Tuesday, September 4, 2012
Antioxidant Therapy for Idiopathic Pulmonary Fibrosis
editorials
www.nejm.org november 24, 2005 2285
Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by fibrosis and remodeling of the lung parenchyma. The median survival of patients with the disease is about three years after diagnosis or five years after the onset of symptoms.
The pathological findings are those of usual interstitial pneumonia.1 In many instances, the diagnosis can be made when typical clinical and radiologic features are present.2-5 The classic radiologic features are a patchy pattern of peripheral “honeycombing” that is more prominent in the bases of the lungs, traction bronchiectasis, and the absence of prominent ground-glass opacity. When these findings are not present, a surgical biopsy of the lung is needed for diagnosis. A consensus statement on IPF from the American Thoracic Society–European Respiratory Society recommends therapy with prednisone and a cytotoxic agent, such as azathioprine. 6 However, there is little evidence that these agents alter the natural history of the disease. There may be some benefit from prednisone since it can help suppress cough in patients with this disease. However, there is no strong evidence supporting the clinical effectiveness of these treatments in patients with IPF. Indeed, since prednisone and cytotoxic agents do not benefit patients with IPF, it is reasonable to assume they cause harm, because each of these drugs is known to have substantial adverse effects. One of the side effects of prednisone is to promote physical deconditioning. This is especially important for patients with IPF, whose exercise capacity is already limited because of dyspnea. Cytotoxic agents probably cause injury, at some level, to all tissues of the body, in addition to their well-known myelotoxic effects. If a beneficial effect has been hard to demonstrate, why are these agents used to treat IPF? One reason may be a lack of specificity of the diagnosis in earlier studies. Many older studies included a related lung disorder, nonspecific interstitial pneumonia, under the diagnostic rubric we now consider as IPF. Nonspecific interstitial pneumonia can be associated with inflammation in the lung and can respond to drugs such as prednisone and azathioprine. Even though nonspecific interstitial pneumonia has been separated from IPF as a diagnostic entity, many clinicians continue to use prednisone and azathioprine as a treatment for IPF. Another reason for the use of these drugs is the lack of other effective therapies. A recent study suggested that pirfenidone might be useful as a therapy, but its effect as a single agent is not clear.7 Another study using interferon gamma showed no effect on the primary end point,8 although a subgroup analysis suggested an effect on early disease.
The effect of interferon gamma in patients with early disease is now under investigation. A number of other industry-supported trials are also under way. The National Heart, Lung, and Blood Institute recognized the need to develop therapies for the disease by establishing the IPF Clinical Research Network. The hope is that patients will be enrolled in these trials and therapies that are clearly effective will be forthcoming. Although the cause of IPF is not known, less emphasis is now placed on inflammation as a cause of the lung injury in this condition. Current hypotheses suggest that IPF results from repeated or ongoing episodes of acute lung injury that primarily affect peripheral areas of the lung.9 A related theory is that there may be an excess of type 2 helper T-cell (Th2) cytokines that facilitates the lung injury and fibrosis. These observations have kindled an interest in agents that may affect lung fibrosis and repair. In this issue of the Journal, Demedts et al.10 tested another therapy for IPF — antioxidant therapy. In this multicenter study, patients with IPF were randomly assigned to receive prednisone and azathioprine (the “standard of care”) or prednisone, azathioprine, and acetylcysteine. After one year of treatment, patients who received acetylcysteine, in addition to prednisone and azathioprine, had significantly better preserved vital capacity and diffusing capacity for carbon monoxide (DlCO). A substantial number of patients dropped out of the study, and differences in vital capacity and DlCO after one year were relatively small and were probably not clinically significant; the effect on the outcome of the patients who withdrew from the study is Antioxidant! Therapy for Idiopathic Pulmonary Fibrosis Gary W. Hunninghake, M.D.
