Talk:Toll-like receptor

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This article needs to be merged with toll-like receptors. I'd advocate this articles removal, as the toll-like receptors plural is the form most encountered, and that article appears more up to date.

--ZZ 12:09, 9 Sep 2004 (UTC)

No, toll-like receptors should be merged here. Wikipedia article titles almost always use the singular form, not the plural form, see Wikipedia:Naming conventions (pluralization) unless they always appear in the plural form (which is not the case here). --Lexor|Talk 12:40, 9 Sep 2004 (UTC)


Ok thanks for that info.

I only joined yesterday, so I'm still finding my feet. I had a feeling that would be the case maybe.

--ZZ 23:58, 9 Sep 2004 (UTC)

Contents

[edit] 13 or 11

I just completed an essay about TLRs, and last I checked I only found 11 TLRs were identified in mammals; in fact a lot of classmates only managed to find out about 10 (little was known about 11 anayway). If anyone can come up with TLRs 12 & 13 I'd be willing to concede. Otherwise I'll change it to eleven on Monday.

There are other TLRs in non-mammalian vertebrates, but I'm sure that number would exceed 13 (counting ones identified in birds, goldfish, annelids and C. elegans etc) and its unsure if they should be TLRs-proper.

Check out Goldstein's reveiw on TLRs if you can get access to it.

--ZZ 08:22, 10 Sep 2004 (UTC)

Don't be afraid to be bold in updating pages, especially since you have a citation to back you up! I'm no expert in TLRs, and I noticed the inconsistency when I was trying to merge the two versions. I probably should have moved the inconsistent paragraph to the Talk here, until someone with more expertise had a chance to review it, but I was in a hurry... ;-) --Lexor|Talk 09:05, 10 Sep 2004 (UTC)
TLR12_MOUSE, TLR13_MOUSE Are links to the Swissprot entries for mouse TLR12 and TLR13.--KX36 (talk) 16:30, 5 May 2008 (UTC)

[edit] Table

Feel free to fix up that table for better-visualisation, or adding any other things that have been found recently. I'm planning on trying to incorporate as much information from my recent assignment into this article. Including what all that MyD88, TIRAP etc. stands for.--ZZ 05:53, 10 Oct 2004 (UTC) I think I might add the {{cleanup}} tag to this article

Table is fixed-up. --203.206.228.92 03:22, 15 Jun 2005 (UTC)

[edit] wrong link for PRR

Hi,

I just wanted to point out that the link to PRR (pattern recognition receptors) takes you to a page about Pennsylvania Railroads. I would have edited the link, but I am new here and couldn't figure out how to do it.

--Betty

[edit] individual TLRs

Should each TLR get their own entry, or should we just expound on the individuals one under different sections on this page?

Fhayashi 21:51, 24 April 2006 (UTC)

[edit] Reference section

I have removed this section from the article.

References are the papers, books, and websites that were actually USED in the article not just:

  1. Some papers I like.
  2. Some papers I wrote.
  3. Some papers my boss/friend/underlings wrote.


These papers were NOT used to write this article and have way too many things in common to have been used by an impartial editor (except for ref number 4, and maybe the reveiws). I can think of a dozen or so more influential papers. See also WP:COI.

If these are in fact refs, they need to be referenced "in-line" (see WP:CITE).

I apologize if I have removed any legitimate refs, feel free to add them back in, using a proper citation method. Again, WP:CITE. --DO11.10 21:34, 28 October 2006 (UTC)

References

Medzhitov,R., Preston-Hurlburt,P., and Janeway,C.A., Jr. 1997. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity [see comments]. Nature 388:394-397.

Recent review articles on the TLRs:

    • No I used them in making the article. Wouldn't it make sense to check with the people who added the references?--ZayZayEM 06:15, 22 November 2006 (UTC)
It was not that reference that I was talking about, it was this edit when User:66.91.232.161 put a very long list of "references" with the following header:
Many thousands of papers have been published in the TLR field. A very small sampling of original articles pertaining the the identification of TLRs and discovery of their function follows:. That just screams "I know these people and I want to promote their papers."
I apologize if your reference got caught up in this. Actually the "review" articles look okay (which I can see that your ref was part of), I will add them, and the Janeway article, back into the article.--DO11.10 18:11, 22 November 2006 (UTC)

