Guest blog: Premature ideas
On 25 August, in an opinion column for The New York Times, Moises Velasquez-Manoff proposed a set of interesting theories about how diseases of immune dysregulation have increased over the past 60 years, and the relevance of these disorders for autism.
The article was not a scientific manuscript; it was based on opinion and designed to provoke the readers into considering the possible relationship between advances in autism research and more global changes in health and disease.
Based upon his understanding of the recent autism literature, Velasquez-Manoff proposed that at least some cases of autism could be considered inflammatory disorders, and that the inflammation most likely arises during gestation.
It’s true that research over the past few years supports the notion of immune dysregulation during gestation as one possible route to changing fetal neurodevelopment. But this theory is still in its infancy with respect to autism.
As an immunologist, this is an active area of my own research. As someone who has been working in immune-mediated disorders for my entire career, I find recognition of the critical role that the immune system plays in neurodevelopment exciting.
However, there are a few areas that might need clarification for those who are not completely familiar with immune dysregulation in autism.
First, Velasquez-Manoff says:
In autistic individuals, the immune system fails at this (regulation between pro- and anti-inflammatory) 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.
Although this statement is partially correct, research tells us that there is a great deal of variation in individuals with autism when it comes to immune function.
Dangerous generalizations:
Some individuals with autism have a poor, low-functioning immune response that barely releases any kind of immune signal, let alone inflammation. Others have normal, healthy immune systems. And then there are those individuals with the disorder who have an inflammatory immune profile that lacks appropriate regulation.
It is important to remember that generalizing the findings from one subtype or group to another can be dangerous where treatment is concerned.
Maternal immune dysregulation during gestation is a particularly intriguing avenue of research. The article mentioned my work on macaques, in which my colleagues and I showed that pregnant monkeys injected with antibodies from mothers of children with autism go on to have offspring that show autism-like behavior.
Velasquez-Manoff described this as, “In this model, autism results from an attack on the developing fetus.”
The model appears to be gaining support, and our results have been verified in additional monkey studies, and in two separate mouse models.
Velasquez-Manoff is less convinced by research suggesting that a bacterial or viral infection during pregnancy can cause autism: “Yet to blame infections for the autism epidemic is folly. First, in the broadest sense, the epidemiology doesn’t jibe.”
It is true that the incidence of viral and bacterial infections has diminished in the past few decades, but how our bodies handle the infection is really the issue here. It is not as simple as looking at epidemiological data on infection rates to determine whether infection during pregnancy is a factor in autism.
So, although we are beginning to understand the relationship between autism and the maternal response to an immune perturbation during pregnancy, more research is needed to determine why some women get sick during pregnancy and have a healthy child and others do not.
In conclusion, it is certainly possible that a state of chronic inflammation could be a factor in autism pathogenesis in a subset of children with autism, either in the child or through maternal exposure. The opinion piece very eloquently reminded us that we perhaps need to look beyond the scope of a particular disorder to understand the relationship between that disorder and more global health issues.
Could there be a link between the rise in immune-mediated disorders such as autoimmunity and allergies/asthma, and a neurodevelopmental disorder like autism? It is only through the willingness to consider the possible shared mechanisms that we will be able to answer this question and move forward towards prevention.
Judy Van de Water is professor of clinical immunology at the University of California, Davis.
Comments
Hi Judy Van DeWater -
<i>Some individuals with autism have a poor, low-functioning immune response that barely releases any kind of immune signal, let alone inflammation. Others have normal, healthy immune systems. And then there are those individuals with the disorder who have an inflammatory immune profile that lacks appropriate regulation. </i>
I'm racking my brains trying to think of some studies that have shown a depressed immune response in the autism cohort; I guess <i>Altered gene expression and function of peripheral blood natural killer cells in children with autism</i> might fall into this category, though to my eye is more about targeted antimicrobial activity as opposed to inflammation, and <i>Differential monocyte responses to TLR ligands in children with autism spectrum disorders</i> shows a decreased response for some types of stimulants.
Do you have any other examples of studies that show a low functioning immune response?
On the other hand, it seems that a lot of studies tend to show an increased propensity for inflammation from different endpoints; i.e., MIF/CRP/IL-17/HMGB/varied TLR stimulation studies. It seemed especially striking to me that many of these studies showed a correlation between the degree of increased inflammatory biomarker and autism severity. Even though every study has children who fit within the normal curve, it appears that the pattern of published data indicates a child with autism is more likely than not to have biomarkers associated with increased inflammation. Am I off base here?