The new england journal of medicine n engl j med 353;21 www.2286 nejm.org november 24, 2005 not known. The administration of acetylcysteine had no effect on survival. The investigators stated that the rationale for this study was provided by a number of earlier observations showing that patients with IPF have depleted levels of glutathione in the lung and that this depletion can be corrected by treating patients with acetylcysteine. This observation is not unique to IPF and is found in many chronic inflammatory disorders. Glutathione is an important antioxidant in all tissues and is crucial for many aspects of cell metabolism and survival (Fig. 1). Tissues that are depleted of glutathione are more susceptible to injury. Uptake of cysteine by cells is a rate-limiting step for the synthesis of glutathione. Ace- Figure 1.!Synthesis!of!Glutathione. Glutathione is synthesized from three amino acids: l-glutamine, l-cysteine, and l-glycine. Absolute levels of glutathione and the ratio of glutathione to glutathione disulfide are crucial for the maintenance of normal cell metabolism and survival. One function of glutathione is to detoxify a wide variety of reactive oxygen species that are generated within and outside of cells. During this detoxification process, glutathione is converted to glutathione disulfide. Under normal conditions, glutathione disulfide can be reconverted to glutathione, preserving both normal levels of glutathione and the ratio of glutathione to glutathione disulfide. In some conditions of acute or chronic stress, the ratio of glutathione to glutathione disulfide cannot be maintained, and glutathione disulfide is exported from cells. In addition, synthesis cannot proceed fast enough to replenish cellular stores of glutathione. Associated with this process is a depletion of a pool of other mixed antioxidant thiols. This depletion results in altered cell metabolism and injury. The synthesis of glutathione can be accelerated by the administration of acetylcysteine, which crosses cell membranes easily and can be converted to l-cysteine. Uptake of l-cysteine is an important rate-limiting step for the synthesis of glutathione. Acetylcysteine increases the pool of other antioxidant thiols that also protect cells from injury. editorials n engl j med 353;21 www.nejm.org november 24, 2005 2287 tylcysteine is used to increase the production of glutathione because it crosses cell membranes easily and can be converted to cysteine. The drug also increases the pool of other mixed antioxidant thiols. These other reduced thiols can also protect cells from injury. The use of acetylcysteine to prevent acute liver injury in the setting of an acetaminophen overdose has been well demonstrated. Acetaminophen, in large doses, generates a profound oxidant stress in liver tissue that depletes glutathione and other antioxidant thiols. When levels of these thiols drop below a critical level, there may be an explosive onset of liver injury. Acetylcysteine prevents this liver injury by maintaining adequate cellular levels of glutathione and other antioxidant thiols. What can we conclude from the study by Demedts et al.? One obvious conclusion is that acetylcysteine is directly beneficial as a therapy for IPF. However, another conclusion should also be considered. It is possible that the combination of prednisone and azathioprine is toxic to patients with IPF. If this were true, then it would be likely that the effects of acetylcysteine in this study are explained by the drug’s prevention of the toxic effects of prednisone and azathioprine. It is known that azathioprine depletes liver tissue of glutathione and that acetylcysteine can, in some settings, prevent liver injury. 11,12 In support of the latter hypothesis is the observation in the study by Demedts et al. that there were fewer myelotoxic effects in the group of patients with IPF who received acetylcysteine. Thus, it is not clear from this study whether the drug has direct beneficial effects on IPF or whether it prevents the toxic effects of prednisone and azathioprine. Therefore, a prospective study comparing prednisone and azathioprine with placebo is needed to address this issue. If a new study showed toxic effects or no effect of prednisone and azathioprine, investigators conducting studies of new therapies for IPF would be liberated from the use of this “standard of therapy,” and patients would be freed from exposure to these potentially toxic drugs. It is not clear how this study will affect the treatment of IPF. Since there are no therapies that are clearly effective for IPF, many physicians and patients will find the use of acetylcysteine to be very seductive. In many ways, if it were ultimately shown to be effective, it would be an ideal drug (i.e., beneficial with few side effects). Also, acetylcysteine is available without prescription. It is hoped that these observations will not prevent the design of a new study that evaluates whether acetylcysteine directly benefits patients with IPF. For now, physicians caring for patients with this disease should encourage their participation in clinical trials. There are still too many unresolved questions to continue to treat patients by guesswork. From the Department of Medicine, University of Iowa and Veterans Affairs Medical Center, Iowa City. American Thoracic Society, European Respiratory Society. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias: this joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001. Am J Respir Crit Care Med 2002;165:277-304. [Erratum, Am J Respir Crit Care Med 2002;166:426.] Hunninghake GW, Zimmerman MB, Schwartz DA, et al. Utility of a lung biopsy for the diagnosis of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2001;164:193-6. Hunninghake GW, Lynch DA, Galvin JR, et al. Radiologic findings are strongly associated with a pathologic diagnosis of usual interstitial pneumonia. Chest 2003;124:1215-23. Raghu G, Mageto YN, Lockhart D, Schmidt RA, Wood DE, Godwin JD. The accuracy of the clinical diagnosis of new-onset idiopathic pulmonary fibrosis and other interstitial lung disease: a prospective study. Chest 1999;116:1168-74. Lynch DA, David Godwin J, Safrin S, et al. High-resolution computed tomography in idiopathic pulmonary fibrosis: diagnosis and prognosis. Am J Respir Crit Care Med 2005;172:488-93. American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment: international consensus statement. Am J Respir Crit Care Med 2000;161:646-64. Azuma A, Nukiwa T, Tsuboi E, et al. Double-blind, placebocontrolled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2005;171:1040-7. Raghu G, Brown KK. Interstitial lung disease: clinical evaluation and keys to an accurate diagnosis. Clin Chest Med 2004;25:409-19. Gross TJ, Hunninghake GW. Idiopathic pulmonary fibrosis. N Engl J Med 2001;345:517-25. Demedts M, Behr J, Buhl R, et al. High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 2005;353:2229-42. Menor C, Fernandez-Moreno MD, Fueyo JA, et al. Azathioprine acts upon rat hepatocyte mitochondria and stress-activated protein kinases leading to necrosis: protective role of N-acetyl-Lcysteine. J Pharmacol Exp Ther 2004;311:668-76. Lee AU, Farrell GC. Mechanism of azathioprine-induced injury to hepatocytes: roles of glutathione depletion and mitochondrial injury. J Hepatol 2001;35:756-64. Copyright © 2005 Massachusetts Medical Society.
Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by fibrosis and remodeling of the lung parenchyma. The median survival of patients with the disease is about three years after diagnosis or five years after the onset of symptoms.
The pathological findings are those of usual interstitial pneumonia.1 In many instances, the diagnosis can be made when typical clinical and radiologic features are present.2-5 The classic radiologic features are a patchy pattern of peripheral “honeycombing” that is more prominent in the bases of the lungs, traction bronchiectasis, and the absence of prominent ground-glass opacity. When these findings are not present, a surgical biopsy of the lung is needed for diagnosis. A consensus statement on IPF from the American Thoracic Society–European Respiratory Society recommends therapy with prednisone and a cytotoxic agent, such as azathioprine. 6 However, there is little evidence that these agents alter the natural history of the disease. There may be some benefit from prednisone since it can help suppress cough in patients with this disease. However, there is no strong evidence supporting the clinical effectiveness of these treatments in patients with IPF. Indeed, since prednisone and cytotoxic agents do not benefit patients with IPF, it is reasonable to assume they cause harm, because each of these drugs is known to have substantial adverse effects. One of the side effects of prednisone is to promote physical deconditioning. This is especially important for patients with IPF, whose exercise capacity is already limited because of dyspnea. Cytotoxic agents probably cause injury, at some level, to all tissues of the body, in addition to their well-known myelotoxic effects. If a beneficial effect has been hard to demonstrate, why are these agents used to treat IPF? One reason may be a lack of specificity of the diagnosis in earlier studies. Many older studies included a related lung disorder, nonspecific interstitial pneumonia, under the diagnostic rubric we now consider as IPF. Nonspecific interstitial pneumonia can be associated with inflammation in the lung and can respond to drugs such as prednisone and azathioprine. Even though nonspecific interstitial pneumonia has been separated from IPF as a diagnostic entity, many clinicians continue to use prednisone and azathioprine as a treatment for IPF. Another reason for the use of these drugs is the lack of other effective therapies. A recent study suggested that pirfenidone might be useful as a therapy, but its effect as a single agent is not clear.7 Another study using interferon gamma showed no effect on the primary end point,8 although a subgroup analysis suggested an effect on early disease.