[edit] Reversions

Could users Utriv and Jkagan please refrain from reversions without discussions. I may have to alert this inanity to editors under the Three Revert Rule. Please place your arguments here for discussion with other editors--ZayZayEM 02:00, 26 February 2007 (UTC)

[edit] Utriv comments

I am an authority in the field of innate immunity and have particular expertise in the study of TLRs. The Jkagan version of this article shows inaccuracy and bias in the section on the discovery of the TLRs and their function. It is worth noting that J. Kagan is a postdoctoral trainee in the laboratory of Dr. Ruslan Medzhitov, mentioned in both versions of this article. Medzhitov, in turn, was a postdoctoral fellow of the late Charles Janeway. Whether at the behest of his mentor or at his own initiative, Jkagan presents a eulogy for Janeway and his scientific heir (who happens to be his employer) rather than a truthful and accurate history of the field.

Below, I offer my own comments and the text of Jkagan in italics.

Toll-like receptors are founding members of the family of Pattern Recognition Receptors (described above) that function to alert the immune system to the presence of microbial infections. The existence of PRRs was first predicted by Charles Janeway at Yale University in 1989. [1]. In this seminal paper, Janeway laid out much of the conceptual framework for what is today known as the field of Innate Immunity. Janeway predicted that our immune system uses PRRs as tools to identify molecules that would always be associated with infection. The most likely candidates for these infection associated molecules are compounds that are found exclusively on microbes. PRRs would therefore serve the function of detecting microbes and initiating an immune response accordingly. The concept that immune systems decide when to initiate an response based on the microbial nature of the molecules encountered became known as the pattern recognition hypothesis and has extraordinary predictive powers. The first prediction of this is that there must be a set of germline encoded receptors that have the capacity to both detect microorganisms and activate protective immunity. The identification of Tolls as critical players in immunity must be considered in the context of the above mindset permeating the field of immunology at the time.

Though widely cited, Janeway’s 1989 review offered no concepts unfamiliar to contemporary workers in the field of innate immunity. First of all, the existence of innate immunity was well known. The terms “natural immunity” and “host resistance” were used interchangeably with “innate immunity” for decades. It was clear that cells of the mammalian innate immune system, including neutrophils and macrophages, could detect molecules of microbial origin and respond appropriately. These molecules included LPS, dsRNA, trehalose dimycolate, lipopeptides, and flagellin, among others, and had been well characterized; in some cases synthesized artificially. It was obvious that there must be receptors for these molecules, since that is how biological systems detect things. And all of the molecules listed above were widely represented in the microbial world, which was why sensors for them had evolved. Abundant references to a yet-to-be-identified LPS receptor in the decades before Janeway’s paper attest to this. In my own version of the article, brief discussion is accorded the fact that LPS was described by Pfeiffer, who worked with Koch more than 100 years ago. This discussion should perhaps be expanded and annotated. But the main point is: in “pattern recognition receptors” immunology received a new descriptor, but not a new idea. To credit Janeway as the first to recognize that there were receptors for conserved molecules of microbial origin is silly. What of the fMLP receptor? What of complement? What of mannosyl receptors? All are activated by contact with molecules characteristic of a wide variety of microbes, and all were known to exist prior to 1989. The LPS receptor was much sought prior to 1989. To write that the pattern recognition hypothesis has “extraordinary predictive powers” is equally silly, and shows extraordinary bias.

Janeway's pattern recognition hypothesis layed dormant until the late 1990's when studies from a number of labs independently identified TLRs as proteins that fulfill all the mandates needed to be recognized as a PRR. In 1996, Toll was found by Jules Hoffmann and his colleagues to have a role in the fly's immunity to fungal infection[2]. Nearly simultaneously Janeway and Ruslan Medzhitov identified a human Toll receptor that can induce the activation of genes necessary for initiating immunity. [3] Therefore Toll receptors seemed to be capable of recognizing microbes and initiating an immune response and was therefore considered to be a pattern recognition receptor.

