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Ronagon
Thursday, August 16, 2007, 9:08am Report to Moderator Report to Moderator
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I've never been able to make logical sense of a few things regarding the Lewis antigen status thing...

1) What, precisely, do Lewis antigens do, whether secreted or otherwise?

2) Are Lewis antigens measured through a blood test?  After all, if they were just measured with a saliva test, how would you be able to distinguish between a+b- and a-b-, when both would presumably still be bound on a non-secreted cell surface?

3) If one gene controls both Lewis antigen secretion AND blood type antigen secretion, then how is it possible that you could have a Lewis double-negative person who could also be either undetermined as a blood type secretor or non-secretor?  That seems like the action of an independent, though linked, gene or something...
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yaman
Thursday, August 16, 2007, 9:25am Report to Moderator Report to Moderator

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Hi Ron,

I think your confusion arises from "secretion". The way I understand is, it is about whether the ABH antigens being secreted or not, and not about secreting Lewis antigens (I hope I didn't further complicate it).

Anyway, had you been a secretor, then you would be secreting your H antigen in your bodily fluids. You are a nonnie, so you are not able to do this.

The most accurate way of finding whichever you are is the saliva testing, i.e. looking for ABH antigens in one's saliva.

On the other hand, Lewis antigens can only be determined by blood testing. Lewis a+b- is always a non-secretor, and Lewis a-b+ is always a secretor, again the secretion here means that of the ABH antigens and not the Lewis antigens.

Lewis a-b- is a rare case, Lewis a+b+ being even rarer, and in both cases the Lewis typing does not say anything about secretor status. In such cases, it is best to have a saliva test done. Likewise, as you indicated, a saliva test won't tell you whether you are a Lewis a-b+ nonnie or a Lewis a-b- nonnie.

Cheers,
Yaman


"You are never given a problem without the will power to solve it"
Richard Bach - Illusions, The Adventures of a Reluctant Messiah
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Ronagon
Thursday, August 16, 2007, 9:30am Report to Moderator Report to Moderator
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Actually, I did a google search, and I found an excellent graphic that I think cleared everything up for me:

http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=glyco.figgrp.1077

In the graphic, you'll see that there are two ways to test "positive" for the Lewis antigen, but only the top pathway is correlates with secretion. The second pathway from the top does not correlate with secretion, presumably because it's lacking that outer fucose molecule. However, it does test positive for Lewis antigenicity, because it does have that inner fucose molecule.

Apparently, here's the Dick Tracy Decoder Ring for Lewis antigenicity: the presence of an outer fucose correlates with secretion, while the presence of an inner fucose correlates with the ability to merely display antigenicity properties.

In the last two pathways, you'll see that the third pathway possesses that outer fucose, so it secretes... but, since it doesn't possess that inner fucose, it doesn't display antigenicity. To my understanding, this would be the example of that mysterious secretor who tests Lewis negative.

And, we are also told, there is one other way that a person could test Lewis negative, but be a non-secretor.  I think this is exemplified in the final pathway, in which no fucose molecules are tacked on at all.  In other words, since there is no inner fucose, it doesn't display Lewis antigenicity... and, since there is also no outer fucose, it doesn't secrete, either.  

And so, to sum it all up, I think that the four rows can be described as follows:

Top row:        a-b+
Second row:   a+b-
Third row:      a-b- (but blood type antigen secretor)
Fourth row:    a-b-  (but blood type antigen non-secretor)

Am I right about this?  Or is the top row an example of that extremely rare thing, the a+b+?
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Ronagon
Thursday, August 16, 2007, 9:39am Report to Moderator Report to Moderator
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yaman,

Thanks for the info, but I'm still confused with how a person could secrete their blood type antigen, but be a Lewis double-negative, if both systems are controlled by the same gene.  Is there some special failure in blood type antigen secretors who do not also attach that outer fucose molecule, thus testing a-b+?  

I mean, if they're double-negative, there should be no way that secretion should happen, because the same gene that would attach that outer residue would also create a secretable product, automatically... thus making a double-negative always a non-secretor.

Now, if they're both controlled by the same gene, to my mind there should be some external influence going on that causes independence between the two systems.  But if they're not really the same gene, then I suppose they could operate independently somehow, and produce these results.

It's the seeming contradiction here that's driving me nuts.
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yaman
Thursday, August 16, 2007, 9:40am Report to Moderator Report to Moderator

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Ron! Brilliant!

Yes you are right, it's all about Se and Le which are responsible for locating the fucose. Thank you for showing it like that.

Now Le a+b+ is another question. For once you have the Se locus a1-2 FucT, then all a should be converted to b. The top pathway shown there is definitely Le a-b+. We have to look for a+b+ elsewhere I guess.

