Mechanism for complement pathway evolution

ok so, everyone has read or at least heard of Behe's book. I did a search before posting this b/c I'm a newbie and figured this had been previously discussed, however I didnt see a topic it had been.The topic at hand is the complement pathways (classical, atlernative, & lectin)The question is: "Is the evolution (as in goo-to-you evolution) of these pathways possible? or are they indeed irreducibly complex?"-it has been discussed that MASP (from the lectin pathway) can act as a C3 convertase, however it does an extremely bad job of it.-what chemicals acted as opsonins & chemotaxins before complement components? where might they have come from?-at some point a population of organisms had to go from not having any complement components, to having 1, or 2, or more. How did they come about, and then how did the subsequent system come about?many more questions could be asked, but you all get the point.

Thread moved here from the Proposed New Topics forum.

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-what chemicals acted as opsonins & chemotaxins before complement components? where might they have come from?

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I can partially answer this one. The earliest innate immunity came from toll receptors. These receptors were first found in fruit flies and have since been found in almost all life that has an immune system, including mammals. Toll receptors, or toll like receptors (TLR's) as they are named in non-insect species, are less specific than antibodies but similar to C5 in their ability to bind to antigens. Often, TLR's bind to bacterial flagella or viral proteins. The humoral immune system (white blood cells, etc) developed on top of the TLR system as a quicker and more specific response to infection. TLR's are one of the bigger discoveries in the last 15 years within immunology. Others in my lab group are actually studying TLR's as we speak.I will do some research and see if I can't come up with the origin of toll proteins. Hope this answers at least one question.

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The earliest innate immunity came from toll receptors.

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how is it determined that the TLR's came before C5 and other complements. In other words, how exactly is the chronology determined?

Why don't you think about that a minute?Can you think of a way of determining the probable order?

maybe i can, but I didn't ask if I could. I'm asking what others(namely Loudmouth & those he works with) DO in order to determine chronology, because i feel it is relevent and is a viable question.

Looking for an answer from the experts here.Rather that than making up my own.

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how is it determined that the TLR's came before C5 and other complements. In other words, how exactly is the chronology determined?

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The order is determined by phylogenetics. That is, "simpler" life has TLR's but not complement.

That leaves me wanting a more detailed explanation.

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That leaves me wanting a more detailed explanation.

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Ok, ok. I'll try to get some research done today. I am a little curious as to the details myself. It could be that complement developed before white blood cells being that complement can destroy infectious organisms without the aid of WBC's. Complement may have taken on the role of an opsonin during the evolution of WBC's.opsonins = molecules that "tag" bacteria, viruses, antigens, etc. for destruction by the WBC's.

Here it goes. After scouring the primary lit., I found a site that has a great summary on the evolution of the complement system. It is found here. The link will send you to the "evolution and development" section, but the rest of the page is worth a read as well. All of my quotes will come from this site (ignore the footnote numbers) written by John D. Lambris, PhD.It appears I was wrong about complement first being lytic and later being opsonic. It is actually the opposite. The earliest complement-like proteins can be found in sea urchins: "Although complement-like activity has been detected in a variety of invertebrates 72 , the sea urchin (echinoderm phylum) is the most ancient species from which a complement-like component with a high sequence similarity to gnathostome C3 has been purified 73 ." (gnathostome, I am assuming, is referring to jawed vertebrates).Moving up the ladder, we come to the urochordates, an invertebrate chordate that is at the base of the chordate phylum. These creatures have a notochord and central nervous system. They also have a C3 component but lack the lytic (pore forming) pathway fond in higher vertebrates. "In collaboration with Dr. Maria Rosario Pinto’s laboratory in Naples, Italy, we recently demonstrated the presence of two C3-like genes in the invertebrate urochordate Ciona intestinalis 76 . We indicated the presence of their transcription products in blood cells and the encoded proteins in the body fluid. This study provides further insight into the evolutionary origin of the ancestral molecules that gave rise to the different members of the a(2)macroglobulin family of thiol- ester containing proteins (C3, C4, a2macroglobulin)."Next, we move to cartilaginous fish, such as sharks and rays. These are the lowest vertebrates that have the classical complement pathway, or the lytic complement pathway. "The earliest species from which lytic C’ components have been identified are the cartilaginous fish (e.g., sharks) 77 . These animals are also the first to possess an adaptive immune system and the classical pathway of complement activation. Although all three C’ activation pathways have been shown to be present in cartilaginous fish, the nature and similarities of the complement molecules are still ill-defined."So it would seem that complement served a basal role in early innate immunity. Only later, with the advent of an adaptive immune system, did the complement system take on a lytic role. For those who want to do some additional research, agnatha (jawless fish such as lampreys and hagfish) would seem to be the obvious place for further research. I'll look around, but I wasn't able to dig anything up in the first go around.To answer the OP, the complement system, as it is fond in jawed vertebrates, is not irreducibly complex (IC). The classical pathway is not present in lower phyla but yet complement still has a role as an opsonin. That is, you can remove parts of the classical complement pathway and function still exists. The evolution of the classical pathway is not well known, but IC, as in other biological systems, does not pose a problem for the evolution of this system. Complement and TLR's were an adequate system for invertabrate immunity, but advances, such as the adaptive immune system and the classical complement pathway, evolved to increase the response to infection and to also decrease the occurence of autoimmunity that the innate immune response can cause if allowed to run unchecked.Any questions?

