An Immune Disorder at the Root of Autism
By
MOISES VELASQUEZ-MANOFF - Published: August 25, 2012
IN recent years, scientists have made extraordinary advances in understanding the causes of autism,
now estimated to afflict 1 in 88 children. But remarkably little of
this understanding has percolated into popular awareness, which often
remains fixated on vaccines.
Eleanor Davis
So here’s the short of it: At least a subset of autism — perhaps
one-third, and very likely more — looks like a type of inflammatory
disease. And it begins in the womb.
It starts with what scientists call immune dysregulation. Ideally, your
immune system should operate like an enlightened action hero, meting out
inflammation precisely, accurately and with deadly force when
necessary, but then quickly returning to a Zen-like calm. Doing so
requires an optimal balance of pro- and anti-inflammatory muscle.
In autistic individuals, the immune system fails at this balancing act.
Inflammatory signals dominate. Anti-inflammatory ones are inadequate. A
state of chronic activation prevails. And the more skewed toward
inflammation, the more acute the autistic symptoms.
Nowhere are the consequences of this dysregulation more evident than in
the autistic brain. Spidery cells that help maintain neurons — called
astroglia and microglia — are enlarged from chronic activation.
Pro-inflammatory signaling molecules abound. Genes involved in
inflammation are switched on.
These findings are important for many reasons, but perhaps the most
noteworthy is that they provide evidence of an abnormal, continuing
biological process. That means that there is finally a therapeutic
target for a disorder defined by behavioral criteria like social
impairments, difficulty communicating and repetitive behaviors.
But how to address it, and where to begin? That question has led
scientists to the womb. A population-wide study from Denmark spanning
two decades of births indicates that infection during pregnancy increases the risk of autism in the child. Hospitalization for a viral infection, like the flu,
during the first trimester of pregnancy triples the odds. Bacterial
infection, including of the urinary tract, during the second trimester
increases chances by 40 percent.
The lesson here isn’t necessarily that viruses and bacteria directly
damage the fetus. Rather, the mother’s attempt to repel invaders — her inflammatory response — seems at fault. Research by Paul Patterson,
an expert in neuroimmunity at Caltech, demonstrates this important
principle. Inflaming pregnant mice artificially — without a living
infective agent — prompts behavioral problems in the young. In this
model, autism results from collateral damage. It’s an unintended
consequence of self-defense during pregnancy.
Yet to blame infections for the autism epidemic is folly. First, in the
broadest sense, the epidemiology doesn’t jibe. Leo Kanner first described infantile autism
in 1943. Diagnoses have increased tenfold, although a careful
assessment suggests that the true increase in incidences is less than
half that. But in that same period, viral and bacterial infections have
generally declined. By many measures, we’re more infection-free than
ever before in human history.
Better clues to the causes of the autism phenomenon come from parallel
“epidemics.” The prevalence of inflammatory diseases in general has
increased significantly in the past 60 years. As a group, they include asthma, now estimated to affect 1 in 10 children — at least double the prevalence of 1980 — and autoimmune disorders, which afflict 1 in 20.
Both are linked to autism, especially in the mother. One large Danish
study, which included nearly 700,000 births over a decade, found that a
mother’s rheumatoid arthritis, a degenerative disease of the joints, elevated a child’s risk of autism by 80 percent. Her celiac disease,
an inflammatory disease prompted by proteins in wheat and other grains,
increased it 350 percent. Genetic studies tell a similar tale. Gene
variants associated with autoimmune disease — genes of the immune system
— also increase the risk of autism, especially when they occur in the
mother.
In some cases, scientists even see a misguided immune response in action. Mothers of autistic children often have unique antibodies
that bind to fetal brain proteins. A few years back, scientists at the
MIND Institute, a research center for neurodevelopmental disorders at
the University of California, Davis, injected these antibodies into
pregnant macaques. (Control animals got antibodies from mothers of
typical children.) Animals whose mothers received “autistic” antibodies
displayed repetitive behavior. They had trouble socializing with others
in the troop. In this model, autism results from an attack on the
developing fetus.
But there are still other paths to the disorder. A mother’s diagnosis of asthma or allergies during the second trimester of pregnancy increases her child’s risk of autism.
So does metabolic syndrome, a disorder associated with insulin resistance, obesity
and, crucially, low-grade inflammation. The theme here is maternal
immune dysregulation. Earlier this year, scientists presented direct
evidence of this prenatal imbalance. Amniotic fluid collected from
Danish newborns who later developed autism looked mildly inflamed.