Jkagan presents a false history. Indeed, Jules Hoffmann and his colleagues found that Toll had a role in the fly’s immunity to fungal infection (ref. 2). But Janeway and Medzhitov did not make a “nearly simultaneous” discovery. Their paper appeared in print a year later than Hoffmann’s. Moreover, while it need not be noted in the Wikipedia article, it is a fact that Janeway and Medzhitov developed their interest in a human TLR after Hoffmann shared unpublished data with them in 1995. Hoffmann’s contribution was never mentioned in Medzhitov and Janeway’s 1997 paper (ref. 3). Furthermore, Janeway and Medzhitov omitted any reference to the work of Nomura et al (1994), and Taguchi et al (1996), who had preceded them in cloning and mapping a human TLR, and instead, promoted the view that they had “discovered the mammalian TLRs.”
Jkagan’s most serious inaccuracy comes in the last sentence of his paragraph above:“Therefore Toll receptors (sic) seemed to be capable of recognizing microbes and initiating an immune response and was (sic) therefore considered to be a pattern recognition receptor.” Janeway and Medzhitov’s 1997 paper offers no evidence that TLRs “seemed to be capable of recognizing microbes and initiating an immune response.” On the contrary, Janeway and Medzhitov never tested TLR responses to microbial ligands. They merely showed that artificially enforced ligation of a TLR could activate NF-kB (unsurprising since two other members of the same protein family were already known to do so), and could upregulate B7.1 and B7.2 proteins on myeloid cells. They knew of no microbial ligand (and for that matter, no endogenous ligand) that could activate TLR signaling. And if they had, they surely would have said so. They presented no evidence that “h-Toll” was a pattern recognition receptor. Rather, Janeway and Medzhitov later implied that they had known all along that TLRs recognize microbial ligands. Jkagan encourages this perception, but there is no historical basis for it.

Subsequent work established that mammalian Toll receptors, like their fly counterparts, can recognize microbial compounds[4]. This point was clarified by Bruce Beutler's lab using mouse genetics, which is now the tool of choice for the identification of ligands that activate TLRs [5].

Ref. 4 denotes a thoroughly discredited paper that maintained that TLR2 was the receptor for LPS. It is rarely cited today, except perhaps to cause mischief. The paper relied upon a transfection-based assay system in which TLR2 was overexpressed in mammalian HEK 293 cells, which were then exposed to enormous concentrations of LPS, whereupon NF-κB activation was noted. Suffice it to say that TLR2 is not a receptor for LPS, the LPS was probably contaminated with other ligands for TLR2 (possibly lipopeptides, though nobody will ever really know) and the entire story was ultimately an embarrassment to the authors. Ref. 5 perhaps “clarified” that gross methodological errors were committed in Ref. 4. But Jkagan omits mention that Ref. 5 was the authentic discovery of the LPS receptor, and also constituted the discovery that TLRs are, in fact, “pattern recognition receptors.” He further obfuscates matters by suggesting that mouse genetics is the tool of choice for identifying TLR ligands. But here he must be referring to reverse genetics (gene targeting) while Bruce Beutler, senior author of Ref. 5, used forward genetics (positional cloning) in his work.

Tolls derive their name from homology to a family of molecules in the fruit fly Drosophila melanogaster, the prototypic member of which was called Toll. ("Toll," in German, means "amazing" or "cool" [English slang]). In fruit flies, Toll was first identified as a gene important in embryogenesis in establishing the dorsal-ventral axis. First reported by Nomura and colleagues in 1994[6] and mapped to a chromosome by Taguchi and colleagues in 1996[7], "TIL" (in current terminology TLR1) was the first TLR to be identified. Because the immune function of Toll in Drosophila was not then known, it was assumed that TIL might participate in mammalian development. Moreover, it was known that a molecule with a clear role in immune function in mammals, the interleukin-1 (IL-1) receptor, had homology to Toll, in that the cytoplasmic portions of both molecules were similar (first noted by Nick Gay in 1991)[8].

There is nothing egregiously wrong with this part of the text, but it is presented out of sequence, and does not do justice to the contributions of Nomura, Taguchi, and Gay, all of whom were aware of similarity between Toll and mammalian proteins even before the immunologic function of Toll was known. Moreover, the author blurs the distinction between Tolls and TLRs, which is important in this field.
Jkagan is probably aware of some of the objections raised above. But possibly he is not aware of all of them. It is ironic that he refers to the “mindset permeating the field of immunology” at the time the TLRs were discovered as critical players in innate immunity. I was there, and was active in the field long before as well, and I know what the mindset was. He was not there, and he has no firsthand knowledge of the mindset or the events. Evidently he has been educated to hold a particular point of view on the matter. I hope that he will review the subject without prejudice and I will respond to what comments or questions he may have.