The effect of interferon gamma in patients with early disease is now under investigation. A number of other industry-supported trials are also under way. The National Heart, Lung, and Blood Institute recognized the need to develop therapies for the disease by establishing the IPF Clinical Research Network. The hope is that patients will be enrolled in these trials and therapies that are clearly effective will be forthcoming. Although the cause of IPF is not known, less emphasis is now placed on inflammation as a cause of the lung injury in this condition. Current hypotheses suggest that IPF results from repeated or ongoing episodes of acute lung injury that primarily affect peripheral areas of the lung.9 A related theory is that there may be an excess of type 2 helper T-cell (Th2) cytokines that facilitates the lung injury and fibrosis. These observations have kindled an interest in agents that may affect lung fibrosis and repair. In this issue of the Journal, Demedts et al.10 tested another therapy for IPF — antioxidant therapy. In this multicenter study, patients with IPF were randomly assigned to receive prednisone and azathioprine (the “standard of care”) or prednisone, azathioprine, and acetylcysteine. After one year of treatment, patients who received acetylcysteine, in addition to prednisone and azathioprine, had significantly better preserved vital capacity and diffusing capacity for carbon monoxide (DlCO). A substantial number of patients dropped out of the study, and differences in vital capacity and DlCO after one year were relatively small and were probably not clinically significant; the effect on the outcome of the patients who withdrew from the study is Antioxidant! Therapy for Idiopathic Pulmonary Fibrosis Gary W. Hunninghake, M.D.
The new england journal of medicine n engl j med 353;21 www.2286 nejm.org november 24, 2005 not known. The administration of acetylcysteine had no effect on survival. The investigators stated that the rationale for this study was provided by a number of earlier observations showing that patients with IPF have depleted levels of glutathione in the lung and that this depletion can be corrected by treating patients with acetylcysteine. This observation is not unique to IPF and is found in many chronic inflammatory disorders. Glutathione is an important antioxidant in all tissues and is crucial for many aspects of cell metabolism and survival (Fig. 1). Tissues that are depleted of glutathione are more susceptible to injury. Uptake of cysteine by cells is a rate-limiting step for the synthesis of glutathione. Ace- Figure 1.!Synthesis!of!Glutathione. Glutathione is synthesized from three amino acids: l-glutamine, l-cysteine, and l-glycine. Absolute levels of glutathione and the ratio of glutathione to glutathione disulfide are crucial for the maintenance of normal cell metabolism and survival. One function of glutathione is to detoxify a wide variety of reactive oxygen species that are generated within and outside of cells. During this detoxification process, glutathione is converted to glutathione disulfide. Under normal conditions, glutathione disulfide can be reconverted to glutathione, preserving both normal levels of glutathione and the ratio of glutathione to glutathione disulfide. In some conditions of acute or chronic stress, the ratio of glutathione to glutathione disulfide cannot be maintained, and glutathione disulfide is exported from cells. In addition, synthesis cannot proceed fast enough to replenish cellular stores of glutathione. Associated with this process is a depletion of a pool of other mixed antioxidant thiols. This depletion results in altered cell metabolism and injury. The synthesis of glutathione can be accelerated by the administration of acetylcysteine, which crosses cell membranes easily and can be converted to l-cysteine. Uptake of l-cysteine is an important rate-limiting step for the synthesis of glutathione. Acetylcysteine increases the pool of other antioxidant thiols that also protect cells from injury. editorials n engl j med 353;21 www.nejm.org november 24, 2005 2287 tylcysteine is used to increase the production of glutathione because it crosses cell membranes easily and can be converted to cysteine. The drug also increases the pool of other mixed antioxidant thiols. These other reduced thiols can also protect cells from injury. The use of acetylcysteine to prevent acute liver injury in the setting of an acetaminophen overdose has been well demonstrated. Acetaminophen, in large doses, generates a profound oxidant stress in liver tissue that depletes glutathione and other antioxidant thiols. When levels of these thiols drop below a critical level, there may be an explosive onset of liver injury. Acetylcysteine prevents this liver injury by maintaining adequate cellular levels of glutathione and other antioxidant thiols. What can we conclude from the study by Demedts et al.? One obvious conclusion is that acetylcysteine is directly beneficial as a therapy for IPF. However, another conclusion should also be considered. It is possible that the combination of prednisone and azathioprine is toxic to patients with IPF. If this were true, then it would be likely that the effects of acetylcysteine in this study are explained by the drug’s prevention of the toxic effects of prednisone and azathioprine. It is known that azathioprine depletes liver tissue of glutathione and that acetylcysteine can, in some settings, prevent liver injury. 