I guess my point is that my reading of the available literature was largely in line with MVM's in this regard; a lot of data that indicated a state of inflammation was present, a good deal that indicated dysregulation was a problem, and very little that showed a less pronounced immune response. With all of the caveats of the complexity of the systems we are trying to understand, the heterogeneous nature of autism, and my obvious shortcomings as a layperson, can you give me some more insight into your thoughts on how the different immune phenotypes in autism might eventually shake out?
Also, can you tell us if CHARGE is making any attempts/progess to define phenotypes based on immune function?
Thank you for working on autism!
- pD
Thanks for your comment. Here is a response from Dr. Van de Water:
To answer you last question first, indeed we are working on phenotyping children with ASD based on their immune profile in both CHARGE and the APP projects at the MIND. This is why I am aware that the data are more complicated in terms immune function than they would appear to be from the published studies. Your understanding of the current literature is excellent, and you are certainly correct when you state that the overall sense of immune function in ASD is an inflammatory state, with the exception of some published studies and specific cellular responses. But the key thing to remember is that the data represent the average not the range of immune responses that we find in our ASD studies. My colleagues and I will soon be presenting data on the range of immune phenotypes and the functional level that we see in our study populations to better understand the immune phenotypes associated with autism. I do want to thank you for you interest and keen understanding of the work that we are doing.
I am so happy to see SFARI reporting on this important topic.
This is ground breaking work and it has been wonderful to see this issue in the mainstream press. The cover story on "The Economist" about the human microbe describes this phenomena well.
For most of us, autism is a lot more than a brain disorder.
Inflammation is the cause of the GI pain that strikes so many on the spectrum. However, I think we will find that POSTnatal immune assaults trigger a big % of ASD. So many of us had uneventful, healthy pregnancies only to see our typically developing toddlers suddenly develop severe chronic illnesses just before a child's rapid cognitive regression.
Given the heterogeneity and complexity of autism etiology it is difficult to attibute a single causal mechamism that is predictive of autism. While the author minimizes the contribution of infections, its far more complicated. The first recognized infection etiology associated with autism was first trimester exposure to the rubella virus. A more comprehensive study of the long term consequences of congenital rubella syndrome is multiple medical complications including risk for increased risk of late onset chronic diseases such as insulin-dependent diabetes (risk 50 times higher than that in the general population), thyroid dysfunction, digestive disturbances, and a rare neuro-degenerative disorder called panencephalitis. These conditions may result from ongoing viral infection, or autoimmune response.
https://www.orpha.net/data/patho/GB/uk-rubella.pdf
Another example is 22q11 deletion syndrome associated with autism. Among the complications are that 77% of all individuals have an immune deficiency, including auto-immune disease. The immmune deficiencies also increase risk for infections.
http://ghr.nlm.nih.gov/condition/22q112-deletion-syndrome
Klinefleter Syndrome which affects only boys. Compared with other men, adult males with Klinefelter syndrome have an increased risk of developing breast cancer and a chronic inflammatory disease called systemic lupus erythematosus. Their chance of developing these disorders is similar to that of normal adult females.
http://ghr.nlm.nih.gov/condition/klinefelter-syndrome
Given the complexity it is nearly impossible to tease out a single causal mechanism. It is a 'which came first, the chicken or the egg' debate. Hopefully afte many years of research the autism research communbity may one day begin tease out the relative contributions of so many risk factors.
I believe a potential under-lying cause of autism, possibly, ADHD and other neurological disorders are a genetic mutation that inhibits transferrin and prevents ferritin transer of oxygen to red blood cells and into the brain and miscellaneous organs. This would "starve" the developing child of critical oxygen throughout the body but particularly in the early brain development. Gut discomfort in autistic people could be a similar reaction to those w/ Coeliac disease, an iron-based inflammatory gluten response. Jaundice at birth could be a ferritin, initial "iron flood," on the newborn's brain and begin the toxicity damage. Further non-functional iron intake as the child ages would continue a toxic iron assault; further deteriorating brain development and functionalities. The compound genetic mutations of HFE and erythrocyte hemachromotosis similarities and the auto-immune inflammatory gene mutation CCR5-32 deletion could indicate a complex inter-relationship w/ iron assault and immune inflammatory response to the iron toxicity. These genetic mutations are very common among Northern European and Irish heritages. Worth looking into as low ferritin is indicated in many disorders and may be misdiagnosed as anemias. When in actuality, it's a ferritin/ transferritin mutation and an iron "over-load."