Utriv 08:53, 27 February 2007 (UTC)

[edit] Compromise comments

I would like to thank to community for taking the time to resolve this issue and I apologize for not participating in this forum earlier. My lack of participation was not due to some bias or inflexibility, but simply because I was not aware of this forum for discussion. Clearly, Utriv has a personal interest in this area as he has most passionately indicated to us. Whether his personal interest influences how he views the literature on this matter is irrelevant since there is no way to prove or disprove this. I expect Utriv to remove all comments from this forum about any potential biases that I may have for these same reasons. After all, Wikipedia is a source of reliable information, not a smear campaign. Do we agree on this Utriv?

What we can agree on is that there is contention with regards to the discovery of TLRs. I propose a compromise: where we leave the section of TLR discovery as is, and include a section on the function of TLRs in the control of various aspects of immunity (cytokine production, DC function in vivo, T-cell function). This will allow for the strict discovery of TLRs to be separated from the discovery of TLR-control of adaptive immunity. —The preceding unsigned comment was added by Jkagan (talk • contribs) 15:16, 1 March 2007 (UTC).

In principle, your suggestion sounds very reasonable. Please draft suggested text for a section on the function of TLRs in the control of various aspects of immunity and post it here. I will review it promptly and suggest changes and/or additions should they occur to me, and we will proceed from there.

Utriv 14:06, 2 March 2007 (UTC)

[edit] Jkagan response

In response to the comments made by Utriv, I have changed the statement "Simultaneously" to "Subsequently" which should be sufficient to indicate the seminal initial contributions of the Hoffmann lab to this field.

I stand by everything else written.

—The preceding unsigned comment was added by Jkagan (talk • contribs) 21:44, 27 February 2007 (UTC).

Jkagan has not made a serious effort to address the points made above, challenging the neutrality and accuracy of his text. He has offered no specific objections to the Utriv text.

Utriv 22:48, 27 February 2007 (UTC)

Nor have you made a serious attempt to find common ground and merge both your versions together. Instead you engage in a reversion war without even explaining your reasoning in the edit summaries. If he offers no specific objections to your text and stands behind what he has written, how is it problematic to incorporate elements of both versions?
While your authority is noted, it is irrelevant to this article. Basing text solely on your authority, or your opinion of someone else's expertise, amounts to a violation of the policy Wikipedia:No original research. What matters more is verifiable and reliable sources for all statements written - as well as for your own objections.
An admin has now protected this article from editing while you guys work things out. Please, try to resolve your differences. I suggest that one of you propose some text here that attempts to combine the best elements of both versions. When the block lifts, it can be incorporated in the article. -Amatulic 02:40, 28 February 2007 (UTC)
Nobody needs to get blocked, or threatened with blocking; the disputants are obviously both knowledgeable about the field but less so about the intricacies of Wikipedia policy. There are a lot people around here quoting policy all of a sudden, but not many trying to work out the best presentation. I've posted to the Wikiproject Molecular and Cellular Biology noticeboard in the hopes of getting more eyes belonging to people familiar with the background.
In any case, it's not clear to me that this article needs to delve this deeply into the history of TLR discovery; a brief summary should be adequate at the level of an encyclopedia article, and has the advantage of avoiding the pitfalls of internal disputes about who knew what and when. A helpful aid in sorting this out would be an authoritative review article that covers the original discovery and development whose narrative could be used as a model. Perhaps Utriv or Jkagan could suggest one, or a few? Opabinia regalis 03:03, 28 February 2007 (UTC)
I agree, if the history article is too contentious, then omit it entirely for now. It might help resolve your divisions if you instead concentrated on describing the structure, regulation and physiological functions of these receptors at a clear but accessible level. TimVickers 03:15, 28 February 2007 (UTC)
Jkagan's edits do seem to be rather biased and possibly vanity edits. He made no effort to maintain the already documented and cited history of TLR discovery and replaced it with his own version of events. The pre-Jkagan history had citations and was quite sufficient (mentioning historic attempts at innate immunity, discovery of Toll, and then of the first, and then subsequent TLRs). Jkagan has added no new or useful information through his edits, and relies heavily on mentioning the efforts of Janeway and his colleagues. I support reversion to the pre-Jkagan version, and then we can move from there.--ZayZayEM 04:02, 28 February 2007 (UTC)

I have taken note of all comments above. The difficulty in fusing the two texts as suggested by Amatulic is that the Jkagan text is inaccurate in ways that I have explicitly pointed out. In making his last reversion, Jkagan offered no comments to dispute the allegation of inaccuracy other than writing that he stood by his version. A “no-it’s-not/yes it is” debate is not helpful. Nor did he point to an error in the Utriv text that he felt was in need of correction. I understand Amatulic’s point that authority alone does not provide adequate support for a text, but in fact, the pre-Jkagan text was well supported by citations of carefully evaluated, diversely authored scientific literature while the Jkagan text was not.

