent processes: information about an entity, and the ability to change that entity. Without afferent input, the ability to manage such an entity is blind, and without efferent output there is no power of control. Further, control requires an ability to analyze such inputs and outputs in regard to how they link. Such analysis must be able to learn and also ignore noise generated by concomitant activities that interact with the afferent and efferent processes. Antigenic recognition provides the afferent input of the adaptive immune system, while antibodies provides its efferent output.  

These afferent and efferent antigenic processes do not exist in isolation in the gastrointestinal tract from the information and control provided by the enteric nervous system and entero-endocrine cells (Castro & Arntzen, 1993; Hansen, 2003; Holzer, Michl, Danzer, Jocic, Schicho & Lipp, 2001; Palmer, Greenwood-Van Meerveld, 2001). The human enteric nervous system consists of a substantial number of neurons 108 (roughly the number of neurons in the rat brain). They are of at least 14 types and employ all the major neuromodulators and neurotransmitters found in the brain. They are intimately through their dendrites woven into the gastrointestinal tract epithelia (see fig 1 from Furness, Jones, Nurgali & Clerc, 2004). They detect many parameters that govern the relationship between the host and symbionts such as the movement of the villi, distortion of the mucosa, contraction of intestinal muscle, changes in the chemistry of the gut lumen and the detection of bacterial products (Furness, Jones, Nurgali & Clerc, 2004). Enteric reflex circuits control blood flow in the lower and upper intestine and the secretion of fluid across the mucosal epithelium. Further, catecholaminergic, cholinergic and peptidergic enteric neurons innervate the interfollicular area of the Peyer's patches in which commensal antigens are processed (Krammer & Kuhnel, 1993; Kulkarni-Narla, Beitz & Brown, 1999), and such innervation modulates immune processing of commensal antigens (Green, Lyte, Kulkarni-Narla & Brown, 2003). Entero-endocrine cells exist in the epithelia sensing the lumen and releasing over 20 hormones. These hormones both locally in the epithelia upon dendrite sensors, and nonlocally, effect the enteric nervous system. The immune system has close connections with such cells (Yang & Lackner, 2004). Both systems form a close interacting and dynamic three way relationship with the innate and adaptive immune systems (Castro & Arntzen, 1993; Green, Lyte, Kulkarni-Narla & Brown, 2003; Krammer & Kuhnel, 1993; Palmer, Greenwood-Van Meerveld, 2001; Yang & Lackner, 2004).  

Did the enteric nervous system evolve its complexity to manage commensals? As found, it seems to be too complex a neurological system to merely control the gastrointestinal tract as a purely digestive organ. Like the adaptive immune system, we should be looking closely as to its role in managing commensal consortia.  

The enteric nervous system and entero-endocrine cells provide physiological information and control that complements that of the adaptive immune system. This information greatly extends the ability of adaptive immunity to control commensals. Notably, antigenic processing provides no information upon the physiological benefits gained from commensals, and only partial information (inflammation related) about their physiological costs. The enteric nervous system and entero-endocrine cells can fill in such information. The enteric nervous system provides effectors such as control over lumen churning and its movement through the various compartments of the gut. In the shark, it is reasonable to presume that it also controls the temperature increase of the intestine that follows a meal to quicken its digestion.  

A further limit upon the adaptive immune system is its ability to analyze and learn about its relationships with commensals. This limit, however, might be overcome through collaboration with the enteric nervous system. This suggestion is, of course, speculative as research in this area does not exist (the question has not been raised). Optimal management by a host of its commensals will need to correlate commensal type with information about its benefits and costs. Ideally, such management needs to be able to compare between different consortia set ups and select those that best suit its interests. Analysis is needed since the consequences of commensals upon the host might be hidden through the interactions of consortia intermediaries or at a delay. For example, if a commensal benefits a host by displacing a pathogen, this needs to be appreciated by the host even though this relationship is hidden. Information about the antigens of the commensal and the pathogen requires analysis in terms of information about long term effects upon the host. Given the interactions between the adaptive immune system and the enteric nervous system, it is not unreasonable to assume some of this analysis is carried out in the integrative circuits of the enteric ganglia.


In what follows, when I refer to the adaptive immune system I also in appropriate contexts should be understood to refer to the whole immunoneuroendocrinal process. 

The adaptive immune system allows each anatomical compartment to be functionally subdivided into many partitions defined by commensal antigens. By partition, I mean that the host can function as if it has many different anatomical compartments where it otherwise would have only one. The partitioning arises from the ability of the host to police the contents of one partition comparatively independently of what it does in other partitions, even though the commensals coexist in the same physical space. Note, here a partition within, say, the host’s lower intestine, is not the same entity as the commensals that resides there, since the partition is defined in terms of the host’s ability to afferently and efferently differentiate between different antigens, and so act discriminately upon their associated commensals. Often, however, a commensal might consist of two closely related populations, one desired and the other nondesired, in which case the host might not be able to partition between them. Moreover, many commensals may be discriminatable but not differentiable in terms of the host’s ability to control them – for example if its antibodies lack specificity or antibody cross reactions happen between those of different commensals.  

One complication upon control is that commensals interact amongst themselves, so that these partitions might not necessarily be controllable in isolation of each other. For example, eliminating one partition (and its associated commensals) might cause commensals in a second partition to die from a lack of a basic food resource provided by commensals in the first partition.  

Symbiotic economics 

Partitioning changes profoundly what might be called the “economics of symbiosis”. Here, I will briefly sketch its possibilities to show the relevance of any such analysis to modeling why the adaptive immune system arose. The ideas of fixed, variable, and marginal costs are core notions in economics and determine many commercial decisions and actions. To take an example, consider why restaurants open for lunch time trade even though they have fewer consumers at that time than in the evening. A restaurateur faces the situation that once fixed costs have been made for evening trade, they do not need to be spent again for keeping the restaurant open at lunch time. The costs of fitting out are fixed – the more the restaurant can be used the greater these costs can be spread. While the extra profit earned at lunchtime would not by itself justify the fixed costs of setting up the restaurant, those costs have already been made. The marginal cost of doing so thus is low which makes the trade needed to make it financially profitable also low.  

