posted 18. March 2003 21:37                   

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I hope my post cleared things up.

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We can look high or we can look low, in books or in journals, but the result is the same. The scientific literature has no answers to the question of the origin of the immune system. (Behe, 1996, p. 138)

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Here is my functional definition of effective antibodies with respect to immunity:

1. The ability to be specific
2. The ability to exhibit great diversity.
3. The ability to neutralize toxins
4. immobilization of microorganisms.
5. neutralization of viral activity
5. clumping together of microogranisms.
6. binding to soluble antigen for the formation of precipitates.
7. activating complement
8. Being able to cross the placenta from the mother to the fetus.

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A more detailed model could proceed as follows (adapted from Lewis 1999): A transposon containing the RAG genes and flanked by RSSs integrates itself into the gene for a primordial antigen-receptor gene, splitting it into two gene segments (V and J). The locus itself is transciptionally inactive in most cell types, and prevents the expression of the RAG genes and removal of the integrated transposon. However, in a lymphocyte-like cell, the locus becomes transcriptionally active, and the RAG genes express themselves and remove the transposon, reuniting the two gene segments. The imprecise joining process generates a level of receptor diversity that favors the organism bearing this transposon, and its descendants thrive with the increased immune capabilities. The gene duplicates, creating multiple pairs of V and J segments, such as those found in sharks, which further increases diversity (Marchalonis, Schluter et al. 1998). Later, the entire locus duplicates, and the two lineages form the heavy and light chains. A gene duplication creates a second locus, and the two lineages become the heavy and light chains. Further gene duplications create additional V, and J gene segments, and an incorrect recombination event creates the D segment. Lastly, a whole genome duplication event creates the genes which would later become the T cell receptors. The steps of this model are based on comparisons between these genes and between those genes in different jawed vertebrates, the details of which will not be discussed in this article (for review see Du Pasquier 2000).

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Of course then you have the memory response, which provides an obvious selective advantage to someone who survives the initial attack (an example of natural selection used by intelligent design).

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With the precursor you describe, the minimal complexity of the recombination machinery is most appreciated. With those organisms that just have innate receptors, or even one or two antibodies, are in an arms race that may be too much for them.

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Just as the Red Queen said, "Sometimes it takes all the running I can do to stay in the same place." At least thats Behe's point. I think thats why it's most parsimonous to say that it arrived in large vertebrates or at least was in wait for large vertebrates, as the result of a lateral gene transfer event.

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I think this also an example that shows just how much intelligent Front-Loading is different from gradual Darwinian evolution, but I digress.

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posted 18. March 2003 23:45                   

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for any organism to have an immune system akin to that seen in mammals, the minimally required molecules are the antigen receptors (immunoglobulin and TCR), the antigen presentation molecules (MHC), and the gene rearranging proteins.

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I think Behe's point here is that there is a dangerous gap between the jump from innate immunity to acquired immunity, acquired immunity is largely successful because it can generate specificity for any kind of foreign substance. Innate immunity cannot. And then there's the fact that if innate immunity consisted of receptors with single specificities, then the likelihood of a foreign substance being recognized diminishes. Even if there are some innate receptors or something like them, with single specificities, a handful of them wouldn't be enough. Which is why Behe says that a system with only a few antibodies are "not sufficient to make a difference". Bacteria would likely be able to evade, or develop resistance to those few antibodies. It has to make a lot and it has to make them fast.

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The similarity of RAG1 to bacterial transposases, the absence of introns in the RAG genes and their abrupt appearance in sharks has led to the suggestion that these jumped into the genome as a lateral gene transfer event. If so this is a remarkable story – that two different genes jumped into the germs cells of an agnathan, integrate into an Ig molecule and then generate the diversity of antibody and TcR molecules. At essentially the same time we get the MHC genes (see below) and probably the jaw and thymus to boot.

