Talk:Toll-like receptor

message: 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)
replies: text: 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)
thread_title:  Singular/plural article title  

message: 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)
replies: text: 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)
replies: text: TLR12_MOUSE, TLR13_MOUSE Are links to the Swissprot entries for mouse TLR12 and TLR13.--KX36 (talk) 16:30, 5 May 2008 (UTC)
thread_title:  13 or 11 

message: 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)
thread_title:  Table 

message: 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)
thread_title:  individual TLRs 

message: 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)
thread_title: Utriv comments

message: 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)
thread_title: Compromise comments

message: 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)
thread_title:  introduction 

message: "do not play a significant role in the adhesion and phagocytosis of microorganisms"  We know now that this is not true: see 'Phagocytosis and antigen presentation: a partnership initiated by Toll-like receptors' by Blander in Ann Rheum Dis 2008. DanMcScience (talk) 20:44, 29 January 2009 (UTC)
thread_title:  Mistake 

message: * Support – Toll like receptor review is a completely unnecessary WP:CFORK of this article.  Boghog (talk) 05:02, 11 January 2010 (UTC)
replies: text: Nevermind; the article was deleted under WP:CSD#G7. PDCook (talk) 12:57, 11 January 2010 (UTC)
thread_title:  Proposed merger of material from [[Toll like receptor review]] 

message: * Support – As stated above, the newly created pattern recognition receptor in innate immune system which a copy and paste of the deleted toll like receptor review is an unnecessary WP:CFORK of this article. Boghog (talk) 19:43, 11 January 2010 (UTC)
thread_title:  Proposed merger of material from [[pattern recognition receptor in innate immune system]] 

message: In the section on 'Activation and effects', it says
:[Following TLR activation], in the case of a bacterial factor, the pathogen might be phagocytosed and digested
and later
:[TLRs] do not play a significant role in the adhesion and phagocytosis of microorganisms
So do TLR play a role in phagocytosis or don't they? AxelBoldt (talk) 20:31, 24 January 2010 (UTC)
thread_title:  Contradiction in 'Activation and effects section? 

message: the table says "bacteria". shouldn't it be "viruses" instead? or maybe "viruses and bacteria"?  — Preceding unsigned comment added by 212.41.71.144 (talk) 13:03, 30 October 2011 (UTC)
thread_title:  localisation of ligands for TLR9 

message: User:128.189.245.44/User: 128.189.244.225 please explain the content removals here and here. Jytdog (talk) 04:12, 9 February 2017 (UTC)
replies: text: now a third time here by yet a third IP address. Jytdog (talk) 21:44, 9 February 2017 (UTC)
thread_title:  removal of etymology 

message: I just found that bit of trivia pointless, there is no merit to having it there.
P.S. I didn't even know what "talk" meant on wikipedia... jeez  — Preceding unsigned comment added by 128.189.240.231 (talk) 22:50, 10 February 2017 (UTC)
thread_title:  IP man 

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thread_title:  External links modified 

message: If you look at the page right now in late 2021, you can read these two statements made:
"Thirteen TLRs (named simply TLR1 to TLR13) have been identified in humans" [...]
And also:
"The TLRs include TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13. Humans lack genes for TLR11, TLR12 and TLR13" [...]
Now excuse my poor command over the english language, but ... if there are 13 TLRs in humans, yet humans lack
genes for 3, why is the number then not 10 instead? This is very confusing to me. Could someone proof-read this
in the article, and explain why three genes are missing (or so it is claimed), but these still (???) count
towards the total number of 13? I think the whole article needs to be a bit stricter in separation; early
on it mixes humans and mice, and while I understand that mice make for good model organisms, a mouse is
not a human. It would be nice if the separation could be stricter and more logical, without the "but humans
lack 3 genes" part - or at the least explain what is meant here. 2A02:8388:1604:F600:3AD5:47FF:FE18:CC7F (talk) 07:58, 9 December 2021 (UTC)
replies: text: Good catch. Can confirm with https://academic.oup.com/gbe/article/12/1/3615/5652095 (Jan 2020 study on TLR evolution in mammals) that agrees with 10 genes in humans (citing 2009 study), but in fact proposes only 8 major subfamilies of TLRs across vertebrates (see Fig. 3). This seems like information that should be updated. They also confirm 13 in mammals, but say there are 12 TLRs specifically in mice (see Fig. 1). Crawdaunt (talk) 12:29, 9 December 2021 (UTC)
thread_title:  Confusion: how many TLRs exist in humans?