The ability to partition the gastrointestinal tract allows a host to exploit not one but many separate and individually low benefit relationships. Without partitioning, a host can only engage in relationships which offer a high net benefit. This is due to the effect of fixed and variable costs and gains in a symbolic relationship.  

    First, there are the costs and gains from the actual independent symbiont. A host, for instance, might gain the advantages of nutrients that it would otherwise miss except for the symbiont. But the host faces several costs with such a relationship. The commensal might take up nutrients which the host might otherwise use, or produce toxins that need to be cleared. The total gain to the host is these costs set aside against the benefits offer by the symbiont.  

      Second, there are fixed costs in physiologically setting up the commensal relationship. Not only might the host have to provide a symbiostome or special environment for commensals but that host must maintain in reserve the means to eliminate the commensals when these relationships goes wrong. Hosting the commensal, moreover, risks opening up the host to the danger that other pathogenic commensals might gain access and invade the host’s body.  

      The host thus needs to expend upon physiologically means to detect such circumstances, and, if need be, eliminate the commensal. Without partitioning, the fixed costs cannot be spread across a number of different commensal relationships. Only in a few circumstances will a symbiont be able to offer sufficient utility to cover these fixed costs. Moreover, where this arises the host might need to specialize its relationship to reduce the overall fixed costs involved and so inhibit the possibility of consortia.  

      Partitioning enables the spreading of these fixed costs across many symbiotic relationships. Since the marginal costs of adding further symbionts becomes lower the more relationships a host has already, there is a natural tendency to expand their number even further. Thus, the specificity created by adaptive immunity changes radically the basis of the economics of having commensal relationships. The partitioning it provides the host allows it to gain benefits from many low value symbiotic relationships. Though individually each of them might yield low benefits, collectively when accumulated together they might offer a substantial advantage to the host.  

      Another significant benefit (particularly given the complementary information provided by the enteric nervous system and entero-endocrine cells) is that a host can actively select commensals. Imagine a commensal that offers a marginally worthwhile benefit to the host such that at certain times it is a cost (say it produces a waste product that is a minor toxin), but on other occasions it is an overall benefit. Since the commensal is only tolerated when it provides a net benefit, it risks being eliminated on the occasions when it fails to provide sufficient utility for the host. Thus it will be under selective pressure to increase the benefit it gives to the host (by say stopping its production of the toxin).  

      The direct benefits of symbiosis suggested above might seem sufficient to explain the rise of adaptive immunity. However, the fact that such benefits exist does not mean they are the only ones. Moreover, their existence does not explain why they became so important with the rise of jawed vertebrates that they caused these organisms (but not other comparable ones amongst the invertebrates) to develop an adaptive immune system. Therefore it merits consideration whether the ability to partition the gastrointestinal tract to manage commensals might offer benefits in a further way. 

      Primary hosts, commensals and conspecies competition 

      Theoretically, a primary host might be able to gain utility from commensals after they transfer to another secondary host. Whether this happens depends upon (1) the degree to which hosts are in interhost competition, (2) whether opportunities exist for commensals to transfer between a primary host and its rival secondary ones, and (3) whether such commensals have different effects upon different hosts. 

      Host animals can be in competition with conspecies in regard to niche occupancy, resources, reproductive opportunities, and the survival of their offspring. The degree of such competition varies with whether a species faces K selection or a r selection (though these two concepts are usually made in the context of comparisons between species in related groups -- such as different species of primates – they can be used to evaluate the relative importance of competition between individuals of the same species in regard to their reproductive fitness). Conspecies competition is particularly intense with K environment selected organisms. These animals have low fecundity, slow maturation and stable populations. In such animals, fitness links less strongly to surviving the environment, than out competing other conspecies in finding and keeping its resources. Another competition exists in the degree to which individuals compete through sexual selection. Animals in K selective environments due to low fecundity and slow maturation invest in few offspring. Such investment links to internal fertilization – an activity which provides opportunities -- courtship and internal sperm competition – in which animals engage in rivalry. Where intense competition exists between individual members of a species, the fitness of a host links not only to its own physiological integrity but that of the conspecies with which it is in direct competition, and so their comparative ability to compete against each other. While such competition might not necessarily involve them directly having physical contact, it often will. In such circumstances, commensals transferred from a host might be able to reduce the physiological well being of its rivals and so increase its competitive advantage over them, and through this its own reproductive fitness.  

      In the history of life, one of the first groups of organisms to face a strong K environment selection and so develop long lives, slow maturation and high investment in a few offspring were the ancient vertebrates with the ability given by tooth jaws to become top level carnivores in the ancient Silesian seas. Sharks are often described as the first K selected animals: they show its influences in an extreme form with very long lives, very prolonged maturation, courtship, sexual intercourse, and the first occurrence of viviparity in vertebrate evolution. Thus, the evolution of jaws would have set the scene for strong competition between conspecies. Below I will discuss the issue of transfer of commensals between hosts but first I will discuss how individuals might use transferred commensals to enhance their own fitness.  

      Individuals have several ways to enhance their survival relative to other individuals in which they are in competition. The handicap principle (Zahavi & Zahavi, 1997) for example offers one illustration. A fit gazelle will jump up and down (stotting) to a potential predator such as a wolf. It does this to show that it is fit and so not worth chasing. As a result, the wolf looking at different gazelles can identify more readily the individuals of a species that are less fit and so they might successfully hunt down. In effect, the fit gazelle has traded some of its fitness – by providing information to predators -- into an advantage over its less fit conspecies.  