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But let’s suppose that eventually a precursor to the current TcR and Ig genes is identified. Does that solve the problem of the immunological “big bang”? Hardly, we are talking about a system that involves 1% of the vertebrate genome. The T cell receptor signaling system is the most complicated signaling receptor system I know of and we still do not know all the parts or what they all do. Beyond that once you can generate combinatorial immunity you now have the potential to damage or kill or damage yourself. Thus it is hard to see how combinatorial immunity can operate without the clonal deletion / selection systems in place and indeed, given the present resolution that is available to us, the thymus appears at the same time (i.e. in sharks) as the combinatorial immune system.

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posted 19. March 2003 01:16                

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It is simply false that all cases of biological complexity are a matter of degree. In fact, this is the point about bringing up IC systems. You see, with IC systems you don't have "degrees". You either have it or you don't.

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It would not be the first time that a secretory system was co-opted into motility, as the cyanobacteria have co-opted a carbohydrate export system to produce gliding motion.

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Yersinia, you misinterpreted my posts here. I am defending Behe's assertion that the VDJ recombinase/antigen receptor is IC. This is correct, you can't have one without the other and still get antibody diversity. The IC nature of the VDJ recombinase/antigen receptor is all or nothing.

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posted 19. March 2003 01:35                   

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Since RAG1 and RAG2 were identified, their evolutionary origin has been an intriguing riddle. We demonstrated in a series of in vitro experiments that RAG1 and RAG2 have an evolutionarily ancient activity, that of transposition—the movement of DNA segments, termed transposons, from one location to another. Transposons are a ubiquitous feature of the genetic structure of life on earth and have been a major force in the evolution of the genome in essentially all organisms from bacteria to humans. Our results revealed that RAG1 and RAG2 can perform a DNA transposition reaction essentially identical to that performed by well-studied bacterial transposition enzymes. After excising a piece of DNA flanked by two RSSs from one location, RAG1 and RAG2 can insert this fragment into a new location in another DNA molecule. This finding provides dramatic support for the theory that RAG1 and RAG2 were once components of a transposable element and that about 500 million years ago this element found its way into the genome of an early vertebrate ancestor. Once present in the genome, this RAG transposon could jump to new locations, and in one of these events, it is postulated to have landed in the middle of a receptor gene, splitting it into two pieces. This split gene is hypothesized to be the evolutionary precursor of all antigen receptor genes.

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Early on, it was suggested that the V(D)J recombination system might have arisen by the fortuitous integration of a transposable element into an ancestral antigen-receptor gene [14]. This hypothesis was strengthened by the discovery that the RAG genes are tightly linked [7], and by the finding that the RAG proteins can act as a transposase. Thus, a plausible model for the acquisition of the V(D)J recombination system during vertebrate evolution is the integration of a transposable element carrying the linked RAG genes into a primordial antigen-receptor gene in an ancestral jawed vertebrate, approximately 450 million years ago (reviewed in [1,11]). Presumably, this initial integration event created the first rearranging antigen-receptor gene; subsequent gene duplication events then created the multiple immunoglobulin and T-cell receptor loci

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Several lines of evidence suggest that the modern immunesystem may have evolved from an ancient
transposon. The organization of the RSSs at the immunoglobulin and T cell receptor loci is reminiscent of the sequences at the ends of transposable elements (Sakano et al., 1979; Thompson, 1995). The close linkage of the RAG1 and RAG2 genes, together with the sudden appearance of recombinatorial immunity in evolution also argues for derivation from a mobile DNA species (Oettinger et al., 1990). Recently, this connection has been supported by studies from our laboratory and others, showing similarities between reactions of the RAG faproteins and the strand transfer reactions of retroviruses and transposons.

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Most strikingly, the RAG proteins have been shown
to carry out a transpositional strand transfer that is very similar to the reactions of known transposases (Agrawal et al., 1998; Hiom et al., 1998).

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posted 19. March 2003 03:01                   

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Yersinia, you misinterpreted my posts here. I am defending Behe's assertion that the VDJ recombinase/antigen receptor is IC. This is correct, you can't have one without the other and still get antibody diversity. The IC nature of the VDJ recombinase/antigen receptor is all or nothing.

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Secondly, my laundry list was not meant to describe the IC "core" of an antibody. Just some of the features needed for a group of effective antigen receptors with respect to immunity.