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"This study provides further insight into the evolutionary origin of the ancestral molecules that gave rise to the different members of the a(2)macroglobulin family of thiol- ester containing proteins (C3, C4, a2macroglobulin)."

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How so? Yes the study indicated "the presence of their transcription products in blood cells and the encoded proteins in the body fluid," but what insight, exactly, does this afford as to the origin of ancestral molecules?

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How so? Yes the study indicated "the presence of their transcription products in blood cells and the encoded proteins in the body fluid," but what insight, exactly, does this afford as to the origin of ancestral molecules?

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Man, you guys are making me work on this one.First, we need to look at the importance of urochordates (sea squirts specifically) in vertebrate evolution. The adult form of the sea squirt is interesting (the tube like thing in this picture) but the real amazing aspect is the larval form. At this stage in life the larva has a notochord that stiffens the tail, a structure that is absorbed by the larva before adult stage. Although it is difficult to see in the photo below, the notochord runs the length of the tail. Also notice the resemblence between a tadpole and the larval stage of the sea squirt. The notochord, in vertbrates, becomes the backbone. So, while sea squirts are not truly vertebrates, they are nonetheless in the ancestral line of all vertebrates. So, if we are looking for things that evolved in vertebrates it is best to start with the urochordates. This is why the sequencing of the sea squirt genome is so important. It gives us a glimpse of the genes that possible gave birth to other systems, such as the complement pathway, in higher vertebrates.In this recent study by Nonaka and Yoshizaki (2004), they found that the complement like proteins (not yet true complement) are actually proteins resulting from the reshuffling of even more ancient proteins. I will bold the important parts. So, we see from this paper that the initial step was to reshuffle already existing protein domains. As an analogy, this is similar to moving leggos around, or moving pieces of an erector set. However, this was only the initial beginnings of the modern complement system. As the above authors noted, "Thus, another integrative step seems to have been required".The study specifically addressed in my previous post came from this paper by Marino et al (2002). A quick quote: "The deduced amino acid sequences of both Ciona C3-like proteins exhibit a canonical processing site for alpha and beta chains, a thioester site with an associated catalytic histidine and a convertase cleavage site, thus showing an overall similarity to the other C3 molecules already characterized." They are saying that the Ciona C3-like proteins have the same features, shape, and characteristics of higher vertebrate C3 proteins.Even more interesting is that the Ciona C3-like protein has a known function similar to that of human C3 protein. From a paper by Pinto et al (2002) (found here): "To address the issue of the presence of an inflammatory pathway in ascidians, we expressed in Escherichia coli the fragment of Ciona intestinalis C3-1 corresponding to mammalian complement C3a (rCiC3-1a) and assessed its chemotactic activity on C. intestinalis hemocytes. We found that the migration of C. intestinalis hemocytes toward rCiC3-1a was dose dependent, peaking at 500 nM, and was specific for CiC3-1a, being inhibited by an anti-rCiC3-1a-specific Ab. As is true for mammalian C3a, the chemotactic activity of C. intestinalis C3-1a was localized to the C terminus, because a peptide representing the 18 C-terminal amino acids (CiC3-1a(59-76)) also promoted hemocyte chemotaxis."And I will even be kind enough to translate for you.Chemotaxis is the attraction of hemocytes (white blood cells in humans) to the site of infection. Hemocytes follow a trail of increasing concentration C3 cleavage products to the site of infection, much like how you and I find the source of a bad smell (ie by following the increasing concentration of the smell). In humans, the cleavage of C3 causes the chemotaxis of white blood cells to the site of infection, and according to the study above, the Ciona C3 like protein does exactly the same thing. So not only are they structurally similar, they also have the same exact function.Evolutionarily speaking, this is a huge find in the area of immunology. Researchers have found the root of the complement pathway. Lower organisms below the ascidians (ascidians = sea squirts, tunicates, or urochordates) do not have a complement system similar to vertebrates. However, by reshuffling already present protein domains, the ascidians evolved the start of the complement pathway. Those evolved proteins also show up in higher vertebrates and serve the same function as they do in the ascidians. More steps were needed before the complete, or classical, complement cascade evolved, but the start of the whole system can be seen in one of our most distant chordate cousins.As a side note, there is also a homolog of C3 in sea urchins as well. It functions as an opsonin, a molecule that "tags" foreing material for destruction by the immune system.Any more questions? (don't make me work any harder, PLEASE!!)

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And I will even be kind enough to translate for you.

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Come on now don't insult my intelligence . On a serious note, great work. Really interesting stuff. I'm not convinced, as you'd probably guess, but nonetheless it is a testament to the wonder of biology. Again thanks for the work, I really appreciate it

indeed, thank you Loudmouth for your posts. very well done.I'll probably post my thoughts tomorrow, because I am entirely too exhausted....this week is final exam wekk....ugh