      The greater physiological well-being of some individuals over others will in many circumstances lead to greater survival. A gazelle that can run faster will tend to out survive one with a subclinical ailment. But often this will not be the case: animals at the top of the food chain will lack predators and the ability to obtain food might depend upon factors that link poorly to physiological well-being, body size, for example. In such circumstances, individuals with greater physiological well-being will need an opportunity to convert that well-being into a competitive advantage. Commensals offer such a means.  

      Commensals hosted in one individual can be transmitted to the competitors of that host in various ways including contact during feeding, mating and shedding into shared environments. Indeed, the continued survival of commensals that are adapted to any species will depend upon the existence of such routes of transmission. Upon passing from one host, the primary one, to another secondary one, a commensal need not necessarily have the same effects upon the second host as the first one. If the commensals in the secondary host (but not in the primary one) cause it morbidity, mortality or reduces its fecundity or capacity to mate, then the primary host from which the commensals came will gain in competitive fitness.  

      Such different effects occurs widely with pathogens. Many organisms and viruses such as those responsible for TB, chlamydia, typhoid and the common cold can grow successfully in individuals that remain unaffected by them and so function as ‘silent’ asymptomatic carriers. For example, up to 94% of those infected with Chlamydia trachomatis can be asymptomatic (Sutton, Martinko, Hale & Fairchok, 2003), and 20% of infants with rhinovirus infection do not show nasal symptoms (van Benten, Koopman, Niesters, Hop, van Middelkoop, de Waal, van Drunen, Osterhaus, Neijens & Fokkens, 2003). These organisms having been hosted by individuals then often infect other individuals in whom they cause morbidity, mortality or infertility. The existence of asymptomatic carriers does not, of course, entail that their hosts gain an advantage from transmitting their pathogens to conspecies. However, it shows that this aspect of the theory – that hosts can vary in the effects of pathogens -- is already widely observed and not itself speculative.  

      The adaptive immune system’s ability to identify and target commensal antigens is partially determined by inherited allelic polymorphisms particularly in MHC genes (Parham & Ohta, 1996). The immune system also varies in inheritable ways in the V region gene segments that encode the variable regions of Ig and TCR (Hughes, 2002). This genetic variation has the consequence that where hosts manipulate commensals in interhost competition, not only the host but its descendents might gain from its effects.  

      As noted, pathogens vary widely in their effects upon infected individuals: some individuals being unaffected in spite of the pathogen continuing to replicate within them (silent carriers), and other individuals upon which the pathogen causes morbidity or mortality. Individuals are not insensitive to these differences: commensals detected to be pathological usually face attempts by the host to eliminate them. Imagine a situation where an organism seeks to provide residency for a diverse and numerous collection of commensals that are not pathogenic – at least to them. Merely by offering commensals residency they increase the chance that such commensals will transmit to competing conspecies. Since commensals vary in their pathogency, many of these commensals while being benign in their original primary host will by chance cause disease when they infect competing conspecies, and so indirectly enhance the primary host’s fitness. Moreover, the factor why an individual is unaffected by a commensal might be inheritable. Therefore this enhanced fitness might feedback not only upon an individual but its progeny. Thus, the adaptive immune system can enhance an individual’s competitive fitness through selecting for having a large consortia of commensals – since statistically – at least for some of those commensals – it will turn out in effect to make them a silent carrier of a pathogen.  

      Since a host that is physiologically well can tolerate a high degree of attrition from pathogens, it can potentially gain an advantage if it can increase the number of pathogens to which it and its competitors are exposed. Such an increase will cause the physiologically less well to suffer the effects of pathogens. A physiologically well host can actively increase the number of pathogens to which conspecies are exposed by hosting as many as it can tolerate within its own body at a subclinical level. This will increase the chance that these pathogens will transmit to more vulnerable conspecies. A host with a strong immune system that chose to handicap itself by keeping pathogens at a subclinical level to heighten their continued infection of others could in this way increase the exposure of its less strong competitors to ailments, and thus convert its immune strength into a competitive advantage.  

      The above scenario concerns only the passive use of adaptive immunity. However, the adaptive immune system offers a more active option. The biological partitions defined by the adaptive immune system potentially allows for the differential selection of commensals in regard to their pathogency upon secondary hosts. First, it can do this by allowing the subclinical tolerance of visiting commensals. By doing this to commensals that it normally would clear, it can allow them to adapt to become residents in itself and so its conspecies competitors -- after all, the bodies of its competitors are physiologically much like itself. Second, by deliberately exposing commensals to, say, weakened innate immune responses, it can select for commensals adapted for overcoming them. Again this would not only apply to itself but also the less strong members of its species. In effect, an individual could raise the bar upon the physiological strength needed to cope with pathogen infection. A physiologically strong individual thus could by handicapping its immune ability act to compromise the health of its competitors.  

      Richard Dawkins has speculated upon the existence of genes that advantage themselves when they ‘spot’ in effect themselves in others. There are many hundreds of allelic variation in the genes specifying the MHC (Parham & Ohta, 1996), and variation exists also elsewhere in the immune system such as the V region gene segments that encode the variable regions of Ig and TCR (Hughes, 2002). Allelic variants that enable an organism to be a silent carrier of a pathogen could in certain circumstances self-select themselves through pathogenical commensals. The circumstance would be those where an infectious commensal was pathogenic except for some tolerance offered by an allelic variant. Any host organism with such an allelic variant would advantage not only itself (through reduced competition) but any other conspecies that also possess that variant (as they would also be tolerant to that pathogen).  

      Another strategy has been suggested by Steven Dower (2000). According to him, a host might duplicate a novel anti-inflammatory cytokine and then change it slightly from the original one. This new cytokine would not offer an immediate benefit to the host, but if it spread, viruses would coevolve with it and its anti-inflammatory control. As a result, such viruses later on when they came to infect individuals without that duplicated cytokine would cause inflammatory responses, and in consequence as Dower puts it “serious disease in the parental host strain”. As he concludes, “the most plausible source of selection pressure for evolution of host defense is competition between hosts, in particular those of the same species, rather than between host and pathogen (2000: p. 368).  

