Joined: May 2002
I'm going to post some posts here for safekeeping on this thread:
Nelson, what is this babble about an immune system producing "not enough specific antibodies to make a difference"?
Way back on the other thread, charlie pointed out to you:
So we have the following facts:
Antibodies do not necessarily have single specificities. Indeed, the vast majority of our circulating immunoglobulins (the so-called "natural" antibodies) are low affinity, broad specificity antibodies directed towards common antigens (bacterial wall moieties, for instance).
Antibodies become highly specific and gain high affinity only late during an antigen-specific immune response, through a process of mutation/selection called affinity maturation. This however has nothing to do with the VDJ recombination process we are discussing here, which takes place, irrespective of antigen, during B cell differentiation in the bone marrow.
"Naive", newly generated B cells, as they emerge from the bone marrow, carry antibodies that are mostly of low affinity. For insatnce, the antibodies produced early during an immune response (which reflect the naive repertoire) bind antigen with a Kd in the 10^-5-10^-6 M range - compared that with the high affinity, "matured" antibodies of late immune responses, which have a Kd of 10^-8-10^-9 M. Most antibodies in the primary repertoire are also not very specific – in fact, polyspecific antibodies abound (which goes along with their low affinity for antigen). As an aside, the vast majority of antibodies in the primary repertoire do not in fact recognize anything at all, and the B cells that make them die after a while without ever seeing any "action" (one of the drawbacks of the darwinian approach of the adaptive immune system – high, widespread wastefulness for rare but exceptional returns).
As for innate immunity receptors, again you are mistaken. While some of them do indeed have broad spectrum, many have quite subtle specificities, for instance TLR4 binds very specifically to the lipid A moiety of the very large bacterial lipolysaccharide (LPS) molecules. Their binding constants also actually compare quite well with those of most primary response antibodies (in the 10^-6-10^-7 M range).
The fundamental difference between adaptive and innate immunity receptors is in fact neither in their affinity nor in their specificity, but in their logic. The adaptive immune system, using VDJ recombination, can generate an almost infinite variety of specificities, and thanks to clonal selection can pick any extremely rare, low affinity antibody molecule and turn it into close to a “magic bullet” (this however has again nothing to do with VDJ recombination). The innate immune system, on the other hand, can count on only a limited array of receptors, which must focus on a few abundant antigens (sometimes classes of antigens) commonly found on pathogens (often, like LPS, molecules that we ourselves do not produce); moreover, the binding of the ligand has to be good to start with, because these antigens cannot undergo mutation and selection processes.
1) Many innate receptors have similar specificity to "naive" (first-generation lymphocyte) recombinant antibodies. Most of the antibodies in your and my blood, right now, are therefore "not specific enough to make a difference". According to you.
2) Specificity is not produced just by having cells that mysteriously produce lots of specific antibodies, it is produced by the selective replication of those very few lymphocytes that happen to match whatever the antigen is. Further somatic mutation and selection is what produces many copies of the very few antibody phenotypes that are "specific enough to make a difference".
3) Therefore at no point are huge numbers of diverse, "single specificity" antibodies produced.
So speaking crudely, phylogenetically, we have this sequence of organisms:
(a) invertebrates, with many non-rearranging receptors of moderate specificity (similar to the specificity of "naive" antibodies)
(b) cartilagenous fish, which add diverse rearranging receptors of moderate specificity, genes in VDJ VDJ VDJ arrangement
© "lower" vertebrates, which have diverse rearranging receptors of moderate specificity in a VVVV DDDD JJJJ-type arrangement
(d) mammals, like lower vertebrates except that a few of the rearranging receptors, which happen to match the antigen, get replicated and gradually improve from moderate specificity to high specificity via somatic mutation & selection.
(charlie can refine the above if I garbled things)
And yet, Nelson, you've been proclaiming for endless pages that there is some sort of requirement somewhere to produce large numbers high-specificity antibodies with different specificities.
Please, Nelson, can you help us out here?
It can't, anymore that a human system can get a V1 fused to a V2 in its Ig clusters. V segments have RSSs only on their 3', and they all have the same spacers (for steric reasons related to RAG structure, recombination only occurs between RSSs that vave different sized spacers), so that recombination cannot occur. What can occur is a V from one shark cluster recombining with a D in another.
Thanks, that's what I was trying to explain when I wrote,
But it wouldn't make a difference anyway, because RAG figures out where to cut based on RSS (IS in above diagram), and these sequences would get copied along with the V, D or J segments as they get duplicated [...]
Yet another supposed reason for the unevolvability of VDJ recombination hits the dust!! It's like shooting skeet.
All Nelson has left is that:
(1) the exact non-rearranging ancestor receptor has not yet been identified, and (2) that he thinks a transposon insertion, a well-known natural event that is happening all the time (it causes some cancers for instance) is "non-Darwinian" and for some mysterious reason therefore an intelligent intervention.
Regarding (1), even though (a) Ig domains are common, (b) we know that non-rearranging receptors would work because we have a bunch of them, and © due to selection for immune system diversity sequence homology will decay very fast.
To emphasize the Ig domain point:
...all those circles are Ig(-like) domains.
Regarding (2), there are a multitude of transposon types and events; there is no need to postulate intelligent intervention in order to explain a transposon inserting into a non-rearranging receptor. Plus, there is the published literature and experiments which the immunologists view as having tested and strengthened the hypothesis.