The many faces of our guardian angel.
The immune system normally represents our guardian angel. It works tirelessly and mostly unseen over a lifetime to enable humans and animals to survive in their environment. It does this by recognizing and fighting off microscopic invaders like viruses, bacteria and all-manner of other lifeforms that either wish to call us ‘home’ or do something far worse.
It’s also an important part of our internal ‘housekeeping’ services; when for example, our own cells become damaged or diseased, they are identified and ‘removed’ with the help of important immune system functions.
The immune system represents one of the most complicated biological systems that we possess; perhaps even rivaling the grey-pink matter that floats around the skull in terms of sheer complexity. It also ages as we age (known as immunosenescence) and, as a result, its function is probably a contributory factor to our own longevity.
The immune system can be primarily divided into two main components: the innate immune system and the adaptive immune system. The innate immune system is sometimes termed the ‘nonspecific’ immune system because it represents our general defense against would-be invaders, termed pathogens (disease causing organisms). Think of this part of the immune system as the general defenses (locks on the doors, moat around the castle, etc).
The adaptive immune system, by contrast, represents the body ‘learning’ at a biological level of ‘what to look for.’ It’s the biological ‘sniper’ of our immune function, identifying, tagging, and eliminating specific targets. The adaptive immune system is constantly adapting to keep us safe from various would-be invaders we inevitably confront on a daily basis.
These two parts of the immune system work together: patrolling, identifying and defending. And when they work well, they are a marvel of biological engineering that enables us to live and function in a pretty hostile natural environment.
When Things Go "Awry”
But…the immune system can also be a double-edged sword. For reasons we still don’t yet fully understand, there are various occasions where the body’s immune functions don’t quite manage to fight off every invading pathogen and infection takes hold. This is also where the concept of inflammation can join the conversation and how, on occasion, a necessary part of fighting infection (acute inflammation) turns into something rather longer-term and chronic with the potential for future adverse effects.
Just as damaging, the immune system can also malfunction in its job of ‘target selection’. Instead of picking out and defending against an external pathogen, it turns on the body’s own healthy tissue (‘self’) and mounts an immune response. This is the basis of what is called autoimmunity, where self is no longer seen as, well, self. The results can be truly devastating in conditions such as juvenile diabetes, lupus and others.
Immune system -> Behavior
One of the newer lines of research is how the immune system may be interacting with the brain to impact behavior.
A prime example of immune system abnormalities leading to behavior effects is in a condition called anti-N-methyl-D-aspartate (NMDA) receptor encephalitis, (yes that is a mouthful). Anti-NMDA encephalitis is where antibodies mistakenly attach to certain receptors in the brain involved in mood and movement. This results in symptoms such as seizures and twitching, as well as behavioral symptoms that mimic those seen in psychosis, for example. Since this is an autism blog we should mention that there are individual case studies published that discuss ‘autistic regression’ in the context of childhood-onset anti-NMDA receptor encephalitis [1].
The Immune System in Autism
To talk about all of the various immune system findings linked to autism would likely fill an entire book. For the sake of organization on this blog post, let’s compartmentalize some those into prenatal and postnatal.
Prenatal
The paper by Amory Meltzer & Judy Van de Water [2] provides a good overview of the current thinking about the immune system’s involvement in autism during critical periods of development.
They discuss how during the nine months before we are born (prenatal), all manner of different exposures have been correlated with offspring autism onset. For instance, prenatal rubella [3] or cytomegalovirus (CMV) [4] infections show a strong association with offspring autism risk, and highlight how a developing immune system might be implicated in-utero.
They also discuss another concept - Maternal Immune Activation (MIA) [5] - as showing a connection to offspring autism based on animal models. Animals (both mice and monkeys) that are given immune-stimulating injections during pregnancy show behavioral differences compared with control animals (for a little more on this subject see our discussion from our previous microbiome post here). Such studies have also been discussed in the context of other labels such as schizophrenia too – this will be an important point to remember further in this blog post.
Exploring the prenatal period a bit further, there is evidence that the immune system in some pregnant mothers may not develop the required ‘tolerance’ of the developing fetus. Research by Dr. Judy Van de Water of the UC Davis MIND institute has found antibodies in the blood of mothers of children with autism that react to the developing fetal brain [6].This theory is termed “Transplacental Maternal Autoantibodies to the Fetal Brain”. Yes, the immune system does have to ‘alter’ during pregnancy to allow for the ‘non-self’ developing fetus to grow. N of One currently has a research study underway with Dr. Van de Water exploring auto-immunity in children with autism.