      The insect intracellular bacteria Wolbachia might be thought to be an example of an invertebrate infection where a commensal has been manipulated as a vector in interhost competition. While Wolbachia infection is invariably spread vertically, it also can spread horizontally. The pathogen infects more the 20% of insect species and varies widely in its effects upon its host. Due to cytoplasmic incompatibility, infected females can breed with both infected and uninfected males, but an uninfected female is incompatible with infected males. This is usually seen as disadvantaging an infected female since her infected male offspring have reduced fecundity with uninfected females. However, studies have shown that the reproductive advantage offered by cytoplasmic incompatibility can result in population replacement of uninfected insects by infected ones. Several issues complicate a comparison with the above proposed interhost competition scenarios. Notably, that its disadvantage concerns reproduction compatibility between infected and uninfected individuals rather than an individual’s ability to engage in resource or sexual competition. Also it appears that females might gain a reproductive fitness as infected insects appear to live longer and show greater fecundity than uninfected ones (infection does not seem to effect males in this manner) (Dobson & Rattanadechakul & Marsland, 2004).  

      The above theory suggests the reverse situation to that at present with pathogen resistance to antibiotics. An important aspect of medical research is to understand how the exposure of pathogens to antibiotics can be done with the minimal development of resistance. This theory suggest hosts due to interhost competition have tried to solve the problem in the opposite direction: how could pathogens learn to overcome the immunity of the body such that they can coexist with hosts at a subclinical level of infection. One way of understanding how this might have been done by hosts would be to examine the circumstances which most readily create antibiotic resistance.  

      The evolution of the adaptive immune system 

      There are three stages to inferring how the adaptive immune system arose with jawed vertebrates. First, the utility – what selective advantage existed for the adaptive immune system as an innovation. These have been discussed above. Second, these proposed utilities suggest factors that must have already arisen before they can themselves arise. These have been partially discussed above. For example, before a commensal can advantage a host in interhost competition, it must be capable of being asymptomatic in some hosts, and pathogenic in others. The evidence that pathogens vary in this way has been briefly reviewed. But there are other circumstances. Notably, commensals must be able to transfer from a host to those conspecies in which it is in competition. This is a major constraint: if the lifestyle of an animal is such that it is unlikely that commensals will spread to other conspecies, or it will infect only those with which a host is not in competition, then the process will not work. A key precondition of interhost competition therefore is interhost commensal transmission.


      The third stage in the inference is to show that circumstances for this started with the jawed vertebrates. That while all organisms might be advantaged if they could somehow kill off their competitors via commensals, that having a jaw created the circumstances for this to happen.  

      Few early gnathostomes or their ancestral cyclostomes are preserved, and those fossils that survive provide only limited information in regard to their capacity for commensals or their behavior or lifestyle (Ahlberg, 2001; Purnell, 2001a; 2001b). Modern cyclostomes are highly specialized and are unlikely to reflect those from which gnathostomes arose. Modern Elasmobranchii are a diverse group with scales and dermal denticles perhaps dating back soon after the first gnathostomes to about 455 million years ago (Miller, Cloutier, & Turner, 2003). The jaw evolved before teeth probably to pump an enhanced flow of water through the gills (a function still done by the jaw of whale sharks, Mallett, 1996). Teeth arose later twice (Meredith Smith & Johanson, 2003) from pharyngeal dentricles (Johanson & Meredith Smith, 2003). Unfortunately, little published research exists upon the gastrointestinal tract microflora commensals in either modern Elasmobranchii nor modern cyclostomes.  

      Another problem is that we do not know exactly in which creatures the adaptive immune system arose. The boundaries are modern Elasmobranchii (with the adaptive immune system) and Lampreys and Hagfish (without it). That leaves a large uncertainty when we look at the fossil record. Did the adaptive immune system arise with ancient Elasmobranchii? with earlier gnathostomes from which Elasmobranchii arose? From agnathan that evolved after the ancestors of modern lampreys and hagfish branched phylogenically off? And what about the wild card of Conodonts which had teeth (but no jaws) – there relationship to other vertebrates is unknown? In what follows, I argue that the circumstances which would favor interhost competition via commensal vectors occurred with a lifestyle associated with toothed jaws, and is one which is still strongly shown in modern sharks. But how this lifestyle links to the paleontological record is open. One can argue for the link between toothed jaws and this lifestyle without having to be precise as to in which group the adaptive immune system which it aided arose.  

      As observed above, a major limitation on interhost use of commensals as vectors is the existence of circumstances in which such commensals can infect competitors. Such transmission is not a trivial problem for commensals in the sea. Commensals outside the body are unprotected from microphagy and suspension feeders. Further, they face destruction if currents raise them into surface waters and expose them to UV light. There is the problem of their diluted dispersal in the vast volume of sea water -- this makes an encounter with another conspecies host unlikely. That their potential hosts swim and are constantly washed by water currents makes attachment to them difficult. On land, in contrast, there are many protective surfaces (under leaves or in the soil), and the two dimensionality of the environment makes encounters more likely. Land animals have to touch surfaces constantly, but water ones can continually swim without physical contact. Sea vegetation might seem to offer a possible route of transmission but carnivores do not interact with it much, even when preying on creatures that live upon it. This is not to deny that parasites are not common in the sea – many maritime ecto- and endoparasites exist – only that their transmission between competing hosts is unlikely unless there are special circumstances.  