Cheers,
Yaman


"You are never given a problem without the will power to solve it"
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Ronagon
Thursday, August 16, 2007, 9:44am Report to Moderator Report to Moderator
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Here is what the article says about the Lewis graph I just posted:

Quoted Text
The Lewis A antigen (Lea) is synthesized by an α13/14 fucosyltransferase encoded by the Lewis (Le) blood group locus (Figures 16.15). The Lewis B antigen (Leb) is synthesized by the concerted actions of the Lewis α13 fucosyltransferase and the α12 fucosyltransferase encoded by the Se blood group locus (Figure 16.15). The nature of the alleles at an individual's Le and Se loci determines the complement of Lewis-active oligosaccharide molecules that will be constructed in that individual (Figure 16.15). Secretor-positive individuals convert type-1 oligosaccharide precursors to type-1 H molecules. The resulting type-1 H determinants may then be used as precursors by the Lewis locus-encoded α13/14 fucosyltransferase to form the Leb structure (Figure 16.15). Individuals that construct Leb exhibit the Le(a-b+) phenotype (Figure 16.15). Nonsecretors do not synthesize type-1 H determinants in secretory epithelia, but such unsubstituted type-1 molecules can be converted to Lea-active oligosaccharides by the Lewis α13/14 fucosyltransferase. These individuals exhibit the Le(a+b-) phenotype (Figure 16.15). Individuals that are homozygous for null alleles at the Lewis locus can have two different phenotypes. Such Lewis-negative individuals who are positive for secretor status construct type-1 H determinants, but these structures remain unconverted to Leb determinants (Figure 16.15). These persons exhibit the Le(a-b-) phenotype. In contrast, in individuals who are Lewis-negative nonsecretors, type-1 precursors are not substituted by either the Lewis or the Secretor fucosyltransferases, accounting for absence of Lea, Leb, or H structures, and their Le(a-b-) phenotype.


After really reading this carefully, it seems to describe the statuses I laid out initially... But, if this is really the case, what does an a+b+ look like?
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yaman
Thursday, August 16, 2007, 9:49am Report to Moderator Report to Moderator

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OK, here's something I found:

http://www.springerlink.com/content/t1845m6323757338/

" We also show that Lewis epitopes on longer and/or more complex core chains appear to be predominant in the Polynesian Le(a+b+) samples. The formation of these extended glycolipids is compatible with the concept that in the presence of reduced secretor fucosyltransferase activity, increased elongation of the precursor chain occurs, which supports the postulate that fucosylation of the precursor prevents or at least markedly reduces chain elongation."

Seems it's about a reduced Se activity..


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Ronagon
Thursday, August 16, 2007, 9:52am Report to Moderator Report to Moderator
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Thanks, yaman.  I hope I've got it right.

If I've truly got it right, then my only question is:  What in the world does a+b+ look like, since the top pathway in the figure seems fully saturated with fucose residues on both the inside and outside?
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yaman
Thursday, August 16, 2007, 9:53am Report to Moderator Report to Moderator

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Here's another and more comprehensive explanation of Le a+b+:

http://cebp.aacrjournals.org/cgi/content/full/10/9/971/F1

In this case, Le enzyme activity is five times greater than Se enzyme activity, hence both Le a and Le b are present.


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Ronagon
Thursday, August 16, 2007, 10:00am Report to Moderator Report to Moderator
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Ohhhhh... waitaminute....  I think I understand now.  

An a+b+ might just be like an AB blood type:  it might be an example of somebody who produces BOTH nonsecreted Lewis antigens AND secreted Lewis antigens at the same time.

I think the whole point of the Lewis system, is that it's a discrete construct, kind of like binary switches... In theory, people either ONLY produce non-secreted Lewis antigen OR ONLY produce secreted antigen.

However, in some people, they might produce both.  In other words, their cells would perform the pathways of BOTH row 1 and row 2.

If I'm right, that means the binary classification of this system is a convenient conceptual abstraction, but not necessarily reality.

I say this because the article you posted, talks about two groups who were both a+b-, yet one was a nonsecretor, and the other was a partial secretor.  Apparently, the system is a good deal more "analog" than purely "binary" or "digital"... more "continuous" than "discrete".
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yaman
Thursday, August 16, 2007, 10:02am Report to Moderator Report to Moderator

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I agree.. I think the mystery is solved now


"You are never given a problem without the will power to solve it"
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Ronagon
Thursday, August 16, 2007, 10:03am Report to Moderator Report to Moderator
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In this case, Le enzyme activity is five times greater than Se enzyme activity, hence both Le a and Le b are present.


Yes, yes.  Thank you for saying that.  It all makes perfect sense now.  Apparently the Lewis "a" form doesn't secrete (and, I guess, correlates with blood type antigen non-secretion), but the Lewis "b" form does (and, I guess, also correlates with blood type antigen secretion).  
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Ronagon
Thursday, August 16, 2007, 10:05am Report to Moderator Report to Moderator
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This raises another question in my mind:  I wonder if the ability to produce both A and B blood type antigens, might also be due to the same gene that allows someone to produce both Lewis a and b antigens simultaneously...

