Neuroimmunology Meets Neurodevelopmental: Innate and Adaptive Immune Function in FXS

Neuroimmunology is a relatively new field at the intersection of neuroscience and immunology. Its purpose is to describe how immune function affects brain development and function, and how signaling between cells in the brain affect levels of pro- or anti-inflammatory signaling molecules, such as cytokines, in the rest of the body. Recent studies in this field have noted associations between maternal infections before birth or during infancy with increased risk for diseases later in life.

A recent study by Milo Careaga, PhD and colleagues at the University of California, Davis, explores how neuroimmunology relates to Fragile X syndrome (FXS). Previous studies describe increased levels of certain cytokines and increased rates of infection in children with FXS. These signs of immune dysfunction might be due to cells in the immune system not responding properly. Alternatively, they might be due to other physiological factors such as increased anxiety, which is often elevated in individuals with FXS and is also associated with elevated cytokine level. Careaga et al. examined whether the immune response at the cellular level was functioning properly in children with FXS.

Researchers took blood samples from 27 boys with FXS and eight typically-developing boys (all aged 2-9 years) and isolated peripheral blood mononuclear cells (PBMCs). These cells are believed to be involved in the development, activation, and response of the immune system. They also express metabotropic glutamate receptors (mGluRs), a protein in cell membranes that responds to the signaling molecule glutamate. Glutamate is a critical signaling molecule, or neurotransmitter, and many brain cells have receptors that bind it. When glutamate binds to its receptor on a cell, it starts a chain of events within that cell and can result in increased or decreased production of particular proteins such as cytokines. Thus, because PBMCs express these receptors, neurotransmitters can affect these cells and thus impact immune function.

Glutamate signaling is particularly relevant in FXS. A variety of studies support the idea that FXS is due in part to overactive mGluR signaling. Typically, once glutamate binds to mGluR, the chain of events in the cell initiates a feedback loop that shuts off mGluR signaling after a short period of time. FMRP, which is a protein produced in low levels in individuals with FXS, is part of this feedback loop and helps to shut down mGluR signaling. The idea is that in FXS, without enough FMRP around, glutamate binding initiates a cellular response that lasts abnormally long, which can have detrimental effects.

The researchers used several kinds of molecules to assess immune function in PBMCs from the participants. First, they applied lipopolysaccharides (LPS) to stimulate the innate immune response or phytohemagglutinin (PHA) to stimulate the adaptive response by T-cells, a type of immune cell. As you might expect, “innate” and “adaptive” refer to the types of immunity we possess either from birth or that we acquire or induce (e.g., via vaccination), respectively. They found that the responses from subjects with FXS did not differ from those from controls, suggesting that the cellular immune response was not abnormal in FXS.

Researchers then assessed how mGluRs can modulate immune function by applying the mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG), which mimics the effects of glutamate binding to the mGluR. They applied DHPG in conjunction with LPS, and separately, DHPG in conjunction with PHA. They found that while DHPG + LPS had an anti-inflammatory effect in typically-developing subjects, this effect was less pronounced in subjects with FXS. Meanwhile, the response to DHPG + PHA did not differ between groups. This suggests that mGluR signaling may play a role in innate immune responses in FXS but not in adaptive immune response.

This study is interesting for several reasons. First, it demonstrates that mGluR function can be assessed without the “difficult, if not impossible,” invasive procedures required to study neurons in children. Second, it implicates a potential mechanism underlying reports of immune dysfunction, or non-optimal immune function, in FXS. Third, the authors suggest that PBMCs could be useful in studies examining the efficacy of drugs that modulate mGluR function.

With growing consensus that immune dysfunction can impact early brain development, this study is an important link between the field of neuroimmunology and neurodevelopmental disorders such as FXS. Future studies may clarify how risk due to gene mutations interacts with risk due to environmental exposures to modulate the development or progression of symptoms in a variety of diseases.

[expand trigclass=”ew-expand” title=”Source”]Careaga, M., Noyon, T., Basuta, K., Van de Water, J., Tassone, F., Hagerman, R. J., and Ashwood, P. (2014). Group I metabotropic glutamate receptor mediated dynamic immune dysfunction in children with Fragile X syndrome. Journal of Neuroinflammation 11, 110. doi:10.1186/1742-2094-11-110.[/expand]