      What is needed for transmission is close contact between conspecies that are in resource or reproductive competition. That entails eating behaviors that bring them to the same resources over which they compete, and reproductive activity that involves internal fertilization. Animals that compete over food but do so without ever physically encountering each other, or spawn their eggs and sperm without females or males touching, will provide little opportunity for commensals to spread from a host to its competitors. Thus if we can show that the evolution of toothed jaws shifted animal behavior such that they started to meet their rivals when eating or that they shifted to having sexual intercourse, then the above ideas about interhost competition become plausible.  

      There is uncertainty about how extinct jawless vertebrates fed. A long held story of the origins of vertebrates has a shift happening during the Silurian age from microphagous into macrophagous eating. The evolution of the jaw improved ventilation needed for an active predator way of life, and this in turn created an organ that made predation super efficient -- a mouth into which could be fitted razor sharp teeth (Purnell, 2001a). The evidence is not so much mixed as insufficient. One main group of extinct jawless fish, the heterostracans, have been shown from microware upon their feeding apparatus to be microphagous suspension feeders (Purnell, 2001b). On the other hand, the feeding apparatus of Conodonts reveal them to be macrophagous.  

      Possessing a toothed jaw closely links to an animal having a carnivorous diet. Already one theory has made a link between such a diet and the evolution of the adapted immune system. According to Takeshi Matsunag and Arman Rahman (1998), the adapted immune system arose to combat increased injury to the gastrointestinal tract when jawed carnivores ingested the hard parts – shells and bones – of prey, and the increased numbers of pathogens coming into them from ingested guts contents. In regard to the latter point, it might be noted (though not by the authors) that sharks commonly eat not only other sharks but conspecies sharks so there is real possibility of species specific pathogens spreading in this way both in modern and extinct jawed vertebrates. However, while sharks do have problems with hard parts, an adaptation exists to cope with this in the form of regurgitating their stomachs by turning them inside out through their mouths like an inverted balloon (Carwardine & Watterson, 2002: p. 68). Given this is an easily evolved adaptation, it is unlikely that ancient jawed vertebrates did not use it making Matsunag and Rahman’s theory unnecessary.  

      However, a carnivorous diet might in other ways cause problems that would favor internal commensals. Sharks are known to have specialized higher vertebrate external commensals – cleaner fish – for dealing with the problems of parasites that attach to their teeth. Vegetarian fish due to the low value of their food lack such parasites and so the need for such commensals. This provides a precedence for the possibility that internally sharks also use commensals but of a microscopic type to control parasites that live within their intestine. This is though a weak argument since internal parasites are mostly a problem because they live off the host and this is something that also applies to vegetarians.  

      Though modern sharks are not direct descendents of the first jawed vertebrates, they can be taken as representative of them, both due to them sharing much the same jaw and body anatomy, and phylogenic relatedness. By examining sharks, two areas can be proposed in which jaws increased greatly the opportunity of commensal transfer between competitors: necrophagous communal eating of large corpses -- and sexual contact.  

      Communal eating and commensal transfer between jawed vertebrates. 

      Vertebrates are not the only creature with a jaw like structure as several beaked carnivorous invertebrates exist such as squid and octopuses. One might also add that other invertebrates such as lobsters have jaw equivalents in the form of their pincers.  

      However, a peculiarity exists that is unique to jawed sea vertebrates: lack of manipulative organs. Squid and octopuses have tentacles that not only catch prey but also handle them; lobsters have mandibles and feet for these functions. Many invertebrates use poison to kill or paralyze their prey because their means of handling them are soft and so vulnerable. In contrast, sharks use their dentition both to slice off flesh for ingestion and for engaging flesh prior to ingestion. This might seem a minor point. But manipulative organs effect the commensality of carnivores. Due to its tentacles, an octopus first engages with its prey using its arms and then these deliver the flesh of its prey to its beak which then ingests it. As a result, two or more octopuses will be less likely to engage with the same large corpse whether killed or scavenged: (a) the animal risks having its arms attacked by the other octopuses, and (b) the arms greatly increase its control over a corpse preventing other octopuses competing to obtain its flesh. In contrast, a jawed fish holds and slices flesh with the same implement of its mouth. A jaw thus does not allow a single carnivorous fish to control a corpse allowing many to feed off it in a ‘feeding frenzy’. Reflecting this, animals with beaks have mouths that are relatively small compared to their body size (they can hold a corpse and take many bites), while jawed vertebrates posses mouths that can extend to accommodate a large – compared to body size – ingestion (they cannot assume they will have a second opportunity to bite). In consequence, carnivorous vertebrates will occasionally (though of course not always) share a corpse with their conspecies allowing for commensal transfer through the oral contamination of the mutual food source. This will provide a route by which oral commensals can transfer between individuals, moreover, ones that are in direct resource competition.  

      Given the cannibalistic eating by sharks, it might be possible that internal parasites are much more likely to spread via direct ingestion. Of course, if a commensal spreads in such a way, the original host does not gain a fitness benefit (unless some immunity to this pathogen is carried genetically by their descendents). This form of potential transfer, moreover, is not unique to jawed vertebrates.  

      Sexual contact. 

      While the life style of early gnathostomes is unknown, some inferences can be drawn from their modern Elasmobranchii descendents. 60% of shark and ray species internally gestate eggs with live-bearing having evolved independently 9-10 times, and maternal care 4-5 times (Dulvy & Reynolds, 1997). Where studied, multiple paternity occurs (Carrier, Murru, Walsh & Pratt, 2003), for example in one female genetic testing found her 32 pups came from at least four fathers (Saville, Lindley, Maries, Carrier & Pratt, 2002). Reflecting this parental investment, courtship and sexual selection occurs widely in modern day sharks (Pratt & Carrier, 2001). This would appear to directly link to the carnivorous life style that associates with carnivorous jawed vertebrates (there are no herbivorous Elasmobranchii). Predators usually are K environment selected species. Sharks are remarkably slow maturers -- some female spiny dogfish do not reach sexual maturity until 35 years of age (Carwardine & Watterson, 2002: p. 72). K selection favors high investment in young. In sharks this is reflected in such things as viviparity and ovoviviparity, and a long duration of gestation (16 months in the Tiger and Blacktip sharks). High material investment links with courtship, mate selection and internalized fertilization (some female sharks also retain sperm for months or even years). Though misnamed by Aristotle, the sharks have a penis equivalent called the “claspers”. Mating involves the male biting the female on her back or her fins which results in injuries -- the areas of such skin to prevent this have become three fold thickened. While these comments apply to modern Elasmobranchii, they reflect the niche in which they exist, and the fact they are toothed jawed vertebrates. Ancient jawed vertebrates are likely to have exploited a similar niche and been shaped by similar factors in their lifestyle.  

