The Immune Factor: A potential contributor to autism spectrum conditions?
After almost two years of the COVID-19 pandemic, I bet we’ve all got a rough idea of how critical our immune system is. This highly organized system keeps us safe from bacteria or nasty viruses, including pluri-variant coronaviruses. It does so by orchestrating a timely and targeted immune response. Such a response comes in very handy, especially in those contexts where the odds to encounter pathogens — like bacteria/viruses — are high, for example, in social gatherings or birthday parties.
The immune response and beyond…
The function of the immune system, however, is not limited to fighting pathogens. There is some evidence that this system also influences the way our brain develops and works. For example, immune factors, from T-cells to cytokines, regulate the formation of brain cells and the signals that are shared among them. As a result, situations in which the immune system does not function properly may trigger a range of brain conditions. Autism spectrum conditions (ASCs) are an example of these.
I am a PhD student at the Department of Forensic & Neurodevelopmental Sciences at King’s College London; with my research project entitled ‘The role of immune-related genetic factors in neurodevelopmental disorders: understanding their link to brain variability and behaviours.’, I aim to clarify the role that the immune system could play in ASCs.
What are Autism spectrum conditions?
ASCs are a group of conditions that usually manifest very early in life, but that last into adulthood. Over the years, there has been growing conversation around the language used to describe variations between peoples’ brains and behaviours. ASCs are just one prime example of what is known as neurodiversity. This refers to the fact that there is no definitive “normal” brain, but rather there is a “typical” one, with variations from the typical simply being “atypical”. Neurodiversity emphasises the fact that neuro-variation does not equate to neuro-deficit; humans naturally vary in cognitive ability, strengths and weaknesses. However, the variation between these strengths and weaknesses can be more pronounced in some people, which can, in turn, bring talent but can also be disabling. Autism is diagnosed in people who have considerable difficulties in social communication and in building interpersonal relationships. Additionally, people with autism may also have repetitive and inflexible behaviors or interests. Though there is much ongoing debate as to whether the increased prevalence in ASC diagnoses are due to increases in screenings thanks to greater attention being drawn to them, or the other way around, both the numbers and the social attention are interesting. We hear about them on social media, and they are even the central theme of some popular TV shows (if you subscribe to Netflix, check out Atypical). The aim of many scientists worldwide is then to understand the factors involved in ASCs with the ultimate goal to improve the quality of life of people who received a formal diagnosis and reduce the challenges they face every day. Sadly, this has turned out way more difficult than expected. What makes it very complicated is the fact that the ASCs seem to be multifactorial, which means that not one but multiple factors can cause them. This multiplicity of factors produces what we call clinical heterogeneity. To put it simply, one person with ASC can be very different from another. If one mainly has social problems, another may mostly struggle with rigid behaviors. To make things more complicated, autism symptoms often occur alongside other mental conditions, like anxiety, or non-psychiatric problems, such as metabolic syndromes. This diversity is so striking that we now wonder: what if there are different subtypes of ASCs? Different routes suggest that the immune system may have something to do with ASCs. We know now that ASCs occur when the brain does not entirely follow its usual developmental trajectory. For example, while brain cells, or neurons, are generally formed by their parent cells in a very precise and regulated manner, in ASCs we witness an overproduction of these neurons. Also, the usual balance between brain signals of excitation (a ‘go’ signal) and inhibition (conversely, a ‘stop’ signal) appears altered in ASCs. What is interesting is that the immune system and its molecules control all these processes in the brain from very early in life. We also see that immune problems, like susceptibility to viral infections or allergies, in some cases come along with symptoms of ASCs. And autoimmune disorders, which consist of misplaced attacks of the immune system towards one’s own cells, are more common in the relatives of a person with autism. Because the ASCs are so heterogenous, is it possible that these immune problems might indicate an immune-based subtype of ASCs? Can genetics tell us more about how the immune system and ASCs are related? Despite what data suggest, we still cannot say confidently that “yes, the immune system has a role in ASCs!”, I believe that genetics can be very useful here. Yeah, I mean that intricate world of genes, DNA chains, and letters that are passed on from one generation to another.
Why genetics? Well, let me explain. Genes are the first-line actors in biology: they control the availability of many proteins and molecules that mediate important biological functions. Many of these genes regulate the level of immune molecules that are necessary to make the immune machine work.
One thing we have now learned about ASCs is that genes have a considerable impact on these conditions. They are indeed among the most heritable neurodevelopmental conditions. Nevertheless, we still do not fully understand which are all the genes particularly important in ASCs. Hence, my question is what if genes that influence immune functioning also contribute to the brain processes and symptoms that describe ASCs?
Immune genes are important to ASCs in general and to some autistic symptoms in particular.
When we took a deeper look at the many genes related to ASCs, we could see that indeed some of them support the work of the immune system. For example, some genes associated with ASCs regulate the level of cytokines, small molecules, that our body produces to fight inflammation in general. Other ASC-associated genes allow instead the formation of antibodies, which are molecules created to fight a specific threat when we encounter it.
Given that people with ASCs have very diverse profiles, we also studied if immune genes are more associated with one or more particular symptoms. We know that, to some degree, autism symptoms can be also found in people without a diagnosis in the form of traits. These so-called autistic-like traits represent variations in attention, rigid behavior, and sociability and they are influenced by specific genes. We, therefore, measured these autistic-like traits in people across countries and we looked at their genetic codes. By doing so, we learned that immune genes are associated with autistic-like rigidity and attention to detail.
What else can we learn about ASCs by looking at immune genes?
So, immune genes are associated with ASCs and autistic traits. There are however many questions that remain unsolved: do these immune genes influence the brain processes in ASCs? Can these immune genes be used to prove the case of an immune subtype of ASCs?
Our research journey has just started but we hope to learn more about the role of immune genes in ASCs. This information can guide us to better define ASCs, explore any immune subtypes and evaluate the benefits of immune-based therapies.
Stay tuned to see what comes next!