Tuesday, July 30, 2013

Genetic glitch at the root of food allergies?

I see a lot of different research articles on a weekly basis, and there is certainly a lot to be excited about in the realm of basic science research when it comes to understanding the immune system and allergic disorders.  I have to admit, though, a recent study published in Science Translational Medicine has my head spinning (in a good way!), and I hope this post accurately communicates why.



I've noticed that the following write-up of this seminal research by Frischmeyer-Guerrerio et al., Genetic Glitch at the Root of Food Allergies Revealed, received a lot of buzz within the food allergy community over the past week.  How many times have you seen the exciting press-releases about new research with a possible cure for food allergies on the horizon (too many to count in my opinion)?  I've been following this type of thing for long enough now to detect a giant heaping pile of BS in the press coverage of science when I see it.  Do I think that that this particular study is any different from the rest?  Maybe.  Do I think that this will lead to an easy, unrealized treatment sitting right in front of our sniffly allergic noses, with a reversal of the sniffling, sneezing, wheezing, itchy, anxiety-generating threat of anaphylactic allergies within the next five years?  Unlikely, but not impossible (I'll explain more toward the end of the post).  What I am confident in (and why my head is still spinning!) is that this study opens a giant research door for MANY allergy/immunology researchers to understand mechanisms underpinning the immune system's march toward an allergic heightened state of alert.  What this means is that I expect many future lines of research generated from this one research article, which will all cite back to Frishmeyer-Guerrerio et al., 2013.  If we can understand biological mechanisms at the level of individual cells in our bodies, then we can begin to figure out molecular targets (e.g. drugs) to push the immune system back into balance.

I do feel, though, that the title Genetic Glitch at the Root of Food Allergies Revealed is misleading. To me anyway, the title implies that we have figured out a faulty gene that somehow causes food allergy for the allergic masses.  The actual research article, TGF-beta Receptor Mutations Impose a Strong Predisposition for Human Allergic Disease, does not make this claim.  The "genetic glitch" actually refers to a rare genetic disorder called Loeys-Dietz syndrome (LDS).

What is LDS and how does it relate to food allergy?

I certainly have heard a good deal of human medical maladies, and yet, I had never heard of LDS.  Part of the reason is likely because the condition and its genetic underpinnings were first described less than 10 years ago (see B.L. Loeys, et al., Nat Gen, 2005). According to the Loeys-Dietz Foundation website, "Individuals with LDS exhibit a variety of medical features in the cardiovascular, musculoskeletal, skin and gastrointestinal systems," and they are quick to point out that understanding of the condition is still very much evolving.  Now introducing to LDS a "new" medical feature, allergy.  Frishcmeyer-Guerrerio et al. present fresh data that the LDS-inducing mutation leads to a much higher rate of allergic disorders (not just food allergies) than the general population lacking the mutation - we're talking a conservative estimate of 31% of individuals with LDS exhibiting food allergy compared to the ~6% of children and 2-4% of adults estimated to be food allergic.  Woah!  Something is going on here.

What is TGF-beta?

Underlying LDS is a genetic mutation in the cell surface receptor for TGF-beta (aka - transforming growth factor beta), which is a protein cytokine.  And what is a cytokine, you might ask?  It is a chemical messenger secreted by various immune cells in the body to communicate a message to other immune cells throughout the body (although the role of many cytokines, including TGF-beta, stretches well beyond the immune system to other organ systems).  In a large body, where immune cells are widely distributed, it is the job of these chemical messengers, hitching a ride in our blood, lymph, and interstitial nooks and crannies, to get the message out to the other appropriate bodily cells if, for example, a barrier breach just occurred in small intestinal fold #3.  Kind of like a store-wide audio announcement that a spill clean-up is needed on Aisle 3, one receptive store employee will clean up the mess, but many other people in the store will hear the message and avoid Aisle 3, or alternatively they may just ignore the message altogether because their job is cashier.   Who "chooses" to hear the message depends on whether the cell has a cytokine receptor on its surface or not.  How a cell "chooses" to respond once the message is received, depends on what happens downstream of that receptor (and probably a whole slew of other factors going on simultaneously in the "body environment" - imagine if the person in the grocery store who is supposed to clean up spills didn't hear the message because he was outside collecting carts and he forgot to assign someone to cover clean-up duty in his absence.  The possible complex scenarios are endless). In the case of TGF-beta receptor signaling, a network of MANY proteins and genes gets turned on (or off, for that matter) when that message gets received.  And that network can interact with other equally (and frighteningly) complex networks of signals (cytokines and more!).  Let's just say these complex networks are what allows the body to respond appropriately under so many different situations.  It's actually a wonder that things don't go wrong more often!

The simple view:  A receptor at the cell surface (dark blue parallel lines) gets activated by the TGF-beta cytokine (light blue ball).  That message then gets relayed to the cell nucleus (arrow from receptor to nucleus), where it affects a multitude of different genes expressed by the cell.  Such signaling and the downstream gene expression could, for example, tell a specific cell type to turn on production of "allergic" cytokines.  Image Source:  http://www.sabiosciences.com/pathwaymagazine/minireview/TGF-beta.php
The complex view:  The signaling cascade downstream of the TGF beta receptor and a few interactions with other receptor signaling networks (e.g. a generic growth factor or a generic cytokine).  This image gives a flavor of some of the complexity residing in the simple view's  arrow (above image) between surface receptor and nucleus.  THIS complexity is a reason why translating basic science research findings to the clinic takes so darn long!  Image source:  http://www.sabiosciences.com/pathway.php?sn=TGF_Beta_Pathway

So why is this finding so exciting to the allergy community at large?