      Sexual intercourse and the close proximity in courting and mating raises the possibility of clocea related commensal transmission. The clocea functions both as an exit for the gastrointestinal tract and an opening to the reproductive organs. Sharks have two uteruses and modern researchers are able to pass endoscopes up into them (Carrier, Murru, Walsh & Pratt, 2003). Thus mobile commensals from the gastrointestinal tract can pass directly via the clocea into the female’s reproductive system. Further, commensals that can attach themselves to male claspers or are able to infect their testes and enter spinal fluid will be able to pass venereally between clocea and reproductive systems. One research group has already observed this risk, “the development of vivipacity may have created a necessity for immunocompetence at this [reproductive tract] mucosa as a result of infection of this mucosa by transfer of micro-organisms or other pathogens on the claspers of the male during mating or by passive entry at other times” (Hart, Wrathmell, Doggett & Harris, 1986: p. 601). Such venereal commensals could cause sterility in a number of ways including blocking the channels through which eggs and embryos pass or by eating eggs, sperm, or the egg case secretions of the nidamental glands.  

      The movement of eggs down the oviduct and the genital track are at particular risk of commensals that alter its environment such as to either infect the eggs, interfere with the fertilization process, the nidamental glands that add of egg casing and albumen, or block its passage by inducing inflammation. As a result, pathways exist for venereally transmitting commensals between individuals that are in sexual competition. For example, a female mating with multiple mates will be able to use them as vectors to pass on reproductive tract commensals to other females in which she is in competition. Commensals adapted to the reproductive organs of one host if venereally transmitted to another could decrease the fecundity of their conspecies rivals. A female, for example, might be able to advantage a venereal symbiont that could infect males that mated with her. These males in turn would transfer this commensal to their future female partners thus reducing the fecundity of her competitors.  

      Consequences upon pathogen evolution. 

      This theory suggests that a three-way coevolution exists between primary hosts (evolving subclinical carrying of pathogens), secondary hosts (fighting pathogens) and pathogens. Interhost competition through commensals will cause later generations: (1) to face pathogens that would not otherwise have existed, and (2) evolve the immune system and a pathogen’s ability to live with it in ways that neither the immune system nor pathogens would have otherwise developed. This three-way coevolution would imply that our present understanding of what drives pathogen and immune evolution may be defective.  

      All pathogens come with multiple tools for entering the host and subverting or counter-acting the host’s immune response to them. According to the standard received two-way view of host pathogen coevolution, every stage of this obstacle course is set up against pathogen survival. There are problems with this two-way coevolution approach, however. Notably, how is it that sufficient individual pathogens can survive each stage of the obstacle course for the pathogen to have sufficient chance to select means to overcome the next ones it encounters? The initial lines of innate defense are effective in destroying most pathogens (invertebrates, after all, manage to survive them without any further protection). Thus only a few pathogens will progress to the next stage. These, however, due their lack of number will lack the genetic variation of the initial pathogen population. In spite of this, individuals amongst them must be able to mutate new innovations to overcome the new immune obstacles they now find placed in their way. If there were only a few obstacles, a two-way coevolution might still be sufficient. But pathogens such as TB have more than a few innovations that ensure their survival. What is puzzling here is that higher vertebrates have gained so little advantaged by having the additional line of defense offered by adaptive immunity. This should have provided a strong barrier to pathogens getting sufficient foothold, to be in a position to survive and so evolve means to subvert a host’s defenses. Maybe these survival tools owe their existence to infections originally in immune compromised individuals. And pathogens have advantages such as a much shorter reproduction time then their hosts and many tens of millions of years in which to evolve – and, of course, horizontal sharing of successful solutions. But the possibility needs to be raised whether this provides sufficient explanation.  

      The two-way view of coevolution also presumes that the host’s immune system has been always selected in regard to providing a better and better system to tend off pathogens. Yet the immune system of jawed vertebrates with both its innate and adaptive arms does not provide better protection than the more limited innate based one of invertebrates. The improvements that have happened with homothermic animals such as somatic hypermutation and antigen selection have not made mammals and birds less prone to disease. Why has its sophistication yielded so little benefit? If we were to insert the adaptive immune system found in mammals into invertebrates, one would imagine that they would become completely free of pathogens. Certain immune obstacles should provide sufficient barriers that they completely stop pathogen evolution. Again one can argue that this underestimates the power of pathogens given their rapid generational time and so capacity to evolve. Further, it might be argued that if the immune system was successful in eliminating pathogens, it would cease to be under selective pressure, and so would weaken to the point that it allowed pathogens a foothold again. However, even if all pathogens ceased, the adaptive immune system would still be under selection pressure due to its role in the surveillance of genetic abnormal cells (neoplasms). The point is not that the two-way host pathogen coevolution is not plausible – it is in certain circumstances, but whether the two-way coevolution approach is so outstandingly successful that it rules out the exploration of alternative scenarios of pathogen evolution.  