Actually, no, that wouldn't work, because the "a" form is always non-secreted, while the "b" form is always secreted.  And, with the "AB" blood type antigen, you can have both either secrete or non-secrete simultaneously.  So they don't even behave the same way...
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Ronagon
Thursday, August 16, 2007, 10:07am Report to Moderator Report to Moderator
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You know, I think I might actually produce a visual graphic that also includes how an a+b+ is produced...  it would visually explain all five possibilities.
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yaman
Thursday, August 16, 2007, 10:08am Report to Moderator Report to Moderator

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Yep, that's the way I get it too.

And while we are at it, Lewis a-b+ patients with gastric carcinoma can exhibit an anomalous expression of Lewis a:

http://www3.interscience.wiley.com/cgi-bin/abstract/112687203/ABSTRACT?CRETRY=1&SRETRY=0

This gets deeper and deeper


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yaman
Thursday, August 16, 2007, 10:11am Report to Moderator Report to Moderator

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Quoted from Ronagon
You know, I think I might actually produce a visual graphic that also includes how an a+b+ is produced... it would visually explain all five possibilities.


Actually there is a graphic, you can find it by following the link in my post (reply 8-14)..


"You are never given a problem without the will power to solve it"
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Ronagon
Thursday, August 16, 2007, 10:11am Report to Moderator Report to Moderator
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Ah, well, I just clicked on that link, and they want me to pay to view it.  Ha ha ha ha  So I'll take your word for it.
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yaman
Thursday, August 16, 2007, 10:17am Report to Moderator Report to Moderator

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Sa Bon Nim
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Funny!,

OK, try this one, Figure 1, and it also shows how the secretion is effected:

http://www.jbc.org/cgi/content/full/271/16/9830


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Ronagon
Thursday, August 16, 2007, 10:18am Report to Moderator Report to Moderator
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Okay, I went back and looked at that link.  Thanks again.

Strictly speaking, however, since the secreted form of Lewis, Lewis b, has both the inner and the outer fucoses, I would think it would register as both Lewis a AND Lewis b, thus making it a+b+... but I suppose what they mean when they talk about double-positive, is when Lewis is detected both on tissue surfaces, and out in fluids.

I guess I just think they need to be more precise in their terminology here.  It's ambiguous to me, and it caused my confusion.
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Ronagon
Thursday, August 16, 2007, 10:23am Report to Moderator Report to Moderator
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Ah. I see. I think.

So, would a+b+ result from a mixture of partial completions of the two-step, Se-Le Lewis "b" pathway, whereby sometimes it might stop after the Se enzyme does its thing, and other times it goes all the way through to the Le enzyme doing its thing, thus producing both "a" and "b" forms? Or does a+b+ come about from both the "a" AND the "b" pathways both being performed to full completion (and, perhaps, a partial completion of the "b" pathway here, too)?

You know, I'm really glad you posted that last link. It helps even more...

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Ronagon  -  Thursday, August 16, 2007, 10:24am
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Ronagon
Thursday, August 16, 2007, 10:26am Report to Moderator Report to Moderator
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My only complaint about that last diagram you showed, is that it gives the formula molecular diagrams, rather than a purely pictorial one, which would simplify things a lot more.

If you could represent the information in that last diagram, in the same visual manner as the very first diagram I posted, then that would make it clear as a bell to just about anyone, notwithstanding those in need of a neurologist.

Revision History (2 edits)
Ronagon  -  Thursday, August 16, 2007, 10:29am
Ronagon  -  Thursday, August 16, 2007, 10:27am
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yaman
Thursday, August 16, 2007, 10:29am Report to Moderator Report to Moderator

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The way I see it is; when Le activity is higher compared to Se activity, you end up with Le converting the Type 1 H (to Le b antigen), as well as some of the Type 1 precursor (to Le a antigen) before they had a chance to be converted to Type 1 H by Se due to Se's lower activity, so you end up with both antigens.

So actually, all you have to do is to put the top and the second pathways together in order to show the a+b+ case.

And I'm glad you started this thread, I had the opportunity to learn more about Lewis system


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Ronagon  -  Thursday, August 16, 2007, 10:32am
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Ronagon
Thursday, August 16, 2007, 10:31am Report to Moderator Report to Moderator
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The way I see it is; when Le activity is higher compared to Se activity, you end up with Le converting the Type 1 H, as well as the Type 1 precursor before it had a chance to be tackled with Se due to Se's lower activity, so you end up with both antigens.


Yes, but that's entirely the point of my last question:  Does a+b+ result from this way that you just described here -- in other words, from the cells performing both "Lewis a" and "Lewis b"pathways, or from the cells both partially and fully performing the "Lewis b" pathway only?
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Ronagon
Thursday, August 16, 2007, 10:33am Report to Moderator Report to Moderator
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In other words, what you seem to just be describing is a situation whereby BOTH pathways are conducted.  But my point is that, what if the results happen from both full and partial completions of just the LEFT-hand pathway in the diagram?
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yaman
Thursday, August 16, 2007, 10:37am Report to Moderator Report to Moderator

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My understanding is, both paths work simultaneously, it's just that more Le are at work than Se.


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