Exploring links among autism, the immune system and the brain
What causes autism, a neurodevelopmental disorder that now affects 1 in 150 children in the United States? Although studies suggest a strong genetic basis, scientists are also looking into possible biological and environmental origins, and among the most fascinating areas under investigation is the link between the immune and nervous systems. Researchers are exploring whether changes within the developing immune system could compromise nervous system development and ultimately lead to such disorders as autism.
UC Davis researchers are at the leading edge of this field of inquiry, spurred on in large part by the synergy created when the M.I.N.D. Institute began supporting scientists from varying backgrounds to work on related problems.
For instance, Kimberley McAllister, and Judy Van de Water, basic scientists at UC Davis’ Center for Neuroscience and M.I.N.D. Institute respectively, are working on complementary aspects of the immune system-autism question. Their M.I.N.D. Institute-funded studies are creating a unique set of parallel building blocks that could well lead one day to a definitive identification of a potential contributor to autism.
“The synergy between the outstanding basic science research at the Center for Neuroscience and the translational focus of the M.I.N.D. Institute helps basic scientists like me to design their experiments in a way that maximizes the potential for understanding disease,” explains McAllister, an associate professor who began her academic studies as a medical student before getting hooked on basic science and switching tracks, ultimately earning a doctorate in neurobiology from Duke University in 1996.
A focus on MHCIs
McAllister’s laboratory studies how synapses, the points at which impulses pass from one nerve cell to another, are initially formed and are subsequently altered by experience. She believes that environmentally triggered changes in certain immune system molecules within the developing brain could interact with genetic factors to cause several neurodevelopmental disorders, including autism.
She and her team have recently received grants from Autism Speaks, a nonprofit funding biomedical autism research, and the M.I.N.D. Institute to test this idea. The rationale behind this theory is:
- MHCI (short for ”major histocompatibility complex I”) molecules mediate the adaptive immune response.
- MHCI molecules are present in nerve cells, or neurons.
- It’s possible that changes in MHCI in developing brain neurons contribute to autism by altering the way that synapses develop.
- Those changes in MHCI are typically triggered by environmental factors or an immune response.
- Environmental factors (such as an immune response) may alter synaptic connectivity in the developing brain.
- Rather than impact MHCI directly, environmental factors affect MHCI through cytokines, proteins that regulate intercellular communication within the immune system.
- Several cytokines have been found to be up-regulated, or overly active, in the brains of children with autism.
- Perhaps these cytokines alter synaptic connectivity in the developing brain by altering MHCI levels, and those alterations in turn contribute to autism.
“This is an exciting but as yet untested hypothesis,” she explains, “If it proves true, then understanding how MHCI molecules and cytokines act in the developing brain could, in the future, reveal possible therapeutic targets for preventing or treating autism.”
McAllister, who received the Young Investigator Award in 2006 from the Society for Neuroscience for her highly regarded work, points out that we are far from understanding the role of immune molecules in normal brain development generally, much less their role in such disorders as autism. But the tools are now available to make rapid progress in this area.
“The science of brain development is remarkable. It’s amazing how environment and experience physically change the connectivity of the brain,” she says. “Ultimately, the goal of my research is to try to understand just how that happens.”
Autism and antibodies
Van de Water and her team are investigating biologic mechanisms of the immune system in relation to autism, focusing on both the blood factors and cells that are involved in a healthy immune response.
For example, they are currently analyzing an antibody subtype that’s responsible for the majority of the immune response to invading pathogens. Called immunoglobulin G, or IgG, its levels are much lower than normal in children with autism. This indicates problems in proper signaling of cells to produce certain proteins or factors, potentially rendering these children more susceptible to infections.
“Indeed, this tells us that there is likely something wrong in communication among cells within the developing immune systems of these children,” says Van de Water, who is also a professor in rheumatology, allergy and clinical immunology. “It may be a very basic cell-signaling pathway problem – that is, cells are not being signaled correctly to produce needed amounts of IgG.”
Her further work has led to the identification of IgG antibodies to human brain proteins as a potential marker of autism, an important development in light of the dearth of biological diagnostic tools or therapeutic targets for this disease. In this case, children with autism appear to have very specific antibodies to proteins in the brain, which may indicate damage to a region of the brain.
Vaccines and autism
Van de Water began her academic career pursuing a bachelor’s degree in biological sciences at UC Davis. An internship in an immunology lab there so intrigued her that she decided to specialize in the field, eventually earning a Ph.D. in immunology in 1988. Her specialty is autoimmunity, a condition in which the immune system starts reacting against an individual’s own body.
“Until the late 1990s, researchers investigated autism primarily from the viewpoint of behavior and genetics, not biology. Then came MMR,” she explains, referring to a live viral vaccine against measles, mumps and rubella (MMR) that was implicated as a cause of autism in a controversial 1998 study. The M.I.N.D. Institute issued a call for projects that might shed light on the question. Van de Water signed up and she has been with the institute ever since.
Her studies found that antiviral responses are fairly normal in people with autism – but antibody responses to vaccines against bacteria were lower than expected. This suggests that the problem may lie in the way that invading pathogens are processed.
Today, her goal is also to study what happens during gestation that may affect neurodevelopment, including whether the mothers of children with autism have autoantibodies to fetal brain proteins. “Through the years we’ve learned that many children with autism don’t have healthy immune systems. We are attempting to answer questions such as, ‘Why do they have such dysfunctional systems?’ and ‘To what extent is the dysfunctional immune system linked to abnormal brain development?’” she says.
Developments in the field are moving fast. As M.I.N.D. Institute Research Director David Amaral explains, “While the brain was long thought to be an immunologically ‘privileged’ part of the body, meaning devoid of an immune system, we now know that the immune and nervous systems are intimately interconnected.”
He adds, “The M.I.N.D. Institute is proud to support cross-disciplinary researchers of the caliber of Drs. McAllister and Van de Water as they further unravel such mysteries to advance an understanding of all the causes of autism.”