Better no history for the present (as suggested by Tim Vickers) than a false history or a self-serving one. But on the other hand, a true history based on serious scholarship and careful documentation would be the best option.

ZayZayEM, who has previously written for this page, supports reversion to the pre-Jkagen text. I agree that this is the best option. But I would also ask that the page be watched carefully for unsubstantiated edits and reversions henceforth and protected if necessary. I care very deeply about historical accuracy in this field. I also would like to get beyond history per se and see the page become a far more detailed source of information about TLRs, which are some of the most important molecules in the immune system. Utriv 07:26, 28 February 2007 (UTC)

I also support reversion to the version prior to your edit war. Also, if Jkagan doesn't address the concerns raised or provide a rationale for his edits beyond "I stand by everything I wrote" then it's justified to revert those edits until they are adequately explained. However, I also still recommend attempting to merge whatever parts of Jkagan's text can be merged rather than rejecting it all outright. Utriv's comments on Jkagan's edits above indicate that parts of what JKagan wrote might be acceptable for inclusion. -Amatulic 18:23, 2 March 2007 (UTC)
Actually, Jkagan has now added more statements to this discussion (just a little out of sync that's all). It looks like both parties are happy to work this out and work together and that is GREAT...with two clear experts working on this page I'm sure it will look wonderful! Now that you have both discovered the discussion page, I hope you keep the channels of commomunication open and I'm sure all will go well ;-) I agree with most comments regarding the history, the actual scientific facts about TLRs is much more informative to students (the most likely readers of this article). With that in mind...remember their text books are not as up do date as the knowledge you pick up on the cirucuit...so please be gentle with them when you are introducing new terminology! (I know it must be frustrating Utriv, but I'm sure you understand things take time to change). Thanks guys! Ciar 19:45, 2 March 2007 (UTC)

[edit] TLR14 & others

Hi Ciar,

It would be better if you correct new editing related to new TLRs like here than deleting it. TLR14 has been discovered in many organismes [1][2]. Interestingly, we can also find TLR15, 16, 21, 22,23. So, it is much better to "correct" any info instead of deleting or reverting. By the way, I re-read the paper here and found that you was right, it is mainly located in the ER. Thus, TLR14 (both a and b) are intercellular. Best! Ralhazzaa 12:45, 26 April 2007 (UTC)

Hi Ralhazzaa,
Sure, I'm not disputing that there are TLRs in other organisms that include TLRs numbered 14 and above, but I removed the one you cited from the table for several reasons. Firstly, as you have already noted, the cellular location you had included was not right for the lamprey sequence you had cited so this information was incorrect. Secondly, the ligands and intracellular signaling/adaptor molecules have not been proven yet, but you had included "probable" ligand and an unproven signaling molecule in the table - wikipedia policy is to only cite information that is verifiable and not a point-of-view or original research - so these unfounded items couldn't remain. Finally, the biggest reason is that TLR14 is a name given to gene sequences/putative proteins found in non-mammalian species (e.g. bony fish and jawless fish) and the table on the TLR page is a list of mammalian TLRs - no TLR14 has been described in mammals (to my knowledge) at this time. Maybe a little section could be included in the article to include these other non-mammalian TLRs also, without causing confusion with the different numbers applied to different TLRs of different species. Anyway, no offence was intended and I hope you understand my reasons for the deletion. Take care, Ciar 16:12, 26 April 2007 (UTC)
Hi Ciar,
Thanks for your reply. No offence has been supposed by me :) I'm really appreciating your answer and clarification here. Maybe another subcatagory (or subtitle in the subcatagory) could be established for the non-mam. TLR systems as it looks of significant number and of different phylogeny and role -in general. Best Regards Ralhazzaa 21:22, 28 April 2007 (UTC)

[edit] introduction

the intro confusingly talks about 3 subgroups. Are they subgroups of the TLR (in which case could the table say which subgroup each is in), or are they subgroups of the super family (in which case could the mention of subgroups be removed and put on an article for the superfamily ? Rod57 22:46, 12 September 2007 (UTC)