Of course there are some Igs that are not passed from mother to baby (IgM), but I'm not familiar with any vertebrate that does not have an immunoglobulin that cannot pass from mother to baby. Maybe you can educate me in that one.

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Also you are repeating Inlay's mistake in saying that innate receptors with single specificities are equivalent to antibodies. That is false.

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Nat Immunol 2002 Dec;3(12):1200-7

Identification of diversified genes that contain immunoglobulin-like variable regions in a protochordate.

Cannon JP, Haire RN, Litman GW.

Immunology Program, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Avenue, Tampa, FL 33612, USA.

The evolutionary origin of adaptive immune receptors is not understood below the phylogenetic level of the jawed vertebrates. We describe here a strategy for the selective cloning of cDNAs encoding secreted or transmembrane proteins that uses a bacterial plasmid (Amptrap) with a defective beta-lactamase gene. This method requires knowledge of only a single target motif that corresponds to as few as three amino acids; it was validated with major histocompatibility complex genes from a cartilaginous fish. Using this approach, we identified families of genes encoding secreted proteins with two diversified immunoglobulin-like variable (V) domains and a chitin-binding domain in amphioxus, a protochordate. Thus, multigenic families encoding diversified V regions exist in a species lacking an adaptive immune response.

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Nat Immunol 2002 Dec;3(12):1124-5

Comment on:
Nat Immunol. 2002 Dec;3(12):1200-7.

The origins of the adaptive immune system: whatever next?

Kaufman J.

[...]

The target of this work from the Litman group is, as always, the immunoglobulin (Ig) domain3. As every immunologist knows, Ig domains endow antibodies and T cell receptors (TCRs) with the ability to specifically recognize a wide array of molecular structures, including those from pathogens4. Several different properties and mechanisms have evolved to generate the necessary antibody and TCR diversity5. For example, both antibodies and TCRs are generally encoded by diversified multiple gene families with similar, but nonidentical, sequences. In addition, antibodies and the TCR are generally encoded by variable (V), diversity (D) and joining (J) genomic segments that are assembled by somatic recombination into one gene to generate sequence diversity at the V(D)J junction.

However, Ig domains are not only found in antibodies and TCRs, they also form integral parts of certain natural killer cell receptors (NKRs), as well as major histocompatibility complex (MHC) molecules4. Both NKRs and MHC molecules are also derived from diversified multigene families that lack the Ig recombinational mechanism mentioned above but have extensive allelic and haplotypic polymorphism, which represents another form of diversity. In addition, Ig domains are found in a large number of other molecules that lack extensive diversity and are found on the surfaces of a wide variety of cell types. These include many molecules involved in lymphocyte signaling and adhesion4. Ig domains can also be found in proteins such as muscle proteins and kinases on the inside of cells6. In addition, Ig domains are not restricted to vertebrates, but are found in invertebrates and even in certain bacteria7, 8. Finally, there are various families (or sets) of Ig domains, including the V, C1, C2 and I sets, which differ in the number of -strands and in other sequence features6. As such, Ig domains are clearly one of the major families of the 1000 or so folding patterns that dominate the world of proteins.

Although many other proteins contain Ig domains, the ability of antibodies and TCRs to undergo V(D)J recombination is unique and is considered to be a defining molecular feature of the adaptive immune system. Indeed, the initial event that enabled the emergence of the adaptive immune system is thought to have been the insertion of a transposon into a previously undisrupted V-like exon of an Ig domain-containing gene2, 3, 5. But in which Ig gene did the insertion occur? What did this gene do? In particular, was it involved in some kind of immune recognition, either an innate recognition of pathogen or—given the possibility that the event might have occurred in a colonial organism—an allorecognition of other individuals of the same species? There has been at least one exciting speculative hypothesis concerning the structure and function of the potential ancestral molecule9, but determining the truth of the matter has been difficult.

The obvious approach to answer these questions is to search for a V-like Ig-containing gene in a jawless vertebrate or a nonvertebrate chordate. The trouble is that genomic sequences can change much faster than structure. Although no residues appear absolutely essential for a polypeptide to fold up into an Ig domain, there are a few sequence features that are generally found in V-like sequences, whether from vertebrate proteins such as the TCR or from the Drosophila protein amalgam.

