OAS Wednesday - Activating immunity to suppress autoimmunity.

Every time I see an ad for some remedy that "Helps BOOST the Immune System!"  I die a little inside. It's not just that these products are often homeopathic bull*, but (as I've mentioned before), boosting the immune system can actually be a terrible idea. The immune system is a finely tuned instrument, and too much can be just as bad too little. Too much immune activation leads to allergies and autoimmune disorders like multiple sclerosis (MS) or lupus. We don't know exactly why, but the prevalence of  these "hyperinflammtory disorders," where the immune system is over-active, are on the rise. Unfortunately, most of our treatments (with a few notable exceptions) for these disorders are general blockers of the immune system, and can leave patients vulnerable to infection.

Inflammation scale

Consequently, there is enormous interest in trying to find ways to quiet the immune system to bring it back into balance, without crossing the line into immunosupression. The paper I want to talk about today took what at first glance seems like an odd approach - they activated the immune system in order to silence it.

ResearchBlogging.orgTreatment of Autoimmune Inflammation by a TLR7 Ligand Regulating the Innate Immune System

TLR7 is a receptor of the innate immune system - its normal job is to detect RNA from infectious viruses and activate an inflammatory response. However, the lab authoring this paper had previously shown that repeated stimulation with low doses of a chemical (called 1V136) that is detected by TLR 7 could actually suppress inflammation in the long-term. This isn't terribly surprising - a lot of biological processes have feedback inhibition mechanisms built in - in other words, activation of the system will lead to products that inhibit the system. The signaling pathway downstream of TLR7 is shared by a lot of the innate immune system, so blocking TLR7 signaling blocks all those other systems as well.

It works like this: TLR7 is activated by a low dose of  1v136, leading to some inflammation, but also a feedback signal that blocks future TLR7 signaling (as well as stimulation of other receptors that share the same pathway). The authors wondered whether this feedback could block inflammation coming from another source that normally leads to autoimmunity.

To test this, they used an animal model of multiple sclerosis - a disease in which the immune system attacks the brain. In order to induce this condition, mice are given a "vaccine" that trains the immune system to attack myelin, a critical protein of neurons in the brain. Five days after being given this vaccine, the authors gave some mice the drug 1v136 that triggers TLR7.

I want to give these authors credit - many papers of this sort will start the treatment before they induce disease, which is a little bit disingenuous. We don't know who's going to have MS until they have it, so treatments that might help if taken before the onset of symptoms aren't really useful. These guys start giving the drug on day 5, which is still before the onset of symptoms, but at least it's after they've induced it. It would be more interesting to see what happens if the drug is given after symptoms begin, but this particular animal model probably isn't amenable to that kind of study.

As you can see from the white line in part B above, even the animals that were not given the drug seem to recover, and their recovery is pretty stable over the course of a couple of months. Most people with MS have a disease that is "relapsing and remitting," which means symptoms go away and then come back - usually each relapse is worse than the one before. Any human therapy is going to have to contend with the fact that many patients have had several relapses, and the disease has already progressed before they are diagnosed.

It's also worth noting that this treatment is NOT a selective immunosuppressive - it seems to block immune responses from a variety of sources, so it will likely suffer from the same problem as other drugs - increased susceptibility to infection. That's not necessarily a knock against it - the drugs we have don't work for all patients and having more arrows in the quiver to fight these diseases is always a good thing. And if you're suffering from autoimmunity, an increased susceptibility to infection is worth the relief. I say this as someone who's grandmother died of an infection - one she likely would have survived had she not been on are arthritis meds. But without those meds, the two decades leading up to her death would have been filled with horrendous pain in her joints.

Autoimmunity sucks, and it's on the rise, but thankfully we're getting better and better at dealing with it, one experiment at a time.

[OAS (open access science) wednesday is an attempt to highlight research published in Open Access Journals like PLoSeLife and PeerJHere are some reasons why I think OAS is important. Also check out the Open Science Federation]

Hayashi, T., Yao, S., Crain, B., Chan, M., Tawatao, R., Gray, C., Vuong, L., Lao, F., Cottam, H., Carson, D., & Corr, M. (2012). Treatment of Autoimmune Inflammation by a TLR7 Ligand Regulating the Innate Immune System PLoS ONE, 7 (9) DOI: 10.1371/journal.pone.0045860

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Scientists interested in quieting the immune should learn some techniques from librarians; they're very, very adept at silencing things.


Since there isn't a 1:1 dependency between the inflammatory and cell-mediated immune responses, the question that comes to mind is: how do various approaches to quieting the inflammatory responses compare WRT cell-mediated immunity?

By D. C. Sessions (not verified) on 15 May 2013 #permalink

Excellent question. Just so we're on the same page, "cell-mediated" immunity is sort of an outdated term, but broadly it refers to T-cells... I'm pretty sure I understand what you're asking though (feel free to clarify if I go off the rails).

You're right, there's not a 1:1 dependency, but all of the branches of the immune system work together to cause problems in autoimmune disorders. To further complicate things, some auto-immune disorders are considered to be more anti-body (B-cell) based or more T-cell based. However, the cross-dependency means that any drugs that suppress part of the immune system will likely have some effect on autoimmune disorders.

For instance, rheumatoid arthritis is largely considered to be an B-cell mediate disease. B-cells make antibodies that bind to self-antigens, and that's at the root of the disease. But the pathology of RA is because of inflammation - those antibodies find lots of targets, and clog up the joints, which pisses off the macrophages in the area and they make cytokines that recruit other immune cells from the blood and cause swelling. Some of those immune cells are T-cells, which are necessary to provide activating signals and survival signals to the B-cells, which then make more antibodies... It's a self reinforcing cycle, and disrupting any part of it can lead to some relief. The same thing happens during an infection, the difference is that at some point an infection will be cleared, whereas your self-antigens are always there.

Of course, some drugs work better for some autoimmune disorders than others. General anti-inflammatory drugs will work generally, but things that destroy B-cells (look up rituxumab) work best on things like arthritis and lupus which are antibody mediated, whereas drugs that hit T-cells work best in things like MS. On the other hand, rituximab has been used with some success in treating MS, despite the fact that MS is supposed to be a T-cell mediated disease.

I imagine this has just made things more confusing, but the immune system is super complex and everything feeds into or regulates everything else. It's hard to just look at one thing in isolation.

I imagine this has just made things more confusing, but the immune system is super complex and everything feeds into or regulates everything else. It’s hard to just look at one thing in isolation.

Not at all. I know that it's complicated with all sorts of interrelated causal paths. The same relationships that cause multiple consequences for a given stimulus and allow multiple stimuli to lead to any given consequence implies that you're almost certain to have different weights to each path -- and thus some "knobs" will be more effective at controlling a targeted outcome than others.

By D. C. Sessions (not verified) on 15 May 2013 #permalink

It's interesting, your comment about MS being aT-cell mediated disease. I note that Low Dose Naltrexone, an experimental, but highly effective drug for MS and other autoimmune diseases down regulates B-cells and up regulates T-cells.