As I mentioned above, I thought that the "genetic glitch" article title was misleading because allergy sufferers in the general population don't have a TGF-beta mutation, such as in LDS.  The fact, however, that a single genetic hiccup could lead to a preponderance of allergy for people with LDS implies that signaling through TGF-beta and its downstream genetic targets is indeed a crucial pathway in developing an allergic phenotype.  The mutation appears to counter-intuitively I might add, increase the number of immune taming cells, regulatory T cells (Tregs).  If Tregs are immune taming and there are more of them, then how in the world could it lead to more allergy - wouldn't there be less?  Apparently, the researchers found that the Tregs, contrary to their normal role, began secreting a cytokine (IL-13) linked to the allergic phenotype (a T-helper, type 2 cell (Th2) response, for those of you in "the know").  Furthermore, based on multiple lines of evidence, the mutation appears to do this through an increase in TGF beta signaling.  Strange, huh?

We know that for those of us dealing with allergies in the general population (those who don't have LDS), there is likely a complex interplay between multiple genes and our environment at work (e.g. so far, no one single gene or environmental trigger causes allergies in the general population).  However, the researchers looked at Tregs isolated from allergic individuals in the general population and found that they, too, were significantly increased in both the number and the "allergic" Th2 cytokine IL-13 compared to non-allergic controls. So, perhaps, an unknown cascade of events makes your garden-variety allergic individual behave like an LDS allergic individual.  The authors really only looked at a few aspects of immune function, so the proof will be in the nitty-gritty yet to come.  But it's a really promising start.

I will add that there are so many aspects that could be looked at since TGF-beta signaling happens over a lifetime in many different tissue types, not just immune cells (it has multiple functions across space and time).  But I see this finding as being a "Rosetta stone" to understand allergy for the masses.  To borrow from my neuroscience roots, Rett Syndrome is likewise said to be a "Rosetta stone" for what goes wrong in autism spectrum disorders - another condition, like allergy, where a complex interplay between multiple genes and environment is thought to be at play:
But unlike most forms of autism, which have no single known cause, almost all cases of Rett syndrome can be traced to defects in a single gene known as MeCP2.
"Because of similar symptoms and shared genetic links, Rett syndrome is sometimes considered a "Rosetta Stone" that can help us to understand other developmental neurological disorders such as autism and schizophrenia," says Fred H. Gage, a professor in the Salk's Laboratory of Genetics and holder of the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Diseases. 
-From the Salk Institute for Biological Studies
The final point that I will make is that these findings bolster our confidence in using the existing mouse models harboring TGF-beta mutations to study mechanisms of allergy. After all, animal models are incredibly powerful research tools, but only if we're confident they can reliably model human physiology.

An allergy cure on the horizon?

Amazingly, a blood pressure drug, known as losartan, is currently being used to treat individuals with LDS (and a phenotypically related condition, Marfan Syndrome) to help reverse the severe life-threatening phenotype of LDS, aortic aneurysm. Even stranger is that losartan's main action is blocking a completely unrelated target, the angiotensin II type 1 receptor. Researchers just happened to notice that it also appeared to reduce TGF-beta signaling through an unknown mechanism. (Anyone reading about this, who is familiar with the seemingly unrelated pharmacological targets will be probably be just as mystified as me!). If the researchers have any hunch, they certainly aren't giving it away, but I can't wait to find out if LDS patients treated with losartan for the prevention of aortic aneurysm also see a reversal in allergic disorders. If so, could it be used to reverse allergic disorders in the general population? And would it be safe for children under 6 given that TGF-beta is involved in so many aspects of development? That is leaping over a giant chasm of "if this finding is true, then this finding must also be true," and so on, but, this is a drug that is already FDA approved, which could simplify things. Fingers crossed. My fingers already hurt from crossing them in hopes of outgrown allergies (and yes, in case you are wondering, I've only crossed them in odd numbers, since even numbers may negate the beneficial aspects of finger crossing. So scientific, I know.)

What are your thoughts?

I love getting feedback from as diverse backgrounds as possible to help me understand things better. If any of you are experts in these areas, feel free to chime in and verify for accuracy. Likewise, I'm ALWAYS interested to know how non-scientist clinicians/researchers perceive these types of studies and press coverage. Do you feel hopeful? Or is it yet another over-sold "cure" to you?

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3 comments:

  1. I just love reading your blog! You bring the science down for those of us who wish we were scientists, but who will never have your gift.

    Thank you so much for helping us understand this sometimes very confusing world.

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  2. OOPS! Forgot to add that I do appreciate you helping us break down these flashy headlines. I initially ignored the story about LDS--thinking what do I care? I don't even know what it means. But..thanks to you I understand better of the value of the entire article.

    Can't wait to meet you face to face in Vegas at the Food Allergy Bloggers Conference!!

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    1. Caroline, thank you for your kind words! It means a ton to me and gives me motivation to find the time for those more challenging posts. I keep thinking - if only I could clone myself or figure out a way to shirk sleep requirements :). And yes - I am very much looking forward to meeting you at the FAB conference!

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