      Paradoxically, much of the study of pathogen evolution now involves three-way coevolution. Due to the human innovation of antibiotics, pathogens now evolve in regard not only to the immune system but the medical ability to control them. Such medical control itself due to pathogen resistance has had to evolve (through scientific research) new antibiotics, thus making itself an additional factor in pathogen evolution. 450 millions years I suggest another earlier different three-way coevolution started with jawed vertebrates and their pathogens.



        Agrawal. A., Eastman, Q. M., & Schatz,  D. G. (1998). Transposition mediated by RAG1 and RAG2 and its implications for the evolution of the immune system. Nature, 394, 744–751.

        Ahlberg, P.E. (2001). Major Events in Early Vertebrate Evolution: Paleontology, Phylogeny, Genetics & Development. New York: Taylor & Francis.

        Beg, A. A. (2004). ComPPARtmentalizing NF-κB in the gut. Nature Immunology, 5, 13-16.

        Burnet, M. (1959). The clonal selection of acquired immunity. Cambridge: Cambridge University Press.

        Carrier, J. C., Murru, F. L., Walsh, M. T. & Pratt, H. J. (2003). Assessing reproductive protential and gestation in Nurse Sharks (Ginglymostoma cirratum) using ultrasound and endoscopy. Zoo Biology, 22, 179-187.

        Carwardine, M. & Watterson, K. (2002). The shark watchers guide. London: BBC Publications.

        Castro, G.A. & Arntzen, C. J. (1993). Immunophysiology of the gut: a research frontier for integrative studies of the common mucosal immune system. American Journal of Physiology (Gestroinstestine and liver physiology), 265, G599-G610.

        Diaz, M., Greenberg, A. &  Flajnik, M. F. (1998). Somatic hypermutation of the new antigen receptor gene (NAR) in the nurse shark does not generate the repertoire: Possible role in antigen-driven reactions in the absence of germinal centers. Proceedings of the National Academy of Sciences, USA, 95, 14343-14348.

        Dobson, S. L., Rattanadechakul, W. & Marsland, E. J. (2004). Fitness advantage and cytoplasmic incompatibility in Wolbachia single- and superinfected Aedes alopictus, Heredity, 1-8 [Epub ahead of print]

        Dower, S. K. (2000). Cytokines, virokines and the evolution of immunity. Nature Immunology, 1, 367-368.

        Dulvy, N. K. & Reynolds, J. D. (1997). Evolutionary transitions among egg-laying, live-bearing and maternal inputs in sharks and rays. Proceedings: Biological Sciences, 264, 1309-1315.

        Furness, J. B., Jones, C., Nurgali, K., & Clerc., N. (2004). Intrinsic primary afferent neurons and nerve circuits within the intestine. Progress in Neurobiology, 72, 143-164.

        Gewirtz, A. T. & Madara, J. L. (2001). Peroscope, up! Monitoring microbes in the instestine. Nature Immunology, 2, 288-290.

        Green, B.T., Lyte, M., Kulkarni-Narla, A. & Brown, D. R. (2003). Neuromodulation of enteropathogen internalization in Peyer's patches from porcine jejunum. Journal of  Neuroimmunology, 141, 74-82.  

        Hansen, M. B. (2003). The enteric nervous system I: organisation and classification.. Pharmacology and Toxicology, 92, 105-113.  

        Hanssen, S. A., Hasselquist, D., Folstad, I. & Erikstad, K. E. (2004). Costs of immunity” immune responsiveness reduces survival of a vertebrate. Proceedings of the Royal Society, London B, 271, 925-930.

        Hart, S., Wrathmell, A. B., Doggett, T. A. & Harris, J. E. (1986). Aspects of the immunology of the female genital tract of the elasmonrach, Scyliorhinus canicula, L. Developmental and Comparative Immunology, 10, 597-602.

        Holzer, P., Michl, T., Danzer, M., Jocic, M., Schicho, R. & Lippe,  I. T. (2001). Surveillance of the gastrointestinal mucosa by sensory neurons. Journal of Physiology and Pharmacology, 52, 505-521.  

        Hooper, V. L., Bry, L., Falk, P. G. & Gordon, J. I. (1998). Host-microbial symbiosis in the mammalian intestine: exploring an internal ecosystem. BioEssays, 20, 336-343.

        Hughes, A. L. (2002). Natural selectiona and the diversification of vertebrate immune effectors. Immunological Reviews, 190, 161-168.

        Johanson, Z. & Meredith Smith, M. (2003). Placoderm fishes, pharyngeal dentricles and the vertebrate dentition. Journal of Morphology, 257, 289-307.

        Kaufman, J. (2002). The origins of the adaptive immune systems: whatever next? Nature Immunology, 3, 1124-1125.

        Klimovich, V. B. (2002). Actual problems of evolutionary immunology. Journal of Evolutionary Biochemistry and Physiology, 38, 442-451.

        Kraehenbuhl, J-P. & Corbett, M. (2004). Keeping the gut microflora at bay. Science, 303, 1624-1625.

        Krammer,  H. J. & Kuhnel, W. (1993). Topography of the enteric nervous system in Peyer's patches of the porcine small intestine. Cell and Tissue Research, 272, 267-72. 

        Laird, D. J., De Tomaso, A. W., Cooper, M. D. & Weissman, I. L. (2000). 50 million years of chordate evolution: seeking the origins of adaptive immunity. PNAS, 97, 6924-6926.

        Lee, S. S., Tranchina, D., Ohta, Y., Flajnik, M. F. & Hsu, E. (2002). Hypermutation in shark immunoglobulin light chain genes results in contiguous substutions. Immunity, 16, 571-582.

        McFall-Ngai, M. J. (2002). Unseen forces: The influence of Bacteria on animal development. Developmental Review, 242, 1-14.

        Macpherson, A. J. & Therese, U. (2004). Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria. Science, 303, 1662-1665.

        Mallett, J. (1996). Ventilation and the origin of jawed vertebrates: a new mouth? Soological Journal of the Linnean Society, 117, 329-404.