Postnatal
Many postnatal immune system issues and abnormalities have also been explored in children with autism. Abnormalities have been observed in the levels of cytokines and chemokines, chemical messengers that the body uses in many ways related to the immune system, in those with autism [7]. Many of these compounds (which tend to have alphabet soup types of names such as IL-7, IL-10, etc) tend to be categorized as either ‘pro-’ or ‘anti-inflammatory [8]. Generally speaking, the evidence is pointing towards an over-representation of pro-inflammatory compounds in relation to autism. Perhaps, also unsurprisingly, atypical patterns of cytokines have been noted as corresponding with the presence of gastrointestinal (GI) symptoms in autism [9], hinting at some important biological connections between immune system and GI function. Although it is beyond the scope of this document, interested readers may want to further explore the literature on the Th1 and Th2 (T helper cells) response with autism in mind.
The work of Harumi Jyonouchi and colleagues [10] has also revealed some potentially meaningful, postnatal differences in the immune systems of children with autism. Their research has found that children who have a history of behavioral changes following infection generally demonstrate immunodeficiency, functional GI problems, altered cytokine profiles, and dysregulated gene expression.
The overrepresentation of allergic disease is another interesting finding implicating the immune system in autism. Earlier this year, Xu and colleagues at Iowa College of Public Health discovered a rate of allergic disease in kids with autism that was nearly three times the rate of those without autism. Food allergies were particularly prevalent (11.25%) and remained significant even after adjusting for age, sex, race, education, income, and geographical region [11]. Interestingly, food allergies, a recognized disorder of immune function, has been on the rise in concert with autism rates over the last few decades [12].
The "fever effect", a documented phenomenon where some children with autism experience
temporary improvements in their autism symptoms when they have a fever (and sometimes even before), is also another strong clue that the immune system plays a role in the symptoms of autism.
[13]
Fever, after all, is an immune system response to some type of infection. The fact that many observe the fever response before the actual fever sets in, is an intriguing clue that the behavioral changes may be due to some immunological change(s) that are not related to the mere elevation in temperature. N of One has supported research that attempts to understand and harness the fever effect (see here) and will continue to look for opportunities to do so.
Finally, when contemplating immune system involvement in autism, we must also recognize the works of the late Paul Patterson at CalTech who pioneered the MIA mouse model discussed above and which has also been notably utilized by N of One supported researcher Dr. Robert Naviaux [14]. In 2012, Patterson and his colleagues took MIA mice that showed an altered immune profile and performed a bone marrow transplant, in an attempt to “reset” its immune system [15]. Consequently, those MIA mice that had previously displayed stereotypical behaviors for autism, lost those behaviors.
Interestingly, there are some documented cases of cancer patients with schizophrenia (another neurological condition resulting in behavioral effects), being cured of both conditions after receiving bone marrow transplants (media here). Of course, no one is suggesting that a bone marrow transplant is a considerable treatment for autism – and autism ≠ schizophrenia – however, these intriguing findings demonstrate the relationship between behavior and the immune system and how far our thinking about the underlying biology of conditions like schizophrenia and autism may need to evolve.
Interventions?
In light of the compelling research implicating the immune system in autism, researchers have begun the task of applying that research to developing various treatment options, termed “translational research”.
The paper by Josemar Marchezan and colleagues [17] published just last month (Sept 2018) provides a list of such interventions while also leaving the door wide open for many options to be expanded upon in order to determine their exact mechanisms and how we might improve on their use in autism. They include medicines that are typically indicated for treating inflammation, such as the corticosteroids [18] and sulforaphane (see our N of One supported Johns Hopkins sulforaphane study here), to other medicines such as risperidone, more commonly known for its antipsychotic actions. Recently, top autism researcher Dr. Richard Frye published a paper describing the use of Intravenous Immunoglobulin (IVIG) [19] as a potential treatment for some cases of autism. [20]
Another interesting finding and potential intervention mentioned in Marchezan’s work was the suggestion that microbiome restoration could potentially be modulating the immune system in autism in addition to (or perhaps together with?) correcting functional GI issues and bacterial composition. Just one more indication that the interplay between these important biological systems (and consequently, areas of medical practice) may hold the key to unlocking answers for those with autism and why more interdisciplinary research is key.
Recently researchers at Duke University led by Joanne Kurtzburg [21] found significant improvements on ‘gold standard’ autism testing for patients who received autologous stem cell infusions. The intervention was being tested based on the hypothesis that stem cells could potentially modulate inflammatory processes in the brain of those with autism. Interestingly, maternal fetal antibodies, proinflammatory cytokines, and excessive microglial activation were all mentioned as red flags leading researcher to believe that stem cells could serve a purpose in the treatment of autism. Study authors describe a “large unmet need for more effective treatments targeting core symptoms of ASD” and we could not agree more.
Where next?
