Immune Reactions Induce Learning Difficulties: Potential Implications for Vaccine-Autism Link

Allow me to preface this post with a firm affirmation that I wholeheartedly support the use of vaccines. Vaccines, along with improved sanitation and hygiene, have resulted in massive increases in public health, and overall have had overwhelmingly positive effects on their recipients, and indeed, society in general. For that matter, I recently published a post that included an infographic that very effectively illustrated the positive effect that vaccines have had with respect to public health.

Furthermore, I was not then, am not now, nor will I ever be a proponent or the debunked Wakefield study that purported to show a relationship between the Measles-Mumps-Rubella (MMR) vaccine with autism.

That said, data such as those shown in Figure 1 below, that show rates of autism over time in the U.S.A. and U.K., and further note the specific years that the MMR vaccine introduced in those countries, are constructed to lead the reader to believe that the noted increase in the rate of autism diagnosis correlates with the introduction of the MMR vaccine.

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Figure 1. Alleged correlation between vaccines and autism rates in the USA and UK

While I certainly recognize that correlation does not equal causation, meaning there could be some other reason for this apparent correlation. For example, Dr. Steve Novella’s Blog published a graph show the relationship between organic food consumption and autism rates (Figure 2).

Autism-Organic-1
Figure 2. Alleged correlation between organic food purchase and autism rates

Most people are unlikely to believe that the purchase of organic food is likely to have induced the increased rates of autism diagnosis reported, despite the extremely tight correlation between the lines.

With all of that said, I’ve never been entirely comfortable with the explanation that the increase in autism comes from better diagnosis, etc. I didn’t–and don’t–actively disbelieve the explanation, like I said, I’ve just never been entirely comfortable with it.

As a scientist, I consider being uncomfortable with certain ideas to be a positive thing; it serves as the basis for future reading, learning, and perhaps someday, even larger scale research projects.

Given that, I’ve always considered myself open to other explanations, and don’t operate from the assumption that the apparent correlation between vaccines and autism is a function of better diagnosis is so-called “settled science.”

I remain open to other potential explanations.

With that preface behind me, an interesting article titled: CX3CR1+ monocytes modulate learning and learning-dependent dendritic spine remodeling via TNF-α (behind a paywall, you’ll need institutional access), published May 15, 2017 in Nature Medicine has brought this particular issue to the forefront of my mind once again.

The authors report having discovered a mechanism whereby learning and/or memory related difficulties may result from the immune system’s reaction to viruses. The study, performed in mice, suggests that the presence of a virus in the bloodstream activates a particular subclass of monocytes, which are type of white blood cell that can further differentiate into phagocytes or antigen presenting cells.

Evidence from this study obtained in mice suggests that the entry of a virus anywhere in the bloodstream activates this specific subpopulation of monocytes (CX3CR1highLy6Clow), which then release the inflammatory cytokine TNFα. The authors of the study report that TNFα subsequently travels to the brain, blocking the formation of nerve cell connections required to synthesize memories from sensory information.

Furthermore, activation of CX3CR1highLy6Clow monocytes impaired motor learning and learning-related dendritic spine plasticity through tumor necrosis factor (TNF)-α-dependent mechanisms.

The study reports that mice exposed to a mimic of viral infection eliminated more than twice the percentage of dendritic spines relative to mice whose immune systems were not activated, implying a disruption of synaptic networks. It’s currently believed that changing or altering networks of dendritic spine serves as the basis for memory formation.

To put it more succinctly, activation of the murine immune system by viruses causes a loss of connections among nerve cells within the cortex of the brain, the region thought be responsible for learning. Mice infected with viruses perform more poorly on established learning tests. This research provides a potential mechanism for the observed link between cognitive difficulties and viral infection.

Interestingly, the authors report that the observed changes in the nerve connections were stimulated by viral contact with monocytes in the body, not within the brain. If accurate, this is very significant; to my knowledge this is the first published evidence that links viral infection and subsequent immune system activation with specific, measurable changes in neuronal connections within the brain.

“This study in animals resonates with what we see in the clinic, where patients with acute or chronic infectious diseases often have weaker performance on motor skills and experience memory decline,” says Guang Yang, PhD, assistant professor in the Department of Anesthesiology, Perioperative Care, and Pain Medicine at NYU Langone. “Our results suggest that existing anti-inflammatory treatments that target TNFα may protect against brain dysfunction during peripheral infection.”

The authors also quantified the levels of various cytokines, including TNFα, at several time points following exposure the viral mimic, and report a larger, longer-lasting increase in TNFα relative to other cytokines. The authors suggest that the impact of systemic immune response on brain cell connections was executed through TNFα signaling. Indeed, mice engineered to lack TNFα signals in white blood cells saw neither a drop in dendritic spine formation nor in motor learning ability when exposed to the viral mimetic.

Though the authors do not include any specific reference to potential implications for vaccines, the relationship is clear to anyone familiar with vaccines and how they function.

For the sake of brevity, clarity, and that claims of a relationship between autism and vaccination are often specifically levied agains the MMR vaccine, I’ll discuss just this vaccine.

As indicated above, the MMR vaccine provides protection against measles, mumps, and rubella, all of which are viral diseases. Indeed the vaccines themselves contain live attenuated viruses. Attenuated refers to the fact that the virus is somehow weakened or made less pathogenic/infectious for humans. This is often accomplished by growing viruses in cells that typically not host cells.

Thus, the MMR vaccine can be classified as a “mimic virus” similar to that which the researchers used in their experiment. The MMR vaccine induces, among other things, a TNFα-mediated response.

Finally, a study from 2005, Immunological findings in autism, reports that

Viruses may initiate the process but the subsequent activation of cytokines is the damaging factor associated with autism…. Cytokine alteration of TNF-alpha is increased in autistic populations.

Though much of this study focused on the potential link between mercury used to preserve vaccines, the subsequent immune response, and the autism that allegedly results–and is most certainly wrong with respect to this–you’ll note that mercury is the first part of that cascade potentially leading to autism. The point that the authors made about the immune response and the subsequent neural damage it can inflict, leading to autism may not be off base.

In other words, perhaps we were wrong about mercury in vaccines, but could there be something more fundamental related to viral infection or vaccination that can potentially lead to autism? I certainly won’t offer any definitive conclusions at this point, but will acknowledge that this particular study raises some questions about the use of vaccines in infants that we would do well to take seriously.

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