The title of a paper in the advanced online publication section of Nature refers to a possible link between environmental toxins and autoimmune disease: an irresistible hook, and of course I could not resist. So followed some excited perusal of Veldhoen et al (doi:10.1038/nature06881) and another paper on the same subject, Quintana et al (doi:10.1038/nature06880), also in the AOP section.
So is there a link between environmental toxins and autoimmunity? Well, maybe, though I am not entirely convinced of that aspect of things, and here is why. Both papers discuss the effect of triggering the aryl hydrocarbon receptor (AHR) on T cells (description in the sidebar, for those of you are interested). The AHR, to my chemistry-ignorant mind, is a protein that binds hydrocarbon molecules with aromatic rings. The AHR is a type of protein, called a transcription factor, that decides when genes are turned on. In tune with this known ability of the AHR, both studies find that triggering the AHR on a subset of T cells called helper T cells turns on genes that influence the function of these T cells.
Helper T cells can direct the immune response along different paths, towards a more allergic response, one that is better suited to the fighting of infection, or towards a more inflammatory response which can result in the immune system attacking oneself—“auto”immunity. Helper T cells work by producing cytokines, small proteins that zip around the body carrying messages from one cell to another. Helper T cells that produce the cytokine IL-17, called Th17 cells, play a large role in autoimmune diseases: for instance, blocking IL-17 in a mouse model of multiple sclerosis, experimental autoimmune encephalitis (EAE), protects mice from getting the disease. Other helper T cells—regulatory T cells or Tregs—combat autoimmunity by battening down active T cells, and giving mice Tregs can protect them from a variety of autoimmune diseases. So helper T cells can go either way, either promoting or suppressing autoimmune disease.
Veldhoen et al find that triggering the AHR on helper T cells through its ligand FICZ* enhances the generation of both mouse and human Th17 cells. Treating mice with FICZ also accelerates the progress of EAE, suggesting that triggering the AHR enhances autoimmunity. FICZ is generated by UV treatment of tryptophan, an essential amino acid, and the authors suggest that it may be generated by exposure of the skin to UV light, thereby connecting environmental factors to an autoimmune disease. A connection I find a bit tenuous, but the idea is interesting and novel, and I am very curious to know what they find next.
Quintana et al present a more detailed study, with results that suggest something different. They find that triggering the AHR through a more famous ligand, TCDD**, leads to the enhanced development of Tregs, the tranquilizers of the immune response. Now, TCDD is thought to be very toxic, and is found in the environment (most infamously, in Agent Orange), but it seems to actually counteract autoimmunity, because treating mice with TCDD considerably slows down their development of EAE. Qunitana et al also agree that FICZ treatment enhances the generation of Th17 cells, and simultaneously retards Treg formation.
Both compounds bind to the AHR with different affinities, and possibly in different ways, which might explain their opposing actions. In any case, aromatic hydrocarbons are capable of modulating the immune response and shaping its eventual outcome, an exciting and novel set of findings. That they have such strong effects (reversing or accelerating EAE is pretty strong) certainly suggests that they bear further study, and back up the idea that things in the environment can have an effect on our immune systems. After all, having too many Tregs because you were exposed to TCDD may save you form some autoimmunity, but too-tranquil T cells are not very good at fighting off infections. Similarly, too much sun can turn tryptophan—which we absolutely need—into FICZ, which can then diffuse off into our bodies and do something to exacerbate autoimmunity somewhere. Food for thought.
*6-Formylindolo[3,2-b]carbazole (FICZ)
**2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD, dioxin)
The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins
Marc Veldhoen, Keiji Hirota, Astrid M. Westendorf, Jan Buer, Laure Dumoutier, Jean-Christophe Renauld & Brigitta Stockinger
doi:10.1038/nature06881
Control of Treg and TH17 cell differentiation by the aryl hydrocarbon receptor
Francisco J. Quintana, Alexandre S. Basso, Antonio H. Iglesias, Thomas Korn, Mauricio F. Farez, Estelle Bettelli, Mario Caccamo, Mohamed Oukka & Howard L. Weiner
doi:10.1038/nature06880
9 comments:
Fantastic post! I haven't read the actual papers--did either one look at how long the effects of FICZ or TCDD lasted, and what is the lifespan of Th17 cells or Tregs? I'm wondering whether it would take chronic exposure (there's probably dose dependence too) to have longterm effects on the immune system.
It's interesting that activation of the AHR with different ligands has opposite results. I foresee microarray experiments on T-helper cells treated with either FICZ or TCDD coming up!
Their EAE experiments were pretty long-term, at least in mouse terms, upto almost 30 days in both cases, but I don't know what the half-life of the compounds is. Or how long the Tregs persist, it is the key as you say.
Funny that you mention microarray, they found AHR in a microarray on Th17 cells :)
Veo, I would love to do mouse experiments that are 30 days long. Some of mine are over a year long! Needless to say, I spend a lot of time praying none of the mice get pinworm or MHV....
Did the authors of the paper that claims induction of Tregs actually look at absolute numbers, or do they base their theory solely on % increase? Just asking since TCDD is of course very toxic. So, did a lot of cells die, and Tregs died less?
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Smoking increases the risk of several autoimmune diseases, primarily because of the chemicals in cigarettes.
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This is the perfect blog for anyone who wants to know about this topic. Helper T-cells protect our bodies against disease by eliminating cancerous cells, and those infected with viruses and bacteria....
Thank you!
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