It is becoming more readily accepted by the medical and research community that various facets of immune function show some connection to autism. If the emerging data is telling us anything, it is that the immune system is an area of research that potentially holds promise for meaningful, translational research in autism.
At N of One, we envision a day where quality, reliable, immunological panels are recommended at the time of autism diagnosis in order to determine and/or rule out any potential immune system disruptions that might be contributing to or exacerbating the symptoms of autism for each individual child. Our current autoimmune work with the MIND Institute represents just one area that needs to be investigated further.
We hope you agree and will help us to make this vision a reality by supporting N of One and sharing this and other N of One information with your friends, family and members of your community.
References
[1] Hacohen Y. et al. N-methyl-d-aspartate (NMDA) receptor antibodies encephalitis mimicking an autistic regression. Dev Med Child Neurol. 2016 Oct;58(10):1092-4.
[2] Meltzer A. & Van de Water J. The Role of the Immune System in Autism Spectrum Disorder. Neuropsychopharmacology. 2017 Jan;42(1):284-298.
[3] Hutton J. Does Rubella Cause Autism: A 2015 Reappraisal? Front Hum Neurosci. 2016 Feb 1;10:25.
[4] Maeyama K. et al. Congenital Cytomegalovirus Infection in Children with Autism Spectrum Disorder: Systematic Review and Meta-Analysis. J Autism Dev Disord. 2018 May;48(5):1483-1491
[5] Malkova NV. et al. Maternal immune activation yields offspring displaying mouse versions of the three core symptoms of autism. Brain Behav Immun. 2012 May;26(4):607-16.
[6] Jones KL. & Van de Water J. Maternal autoantibody related autism: mechanisms and pathways. Mol Psychiatry. 2018 Jun 22.
[7] Masi A. et al. Cytokine levels and associations with symptom severity in male and female children with autism spectrum disorder. Mol Autism. 2017 Dec 2;8:63.
[8] Masi A. et al. Cytokine aberrations in autism spectrum disorder: a systematic review and meta-analysis. Mol Psychiatry. 2015 Apr;20(4):440-6.
[9] Rose DR. et al. Differential immune responses and microbiota profiles in children with autism spectrum disorders and co-morbid gastrointestinal symptoms. Brain Behav Immun. 2018 May;70:354-368.
[10] Jyonouchi H. Children with autism spectrum disorders experiencing neuropsychiatric symptoms, cognitive skills, and gastrointestinal symptoms exhibit distinct innate immune abnormalities and transcriptional profiles in peripheral blood monocytes. Journal of Immunology. 2011 April; 186 (1 Supplement) 47.7.
[11] Xu G. Association of Food Allergy and Other Allergic Conditions With Autism Spectrum Disorder in Children. JAMA. 2018 June 1(2):e180279.
[12] Tang M. Food Allergy: Is Prevalence Increasing? Internal Medicine Journal. 2017 March.
[13] Curran LK. Behaviors associated with fever in autism spectrum disorders. Pediatrics. 2007 Dec;120(6):e1386-92.
[14] Naviaux R. Antipurinergic Therapy Corrects the Autism-Like Features in the Poly(IC) Mouse Model. PLOS One. 2013 March.
[15] Hsiao E. Modeling an autism risk factor in mice leads to permanent immune dysregulation. PNAS. July 2012 109 (31) 12776-12781.
[16] Miyaoka T. Remission of Psychosis in Treatment-Resistant Schizophrenia following Bone Marrow Transplantation: A Case Report. Frontiers Psychiatry. September 2017
[17] Marchezan J. et al. Immunological Dysfunction in Autism Spectrum Disorder: A Potential Target for Therapy. Neuroimmunomodulation. 2018 Sep 5:1-20.
[18] Duffy FH. et al. Corticosteroid therapy in regressive autism: a retrospective study of effects on the Frequency Modulated Auditory Evoked Response (FMAER), language, and behavior. BMC Neurol. 2014 May 15;14:70.
[19] Wikipedia – Intravaneous Immunoglobulin Therapy “is the use of a mixture of antibodies (immunoglobulins) to treat a number of health conditions. Immunoglobulin therapy is also used in some treatment protocols for, some autoimmune disorders, some neurological diseases, some acute infections and some complications of organ transplantation.”
[20] Connery K. Intravenous immunoglobulin for the treatment of autoimmune encephalopathy in children with autism. Translational Psychiatry. 2018 August; 8: 148.
[21] Dawson G. Autologous Cord Blood Infusions Are Safe and Feasible in Young Children with Autism Spectrum Disorder: Results of a Single‐Center Phase I Open‐Label Trial. Stem Cells Translational Medicine. 2017 May; 6(5): 1332–1339.