Allergy Enhances Neurogenesis and Modulates Microglial Activation in the Hippocampus

Barbara Klein.  Paracelsus Medical University

There is a great deal of scientific work on the relationship between states of inflammation in the body – routinely caused by bacterial or viral infection – and the brain. Specifically, the idea that inflammation in the periphery can communicate itself to the brain and cause a complementary state of neuro-inflammation, involving primed and hostile brain immune cells called microglia, that can easily get out of hand and cause states of depression and social withdrawal in the short-term, and the type of neuro-degeneration we see in Alzheimer’s and other degenerative cognitive diseases, in the long-term. In fact, in Body by Darwin I cite the work by Clive Holmes and Hugh Perry, from the University of Southampton, which started with the observation that those dementia patients that suffered from any one of a number of chronic inflammatory conditions like cancer, heart disease, diabetes or arthritis, together with the spike of a recent infection, were cognitively declining at a much faster rate than Alzheimer’s patients who were free of this disease background.

So you might imagine that an allergic reaction in the body, which causes an aberrant immune system response involving a whole slew of inflammatory chemical messenger molecules called cytokines, would have the same detrimental effect on cognition and brain health. But according to this recent paper in Frontiers in Cellular Neuroscience, written by Barbara Klein et al from Paracelsus Medical University in Austria, quite the opposite is true. Allergy appears to cause neurogenesis in the hippocampus (the part of the brain heavily involved in learning and memory) and a strong regulation of microglial activity.

Klein believes this surprising, and paradoxical, effect is specific to the hippocampus (it is not seen in, for instance, the prefrontal cortex) and also to the type of immune response that is evoked by pathogens, on the one hand, and allergens on the other. Pathogens typically evoke the so-called Type I immune response, whereas allergens evoke a Type II response which involves the release of a specific set of cytokines including the interleukins 4, 5 and 13, and, through them, the further release of pro-inflammatory cytokines interferon gamma and tumor necrosis factor alpha. Nevertheless, Klein’s findings also run counter, as she admits, to a sizeable literature where rodent models of allergic rhinitis result in social isolation and anxiety; airway-induced allergy can lead to increased tau phosphorylation (implicated in the development of Alzheimer’s disease); and can lead to increased insulin resistance and inflammation in the brain. In humans, there is evidence that individuals suffering from seasonal allergic rhinitis perform worse in cognitive tests and there is a positive correlation between allergic rhinitis and mood disorders, such as anxiety and depression. Similarly, she says, children with asthma have higher rates of depression, behavioral disorders, and learning disabilities. There is also a correlation between allergies and epilepsy in children.

But the evidence is conflicting, she says, with contradictions arriving from a longitudinal study in a population-based twin sample which showed a positive association between a history of atopy and dementia while another study reported recently that Alzheimer’s patients who also suffered from allergies had an improved biomarker profile, closer resembling that of healthy subjects (i.e., higher beta-amyloid42 levels in the cerebrospinal fluid), and had a better cognitive performance, which might indicate a beneficial effect of allergy on Alzheimer’s disease.

Using a rodent model, Klein looked at the effect of exposure to Timothy grass pollen on the hippocampus. The ensuing allergy seemed to have a positive impact on the production of new neurons and led to a down-regulation of microglial activation in this region. Why are microglia deactivated in the hippocampus of allergic mice, she asks? “It is tempting to assume that this might be a regulatory mechanism protecting the hippocampus, which is central for many important processes, from the immune response in the periphery. An alternative hypothesis would be that this down-regulation is directly caused by the elevated levels of TH2 cytokines in the blood. It is even more challenging to speculate about the functional consequences of this observed down-regulation of microglial activation below the normal “surveying state” in the young hippocampus. If immune surveillance in the hippocampus is down-regulated for extended periods, this may have detrimental consequences.” Similarly, their experiment did not run for long enough to attempt to answer the obvious question as to whether the increase in neuron production leads to beneficial changes to long-term potentiation (traffic across neural networks) and, consequently, learning and memory.

It all goes to show what a confoundingly complex apparatus the immune system is – riddled with apparent paradoxes and contradictory findings. And while a TH2-polarized allergic immune response might promote neurogenesis and down-regulate microglia in the hippocampus over the duration of a short experiment, Klein can as yet have no idea if this also has a beneficial effect on the normal function of the central nervous system and what happens if this immune response persists for a longer time.