Debate swirls around the reality of the autism phenomenon, and rightly
so. Diagnostic criteria have changed repeatedly, and awareness has
increased. How much — if any — of the “autism epidemic” is real, how
much artifact?
YET when you consider that, as a whole, diseases of immune dysregulation
have increased in the past 60 years — and that these disorders are
linked to autism — the question seems a little moot. The better question
is: Why are we so prone to inflammatory disorders? What has happened to
the modern immune system?
There’s a good evolutionary answer to that query, it turns out.
Scientists have repeatedly observed that people living in environments
that resemble our evolutionary past, full of microbes and parasites,
don’t suffer from inflammatory diseases as frequently as we do.
Generally speaking, autism also follows this pattern. It seems to be
less prevalent in the developing world. Usually, epidemiologists fault
lack of diagnosis for the apparent absence. A dearth of expertise in the
disorder, the argument goes, gives a false impression of scarcity. Yet
at least one Western doctor who specializes in autism has explicitly
noted that, in a Cambodian population rife with parasites and acute
infections, autism was nearly nonexistent.
For autoimmune and allergic diseases linked to autism, meanwhile, the
evidence is compelling. In environments that resemble the world of yore,
the immune system is much less prone to diseases of dysregulation.
Generally, the scientists working on autism and inflammation aren’t
aware of this — or if they are, they don’t let on. But Kevin Becker, a
geneticist at the National Institutes of Health, has pointed out that
asthma and autism follow similar epidemiological patterns. They’re both
more common in urban areas than rural; firstborns seem to be at greater
risk; they disproportionately afflict young boys.
In the context of allergic disease, the hygiene hypothesis — that we
suffer from microbial deprivation — has long been invoked to explain
these patterns. Dr. Becker argues that it should apply to autism as
well. (Why the male bias? Male fetuses, it turns out, are more sensitive
to Mom’s inflammation than females.)
More recently, William Parker
at Duke University has chimed in. He’s not, by training, an autism
expert. But his work focuses on the immune system and its role in
biology and disease, so he’s particularly qualified to point out the
following: the immune system we consider normal is actually an
evolutionary aberration.
Some years back, he began comparing wild sewer rats with clean lab rats.
They were, in his words, “completely different organisms.” Wild rats
tightly controlled inflammation. Not so the lab rats. Why? The wild
rodents were rife with parasites. Parasites are famous for limiting
inflammation.
Humans also evolved with plenty of parasites. Dr. Parker and many others
think that we’re biologically dependent on the immune suppression
provided by these hangers-on and that their removal has left us prone to
inflammation. “We were willing to put up with hay fever, even some autoimmune disease,” he told me recently. “But autism? That’s it! You’ve got to stop this insanity.”
What does stopping the insanity entail? Fix the maternal dysregulation,
and you’ve most likely prevented autism. That’s the lesson from rodent
experiments. In one, Swiss scientists created a lineage of mice with a
genetically reinforced anti-inflammatory signal. Then the scientists
inflamed the pregnant mice. The babies emerged fine — no behavioral
problems. The take-away: Control inflammation during pregnancy, and it
won’t interfere with fetal brain development.
For people, a drug that’s safe for use during pregnancy may help. A
probiotic, many of which have anti-inflammatory properties, may also be
of benefit. Not coincidentally, asthma researchers are arriving at
similar conclusions; prevention of the lung disease will begin with the
pregnant woman. Dr. Parker has more radical ideas: pre-emptive
restoration of “domesticated” parasites in everybody — worms developed
solely for the purpose of correcting the wayward, postmodern immune
system.
Practically speaking, this seems beyond improbable. And yet, a trial is
under way at the Montefiore Medical Center and the Albert Einstein
College of Medicine testing a medicalized parasite called Trichuris suis
in autistic adults.
First used medically to treat inflammatory bowel disease, the whipworm, which is native to pigs, has anecdotally shown benefit in autistic children.
And really, if you spend enough time wading through the science, Dr.
Parker’s idea — an ecosystem restoration project, essentially — not only
fails to seem outrageous, but also seems inevitable.
Since time immemorial, a very specific community of organisms —
microbes, parasites, some viruses — has aggregated to form the human
superorganism. Mounds of evidence suggest that our immune system
anticipates these inputs and that, when they go missing, the organism
comes unhinged.
Future doctors will need to correct the postmodern tendency toward
immune dysregulation. Evolution has provided us with a road map: the
original accretion pattern of the superorganism. Preventive medicine will need, by strange necessity, to emulate the patterns from deep in our past.
Reacties
Een reactie posten