[...]

Are these VCBP genes direct ancestors of the antigen-specific receptors of the adaptive immune system? It is not at all obvious. First, the few chitin-binding sequences described in vertebrates are not associated with V-like Ig domains10. Second, the lack of J sequence motifs (in particular, the lack of GxG) and certain other residues11 suggests that these sequences do not encode the kind of heterodimers (or even homodimers) formed by antibodies or TCR V domains. Third, the VCBPs have two linked V-like domains rather than the V-C1 domains characteristic of antibodies and TCRs. Fourth, the lack of hydrophobic sequences suggests that VCBPs are missing transmembrane regions and are, therefore, unlikely to encode membrane proteins that signal cell activation, in the way that antibodies and TCRs signal lymphocytes. Finally, the kind of diversification described for VCBPs is characteristic of many multigene families with a variety of functions. For instance, the HOX multigene family of transcription factors involved in development has much the same characteristics12, including a lack of diversification by somatic recombination.

This is not to say that the VCBP genes are uninteresting, far from it! The signal sequences suggest that VCBPs are secreted, with the chitin-binding domain potentially involved in recognition of arthropod parasites and the V-like domains mediating an effector function such as binding to phagocytic cells among other possibilities. If true, such genes are an example of the evolution of defense systems that use similar structural domains in functionally different ways. In addition, the approach developed by Litman and colleagues is potentially an important step forward in the search for the ancestor of the adaptive immune system. Having found the VCBPs with certain selection and screening criteria, who knows what might be found the next time if different criteria are used? Whatever next?

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And this brings me to your imaginary scenario where things get by without acquired immunity.

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Indeed, the initial event that enabled the emergence of the adaptive immune system is thought to have been the insertion of a transposon into a previously undisrupted V-like exon of an Ig domain-containing gene 2, 3, 5.

[...]

2. Litman, G.W., Anderson, M.K. & Rast, J.P. Annu. Rev. Immunol. 17, 109-147 (1999). | Article | PubMed |

3. Flajnik, M.F. & Kasahara, M. Immunity 15, 351-362 (2001). | PubMed |

5. Tonegawa, S. Nature 302, 575-581 (1983). | PubMed |

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Generic binders are only analogous to antibodies, as I stated, when you get specific with your scenario, there a lot of "ad hoc penalties" that you don't consider, as I stated:

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I think Behe's point here is that there is a dangerous gap between the jump from innate immunity to acquired immunity, acquired immunity is largely successful because it can generate specificity for any kind of foreign substance. Innate immunity cannot. And then there's the fact that if innate immunity consisted of receptors with single specificities, then the likelihood of a foreign substance being recognized diminishes. Even if there are some innate receptors or something like them, with single specificities, a handful of them wouldn't be enough. Which is why Behe says that a system with only a few antibodies are "not sufficient to make a difference". Bacteria would likely be able to evade, or develop resistance to those few antibodies. It has to make a lot and it has to make them fast.

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You don't factor any of this in your Rudyard Kipling story.

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As for Inlay's scenario, you can see the unselectable steps in that RSS is useless without RAG, even taking transposase function into account.

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And antigen receptors are useless without RSS and RAG.

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Furthermore, he invokes gene duplication without mentioning the fact that many organisms have mechanisms to silence gene duplicates. It's almost like a magic wand.

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Again, more ad hoc penalties.

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I am working on a fuller reply to those points but I want an admission that the RAG, RSS, receptor components are IC.

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And then there's Dr. Peonie's points:

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The origin of virulence is a completely different topic I'm afraid. Billions of invertebrates can't be wrong, but vertebrates can be dead. The "magic line" between small organisms and large organisms is that large organisms have a large library of antigen specific antibodies to choose from when they get attacked. All small animals have is generic binders. This is no good for the vertebrate.

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In this particular case (I'm not as familiar with others) Front-loading is not an emergency back-up system. A lateral gene transfer event is not a Darwinan step by step, gradual pathway, it's the complete opposite of it. Although it may be that "lateral gene transfer" is just a naturalistic way of saying "it just appeared all at once".

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Yersinia, I cannot find where Poenie stated that the complement system evolved. Can you quote him?