        Marchalonis, J. J., & Schluter, S. F. (19980. A stochastic model for the rapid emergence of specific vertebrate immunity incorportating horizatonal transfer of systems enabling duplication and combinatorial diversification. Journal of Theoretical Biology, 193, 429-444.

        Marchalonis, J. J., Kaveri, S., Lacroix-Desmazes, L., & Kazatchkine, M. D. (2002). Natural recognition repertorie and the evolutionary emergence of the combinatiorial immune system. FASEB Journal, 16, 842-858.

        Matsunag, T. & Rahman, A. (1998). What brought the adaptive immune system to vertebrates? – The jaw hypothesis and the seahorse. Immunological Reviews, 166, 177-186.

        Mayer, W. E., Uinuk-ool, T., Tichy, H., Gartland, L. A., Klein, J. & Cooper. A. D. (2002). Isolation and characterization of lymphocyte-like cells from a lamprey. PNAS, 99, 14250-14355.

        Meredith Smith, M. & Johanson, Z. (2003). Separate evolutionary origins of teeth from evidence in fossil jawed vertebrates. Science, 299, 1235-1236.

        Miller, R. F., Cloutier, R. & Turner, S. (2003). The oldest articulated chondrichthyan from the Early Devonian period. Nature, 425, 501-504.  

        Nagler-Anderson, C., Bhan, A. K., Podolsky, D. K. & Terhorst, C. (2004). Control freaks: Immune regulatory cells. Nature Immunology, 5, 119-122.

        Palmer, J. M. & Greenwood-Van Meerveld, B. (2001). Integrative neuroimmunomodulation of gastrointestinal function during enteric parasitism. Journal of  Parasitology, 87, 483-504.

        Parham, P. & Ohta, T. (1996). Population biology of antigen presentation by MHC class 1 molecules. Science, 272, 67-74.

        Pratt, H.L. & Carrier, J.C. (2001). A Review of Elasmobranch Reproductive Behavior with a Case Study on the Nurse Shark, Ginglymostoma Cirratum. Environmental Biology of Fishes,  60,157-188.

        Purnell, M. A. (2001a). Scenarios, selection and the ecology of early vertebrates. In Major Events in Early Vertebrate Evolution: Paleontology, Phylogeny, Genetics & Development. (Editor, P. E. Ahlberg),  pp 187-207,  New York: Taylor & Francis.

        Purnell, M. A. (2001b). Feeding in extinct jawless heterostracan fishes and testing scenarios of early vertebrate evolution. Proceedings of the Royal Society, London B, 269, 83-88.

        Rast, J. P., Anderson, M. K., Strong, S. J., Luer, C., Litman, R. T. & Litman, G.W. (1997). α, β, γ and δ T cell antigen receptor genes arose early in vertebrate phylogeny, Immunity,  5, 1-11.

        Rinkevich, B. (1999). Invertebrates versus vertebrates innate immunity: In the light of evolution. Scandinavian Journal of Immunology, 50, 456-460.

        Rinkevich, B. (2004). Primitive immune systems: Are your ways my ways? Immunological Reviews, 198, 25-35.

        Ruby, E. Henderson, B. & McFall-Ngai, M. (2004). We get by with a little help from our (little) friends. Science, 303, 1305-1307.

        Sakaguchi, S. (2003). Regulatory T cells: Mediating compromises between host and parasite. Nature Immunology, 4, 10-11.

        Saville, K.J., Lindley, A.M., Maries, Carrier, J.C. &  Pratt, H.L. (2002). Multiple Paternity in the Nurse Shark, Ginglymostoma Cirratum. Environmental Biology of Fishes, 63, 347-351.

        Schluter, S. F., Bernstein, R. M., Bernstein, H. & Marchalonis,  J. J. (1999). ‘Big Band’ emergence of the combinational immune system. Developmental and Comparative Immunology, 23, 107-111.

        Stewart. J. (1992). Immunoglobulins did not arise in evolution to fight infection.  Immunology Today, 13, 396-399.

        Sutton, T. L., Martinko, T., Hale, S. & Fairchok, M. P. (2003). Prevalence and high rate of asymptomatic infection of Chlamydia trachomatis in male college Reserve Officer Training Corps cadets. Sexually Transmitted Diseases, 30, 901-904. 

        van Benten, I., Koopman, L., Niesters, B., Hop, W., van Middelkoop, B., de Waal, L., van Drunen, K., Osterhaus, A., Neijens, H. & Fokkens, W. (2003). Predominance of rhinovirus in the nose of symptomatic and asymptomatic infants. Pediatric Allergy and Immunology, 14, 363-370.

        van den Berg, T. K., Yoder, J. A. & Litman, G. W. (2004). On the origins of adaptive immunity: innate immune receptors join the tale. Trends in Immunology, 25, 11-16.

        Van Regenmortel, M. H. (1998). From absolute to exquistie specificity. Reflections on the fuzzy nature of species, specificity and antigenic sites. Journal of Immunological methods, 216, 37-48.

        Xu, J. & Gordon, J. I. (2003). Honor thy symbionts. PNAS, 100, 10452-10459.

        Yang, G. B. &  Lackner, A. A. (2004). Proximity between 5-HT secreting enteroendocrine cells and lymphocytes in the gut mucosa of rhesus macaques (Macaca mulatta) is suggestive of a role for enterochromaffin cell 5-HT in mucosal immunity. Journal of Neuroimmunology, 146, 46-49.  

        Zahavi, A & Zahavi, A. (1997). The handicap principle. New York: Oxford University Press.


Recent Search:

Set Home | Add to Favorites

All Rights Reserved Powered by Free Document Search and Download

Copyright © 2011
This site does not host pdf,doc,ppt,xls,rtf,txt files all document are the property of their respective owners. complaint#downhi.com