Thursday, November 15, 2012

Treating autoimmune disease the low-tech way?

Helminths and asthma
A map of asthma prevalence around the world shows that it is higher in industrialized parts of the world; higher in urban than rural areas, including urban Africa and South America, higher in what was West Germany after the wall came down than what was East Germany, higher in temperate zones than the tropics, and so on.  The question of why has been the subject of much research, much of that focusing on the lowly helminth, at least in tropical regions, parasitic worms that infect the gut of a high fraction of rural children in poverty.  The generic explanation for this has been the 'hygiene hypothesis,' which we wrote about here; basically, too much cleanliness can be a very bad thing.

Worldwide prevalence of asthma; from 'Global Burden of Asthma,' 2004

So, what's the mechanism that could explain the benefit of chronic helminthic infection?  The idea is that the parasites may suppress allergic inflammation, thus protecting against asthma, and indeed the allergy often associated with asthma.

A 2002 paper, e.g., in The Journal of Translational Immunology suggests:
There is good evidence that the expression of inflammation caused by helminth infections can be modulated by the host immune response, and that the failure of the expression of similar mechanisms among individuals predisposed to allergy may be responsible for the clinical expression of allergic disease. Further, there is accumulating evidence that helminth infections, particularly those caused by intestinal helminth parasites (or geohelminths) may be capable of modulating the expression of allergic disease.
Helminths and autoimmune disease in general
It turns out that a map of prevalence of any autoimmune disease around the world would show much the same trend as that of asthma -- higher prevalence in richer countries than lower, and presumably this is a true effect, not simply due to ascertainment bias based on poor access to health care in poorer parts of the world. Thus, the same question has been asked of other autoimmune 'diseases of westernization,' -- inflammatory bowel disease of Crohn's, rheumatoid arthritis, type 1 diabetes and multiple sclerosis. There are even suggestions that perhaps a third of the cases of autism could be due to autoimmune disease, as described in this piece in The New York Times in August. Could helminth infection be protective?  Many studies looking at preventing or treating these diseases with infection in mouse models have been reported, a few done in humans, including some self-experimentation, and many have been found to prevent disease entirely, or to alleviate symptoms (here's a pretty extensive table of the studies that have been done, in Parasitology Research Monographs). 

Now a piece in Nature ("Autoimmunity: the worm returns") reports the work of a gastroenterologist as he endeavors to determine the effects of helminth infection specifically on people with inflammatory bowel disease and multiple sclerosis. The author, Joel Weinstock, has worked for decades on inflammatory bowel disease, long wondering why it has become so prevalent in the last century.  He also knows his parasites, so that thinking about the possible connection between eliminating parasite infections and disease was not at all far-fetched.

Of course, as Weinstock also points out, parasite infections can have disastrous consequences, damaging the liver, bladder, or eyesight, e.g., so he had to proceed with caution.  But, as he describes, history and the map of the US seem to lend support to the idea of too much hygiene being a dangerous thing, so this was an insight he couldn't not pursue. 
In the United States and Europe, Crohn's disease first emerged in affluent populations living in hygienic conditions in the more northerly latitudes, where colder temperatures are less hospitable to soil-borne helminths. One of the last US groups to present with Crohn's disease was African Americans, who are, on average, poorer than their white counterparts. Similarly, in Europe, autoimmune diseases are more common in the richer Western Europe than in Eastern Europe.
Today, Native American reservations, which have relatively high rates of infection with parasitic worms, also have lower rates of inflammatory bowel disease. Latinos born and raised in South America rarely develop this gut disorder. If their children are born in the United States, where conditions are often more sanitary, they have a much higher risk of the disease.
Correlation does not equal causation, however, and the link had to be demonstrated. So, he began giving helminths to the mice in his lab that were models for inflammatory bowel disease, and did in fact show that they were protected against disease. He then moved on to treating volunteers, in whom he saw no adverse effects, and usually actual attenuation of disease, both bowel disease and MS. Pharmaceutical companies are now becoming interested, and double-blind studies of the effect of helminth infection on autoimmune disease are now being done.

How might parasites be protective?
Weinstock suggests that worms 'seem to have three major effects on the immune system.'  First, they cause changes in regulatory T cells so that they tone down the immune response, including autoimmune responses.  Second, they 'seem to act on other cells -- dendritic cells and macrophages,' which prevents the ramping up of the inflammatory response.  Yes, this is redundant, as Weinstock has shown in experimental studies.  And, third, they 'seem to alter the bacterial composition of intestinal flora,' in a way similar to ingesting 'probiotics,' helping to maintain intestinal health.