11,12 In support of the latter hypothesis is the observation in the study by Demedts et al. that there were fewer myelotoxic effects in the group of patients with IPF who received acetylcysteine. Thus, it is not clear from this study whether the drug has direct beneficial effects on IPF or whether it prevents the toxic effects of prednisone and azathioprine. Therefore, a prospective study comparing prednisone and azathioprine with placebo is needed to address this issue. If a new study showed toxic effects or no effect of prednisone and azathioprine, investigators conducting studies of new therapies for IPF would be liberated from the use of this “standard of therapy,” and patients would be freed from exposure to these potentially toxic drugs. It is not clear how this study will affect the treatment of IPF. Since there are no therapies that are clearly effective for IPF, many physicians and patients will find the use of acetylcysteine to be very seductive. In many ways, if it were ultimately shown to be effective, it would be an ideal drug (i.e., beneficial with few side effects). Also, acetylcysteine is available without prescription. It is hoped that these observations will not prevent the design of a new study that evaluates whether acetylcysteine directly benefits patients with IPF. For now, physicians caring for patients with this disease should encourage their participation in clinical trials. There are still too many unresolved questions to continue to treat patients by guesswork. From the Department of Medicine, University of Iowa and Veterans Affairs Medical Center, Iowa City. American Thoracic Society, European Respiratory Society. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias: this joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001. Am J Respir Crit Care Med 2002;165:277-304. [Erratum, Am J Respir Crit Care Med 2002;166:426.] Hunninghake GW, Zimmerman MB, Schwartz DA, et al. Utility of a lung biopsy for the diagnosis of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2001;164:193-6. Hunninghake GW, Lynch DA, Galvin JR, et al. Radiologic findings are strongly associated with a pathologic diagnosis of usual interstitial pneumonia. Chest 2003;124:1215-23. Raghu G, Mageto YN, Lockhart D, Schmidt RA, Wood DE, Godwin JD. The accuracy of the clinical diagnosis of new-onset idiopathic pulmonary fibrosis and other interstitial lung disease: a prospective study. Chest 1999;116:1168-74. Lynch DA, David Godwin J, Safrin S, et al. High-resolution computed tomography in idiopathic pulmonary fibrosis: diagnosis and prognosis. Am J Respir Crit Care Med 2005;172:488-93. American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment: international consensus statement. Am J Respir Crit Care Med 2000;161:646-64. Azuma A, Nukiwa T, Tsuboi E, et al. Double-blind, placebocontrolled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2005;171:1040-7. Raghu G, Brown KK. Interstitial lung disease: clinical evaluation and keys to an accurate diagnosis. Clin Chest Med 2004;25:409-19. Gross TJ, Hunninghake GW. Idiopathic pulmonary fibrosis. N Engl J Med 2001;345:517-25. Demedts M, Behr J, Buhl R, et al. High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 2005;353:2229-42. Menor C, Fernandez-Moreno MD, Fueyo JA, et al. Azathioprine acts upon rat hepatocyte mitochondria and stress-activated protein kinases leading to necrosis: protective role of N-acetyl-Lcysteine. J Pharmacol Exp Ther 2004;311:668-76. Lee AU, Farrell GC. Mechanism of azathioprine-induced injury to hepatocytes: roles of glutathione depletion and mitochondrial injury. J Hepatol 2001;35:756-64. Copyright © 2005 Massachusetts Medical Society.
An Immune Disorder at the Root of Autism
Immune Disorders and Autism - NYTimes.com 8/26/12 7:28 AM
August 25, 2012
An Immune Disorder at the Root of Autism
By MOISES VELASQUEZ-MANOFF
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.
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
Immune Disorders and Autism - NYTimes.com 8/26/12 7:28 AM
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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.
Immune Disorders and Autism - NYTimes.com 8/26/12 7:28 AM
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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
Immune Disorders and Autism - NYTimes.com 8/26/12 7:28 AM
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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.
Immune Disorders and Autism - NYTimes.com 8/26/12 7:28 AM
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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.
Moises Velasquez-Manoff is the author of “An Epidemic of Absence: A New Way of Understanding
Allergies and Autoimmune Diseases.”
August 25, 2012
An Immune Disorder at the Root of Autism
By MOISES VELASQUEZ-MANOFF
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.
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
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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.
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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
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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.
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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.
Moises Velasquez-Manoff is the author of “An Epidemic of Absence: A New Way of Understanding
Allergies and Autoimmune Diseases.”
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