A little Ni2+ to tickle your TLR4

Conceptually, its not excessively hard to understand how we develop allergies-- Our bodies generate an inappropriate immune response to a protein that wouldnt otherwise cause us any harm, whether its tree pollen or dust mites or peanut proteins.

But whats the deal with nickel allergies?

Nickel is a cation-- Ni2+. Our bodies are chock full of cations-- calcium, iron, magnesium, etc, and they dont cause any trouble (or youd be dead). And there are lots of other cations that dont hurt anyone (aluminum, silver, etc). Why Nickel?

Plus, Nickel is a metal. Its not a chunk of a protein, its a metal. How the hell does that work???

Why, apparently its a side-effect of evolution!

Crucial role for human Toll-like receptor 4 in the development of contact allergy to nickel

One of the ways our bodies defend themselves against pathogens is through pattern recognition. Your body *knows* some things aint right, like double-stranded RNA (that just shouldnt be anywhere) or certain patterns in sugars or non-methylated DNA, things humans just dont make. When they see these things that aint right, they release all kinds of pro-inflammatory messengers to get the big guns, the actual immune cells, to pay attention to them.

Turns out Nickel loves to snuggle up to TLR-4. There are a series of three histidines that just plain love Nickel. When Nickel binds, it sets off a similar pro-inflammatory immune response that a chunk of bacterial guts would (in the case of an appropriate immune response) or dust might guts (in the case of another inappropriate immune response).

This is neat information for people trying to figure out why some people are allergic to Nickel, how we can treat/avoid it, and so on. Its not every piece of the puzzle, but its a neat piece that helps us understand something big (OHHH! Its a duck!).

Its also a piece to another puzzle-- Mice are a crappy animal model for Nickel allergies. But TLRs are pretty evolutionarily conserved. wtf? It seems mice do not have those three histidines that Nickel likes. They might have evolved in humans by chance (neutral mutations) or in response to a specific selective pressure (maybe they were useful for defeating some bacteria humans interacted with)-- but they dont have any negative selective pressures against them. Its only in the modern world, where we interact with metals like Nickel all the time, that it results in a negative phenotype!

It also might be a piece to yet another puzzle-- We add adjuvants to vaccines. Basically, extra stuff that makes the vaccine work better. You can use different adjuvants to nudge the immune system towards one kind of response, or another, or just to get a nice immune response to the vaccine in the first place. Whats a Big Name adjuvant? Aluminum. We arent exactly sure how it works-- maybe through this pathway too?

And then theres still the question I have from the very beginning-- Why Nickel? Why not Copper? Zinc? Iron?

Its the best kind of finding-- one that answers some questions, and makes you ask a whole bunch more.

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Nice find!

Whats a Big Name adjuvant? Aluminum. We arent exactly sure how it works-- maybe through this pathway too?

Pretty sure Alum -> inflammasome activation.

And then theres still the question I have from the very beginning-- Why Nickel? Why not Copper? Zinc? Iron?

You still need T-cells for an allergic reaction. T-cells = protein component. Nickel is able to bind peptides in MHC or bridge pept0de-MHC to the TCR. Things like Fe and Zn are already a part of biological processes, so maybe we've evolved to tolerate those sorts of interactions (or there's negative selection in the thymus for T-cells that respond to MHC-peptide-Fe).

Woo! Thanks for covering this, I missed it.
Also, the fact that they used human TLR4 in mouse TLR4 knockouts? A) Brillant and B) very impressive as a technical feat

"And then theres still the question I have from the very beginning-- Why Nickel? Why not Copper? Zinc? Iron?"

Speculation but iron is all over the place. Much of the reddish dirt and clays have iron oxides in them. Being allergic to something so common could be debilitating. Sounds like something that might be selected against.

Also, if my school biology holds, iron, copper, and zinc have important biological roles in the human body. Can you be allergic to something vital to your biochemistry? Can you do it and live?

I don't remember nickel as being really common naturally or having any biological role. Is that why some of us develop problems?

I am highly dubious of this paper. The very fact they managed to not cite the numerous papers which provide alternate explanations - including ones which pretty much refute their conclusion - is concerning to say the least.

Ni2+ behaves much like a superantigen; it can directly X-link MHCs to TCRs, thus (in theory) bypassing the need for co-stimulation. That previous finding alone makes this result suspicious. Super-antigen like mechanisms bypass the "priming" event this paper claims to have found, and the evidence nickel acts in that fashion is pretty strong (and not even mentioned in this study).

But even assuming this paper did identify a "priming" (technically, co-stimulatory) mechanism, its findings are completely in opposition to past studies showing that macrophage and DCs from control patients are completely refractory to Ni2+ stimulation, and its only the DCs and macrophage from pre-sensitized patients that respond to Ni2+. Those previous studies are pretty clear evidence that simply having a human tlr4 isn't enough; contrary to what this new study claims.

Even more suspicious is their lack of response in wild-type mice. Various groups have been inducing Ni2+ hypersensitivity in mice using similar protocols to those used here, since at least 1992 (Griem et al being the first I know of). Somehow that little detail, their inability to replicate those results, and the relevant citations, were left out of this paper...suspicious to say the least.

Just goes to show you, high impact does not mean high quality...

How come my comment got moderated?

More than two links (and note that the sig link counts towards the limit).

As a chemist, nickel(2+) is an interesting ion because it is one of the few common d8 metal systems (with 8 d-orbital electrons). Palladium and platinum are the only other metals with highly stable d8 ions and they are much less likely to oxidize from their metal (un-ionized) form. They are also much less abundant than nickel is.

These d8 metals have unique structural and reactive properties which other metals don't have, particularly in their square planar geometry when forming bonds.

Also, I know chemistry is important, but you don't need to capitalize the word nickel when naming the element (just the chemical symbol, Ni).

Why, apparently its a side-effect of evolution!

Didn't I just write: "Evolutionists can't look at a biological feature and not spin a yarn that proves, in their minds, evolution."

By William Wallace (not verified) on 04 May 2011 #permalink

Iron is not likely to cause allergic reactions. It's not very soluble and has a hard time entering the body.
According to the textbook "Biological Inorganic Chemistry," pg. 60, nickel is present in mamalian blood plasma at the 0.04 micromolar level. There are also many known proteins that use Ni as a cofactor. Also, it is absolutely true that Ni2+ loves histidine. That's how Ni affinity purification works. You can even add imidazole (the functional group of histidine) to a nickel solution and see the color change due to the complex being formed, which shows up spectrophotometrically as a shift in the absorbance peak (originally around ~390 nm, depending on solvent conditions) and an increase in the extinction coefficient, iirc. It's actually a very promiscuous binder, so it's not too surprising that it causes allergic reactions in high concentrations. Probably does a lot of other things we don't know about yet.

By Bill Door (not verified) on 05 May 2011 #permalink

Is there a gene (or genes) known to handle nickle?

By zogthemerciless (not verified) on 06 May 2011 #permalink

A relative of mine who was treated for an impetigo (a strep infection of the skin, treated with mercurochrome prior to the advent of antibiotics) as a child in the '30s has a powerful reaction to mercury of any sort (metallic, inorganic, or organic).

Turns out that lots of things have mercury in them: fillings (he can only have crowns), algicides in swimming pools (usu. only in summer), many ointments (mercuric preservative in ppm ranges), &c. Highly inconvenient for him...