So if this work is right, and if cleanliness is next to godliness, it's starting to look as though the gods don't mind having a whole lot of sick people at their sides.  Weinstock is not suggesting that the industrialized world return to the heavy parasite loads of the recent past, rather that controlled infection might be a good thing.

So low-tech, and yet with the potential to eliminate a huge disease burden.  And not a word about genes!  Of course, one can expect the massive, heavy-handed vested gene industry to start to argue about genetic variation in susceptibility to the parasites.  Of course there will be some of that, but it is likely to be more GWAS minutiae rather than major causal factors.

Herein we must add a caution, however.  One-size-fits-all explanations are rife these days, and it seems unlikely that intestinal worms could explain so many increasing disorders of different types. Usually, the miracle discovery turns out to be a mirage, relevant in some particulars but usually minor ones.  In this case, neither the immune system nor autoimmune diseases nor how the immune system responds to infection with helminths is well-enough understood for the cause and effect here to be convincing.

Empirical data seem suggestive, but the tropics/temperate zone gradient is also associated with numerous other factors, which has lead, e.g., to the sun/vitamin D exposure hypothesis with respect to multiple sclerosis, and clustering of cases has been suggestive of infectious causation.  The hygiene hypothesis is not confirmed in all studies, and data quality is surely not comparable across regions of the world, and so on.  A lot of caveats.  We'll just have to see how this one turns out.


Daniel M Parker said...

Hi Anne,
This is a really fascinating topic. I've got two questions/comments:
As nations underwent industrialization, many or most went through something called the epidemiological transition. One aspect of this transition is a decrease in infectious disease mortality, and perhaps the age groups most affected were the very young. It seems as though a lot of selection would have occurred before age 1. I’ve wondered, and I think I’ve heard people speak about this, if this has anything to do with some of the diseases we now see more prevalent in industrialized, wealthier nations. Do you, Ken, or Holly have any thoughts on this idea?

Ken Weiss said...

A couple of things. If any kind of selection will hasten the evolution of resistance it would be childhood mortality since fitness is reduced to zero in the children (or you could say, in the parents who produce no viably reproductive offspring).

However, there is an old called 'reproductive compensation' that could possibly apply. If the loss of a child early in life leads parents to replace it by having another sooner than they would do otherwise, then heterozygous genotypes for recessive effects could still be born, reproduce and hence perpetuate the relevant alleles.

In wealthier nations recessive traits should appear less often, since the population size is large enough that two carriers would mate less often. Rapid population expansion could raise the frequency of heterozygotes if they have any relevant phenotype. But for dominant susceptibility alleles this would not have an effect other than to continually purge such alleles.

So the genetic mechanism would have a lot to do with what effects one might see.

Anne Buchanan said...

Ack, Dan, I hate to wade in here since you and Ken, at least, know a lot more about this than I do. But here I go. My quick and dirty response would be that where the epidemiological transition happened, it was too recently for selection to be affecting who gets what. I suspect that overwhelming infectious disease is too much of an equal opportunity killer, and who survives is largely luck. I know that some argue that the plague and smallpox were selective, and those who survived might be less susceptible to HIV via the CCR5 mutation, but there's a lot of HIV in people with European ancestry, and anyway that was pre-epidemiological transition, yes?

And then of course there's the question of whether wealthier nations really are post infectious disease.

Daniel M Parker said...

Anne, this continues to be very interesting food for thought. Epidemiological transitions tend to not follow the stereotyped model very well. And here in the U.S. we may actually be seeing the return of lots of infectious disease (though not yet to be a concern for overall mortality). And diseases like HIV follow such different trajectories, to a large extent affecting much different socio-economic class, age and sex groups than typical diseases of the poor...
I've also heard people claim that the influenza pandemic of 1918 (which I won't attribute to any one nation!) was such a big killer because it hijacked strong immune systems, actually killing people with what should have been the best immune responses.

Daniel M Parker said...

Thanks for the reply too Ken. I think that many people who study selection in humans forget that arguably the biggest impediment to passing on your genes has historically been making it past early childhood, let alone even making it to birth. I suppose it’s a less sexy topic for research. And thinking about mortality in children is pretty depressing.