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There is much continuity between the innate immunity of lower eukaryotes and
vertebrates but to say that there “are numerous extant organisms getting by with only
pieces of this irreducibly complex system” seems to confuse the two systems
(innate versus adaptive immunity) one of which seems to have a long evolutionary history
and the other that arises dramatically and suddenly in an event appropriately dubbed the
“Immunological Big Bang”

[quoted here; he also had multiple opportunities to clarify himself on this point if he was being misinterpreted, the complement system was brought up alot]

[furthermore he appears to support the LGT origin of RAG, I think initially he was under the impression that I did not]

[In general Poenie appeared at least equally skeptical of IC-->ID arguments as of the evolutionary model for adaptive immunity]

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With respect to transferring acquired immunity to children, this happens. Antibodies passed from the parent to the child protect the kid from infections which IgG is sufficient and for which the mother had immunity. For example, this protects the child from tetanus, diphtheria, measles, poliovirus, mumps, and H. influenzae , S. agalactiae, and this can happen through the first months of life.

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posted 19. March 2003 03:45                

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I guess you can call it IC if you want, it doesn't matter much to me, since you've already acknowledged that non-rearranging receptors maintain effective immune function. By your define-the-function-exceedingly-specifically-in-order-to-maintain-ICness standards, hemoglobin is also IC. I just hope you realize how many easily evolvable things become IC based with your latest version of "function".

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posted 19. March 2003 03:56                   

Testing an image:



Hey cool, it worked. I am posting this for readers having trouble conceptualizing what exactly we are talking about.

It is important to emphasize that Inlay's model did not come out of the blue, it came out of the literature. E.g., the above graphic is Figure 5 from a (2000) article in Annual Reviews of Immunology (ref below). (I think the model is a bit different than Inlays but it is close).

If the figure is confusing, the things to focus on are the little black and white triangles at the ends of the 'ISs' (proto-RSSs), which are the DNA sequences which tell the RAG proteins where to bind and cut out that chunk of DNA.

The hypothesized history of the transposon procedes from top to bottom. The hypothesized history of the immune receptor reads across the bottom from right to left.

Here is the point of all this: Behe's argument was not just that IC was a barrier to evolution; he further argued that biologists had no idea how various IC systems came about, and he supposedly supported this by searching the literature for such proposals, and found none (recall the big '0' Behe likes to put up on the overhead in his talks).

But in the case of the immune system Behe's arguments regarding the literature have proven indefensible.

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Annual Reviews Immunology 2000. 18:495-527.

The RAG Proteins and V(D)J Recombination: Complexes, Ends, and Transposition

Sebastian D. Fugmann1, Alfred Ian Lee1, Penny E. Shockett1, Isabelle J. Villey1, and David G. Schatz1

(presumably free online as you are seeing the graphic)

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posted 19. March 2003 10:37                    

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But anyway, the evolutionary model doesn't say:

1) large, long-lived organism, then
2) adaptive immunity evolved

...it says:

1) small, lamprey-like organism, perhaps slowly increasing in size and carnivory
2) adaptive immunity evolved
3) allowing large, long-lived vertebrates

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posted 20. March 2003 04:04                   

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Nat Rev Immunol 2002 May;2(5):346-53

Evolution of the lectin-complement pathway and its role in innate immunity.

Fujita T.

Department of Biochemistry, Fukushima Medical University School of Medicine, Japan. tfujita@fmu.ac.jp

Discrimination between self and non-self by lectins (carbohydrate-binding proteins) is a strategy of innate immunity that is found in both vertebrates and invertebrates. In vertebrates, immune recognition mediated by ficolins (lectins that consist of a fibrinogen-like and a collagen-like domain), as well as by mannose-binding lectins, triggers the activation of the complement system, which results in the activation of novel serine proteases. The presence of a similar lectin-based complement system in ascidians, our closest invertebrate relatives, indicates that the complement system probably had a pivotal role in innate immunity before the evolution of an adaptive immune system in jawed vertebrates.

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Can anyone come up with a scenario which might explain the prevention of auto-immune disasters during the early evolution of the immune system?

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