Autism: getting some interference from interferon?

Autism research has on more than one occasion looked at the possibility that there is an immune component to at least some cases of autism. Indeed I hope I am not being too scientifically reckless when I say that immune involvement seems to be becoming quite a central finding to a proportion of people on the autism spectrum as per the results from researchers like Harumi Jyonouchi and Paul Ashwood. The big questions remain however: what are the central immune issues, who exactly on the spectrum are immune findings most pertinent to, and what comes first: autism or immune involvement? (I don't have the answers to these questions by the way, although have recently looked to Paul Patterson for some interesting directions).


Putting such 'chicken or egg' philosophical issues to one side, I offer another review-type entry with the immune system in mind with this post on autism and the interferons. A description first. If you've ever heard mention of the interferons, most likely it will have been referencing the cytokine interferon-gamma or IFN-gamma or IFN-γ (if you prefer the Greek character). Quite a good and comprehensive overview of IFN-γ is this one by Schroder and colleagues* (full-text). 


Bear however in mind that IFN-γ is but one member of family of proteins associated with lots of processes related to the immune system including macrophages (the 'big eaters' of the immune system) following the detected presence of a pathogen (bacteria, parasite, virus). The interferons also play quite an important anti-viral role as per their name.


Allowing for the fact that our immune systems' are probably always to some degree 'activated' given our continually interacting with our environment and all the bugs 'n stuff in it, one can perhaps see that the presence of significant elevations in levels of the interferons might be an important marker as to current the state of the immune system. Importantly, whether it is fighting infection or at least thinks its fighting an infection and how long the fight goes on for. 


So what's the story of interferon and autism? Quite a bit actually:

• Vijendra Singh** was one of the first to report on the presence of elevations in plasma levels of IFN-γ (and another cytokine, IL-12, a stimulator of IFN-γ) among participants with autism compared to asymptomatic controls. Similar increases in levels of IFN-γ in cases of autism were also noted by Croonenberghs and colleagues*** who reported on a few other relevant details also such as "a trend toward a significantly increased production of IL-6" despite no significant group differences between autism and controls. IL-6 you say? Similar findings of elevated levels of IFN-γ in autism have been replicated a few more times bearing in mind the different tissues analysed (here, here and here). 
• Gene Stubbs**** reported results for a small (very small!) participant group with autism based on levels of IFN-alpha (IFN-α) suggesting elevations compared to an even smaller control group. I was intrigued by this preliminary finding given that alpha interferon, normally used as pharmacotherapy for certain types of cancer (here), as well as being involved in immune function also (a) has the propensity to induce neuropsychiatric symptoms (here) and (b) exhibits some opioid activity as per its analgesic effect and affinity for certain types of opioid receptor (here). All that being said, I can't seem to find any other paper in the research literature which has looked at IFN-α in cases of autism. Perhaps it just isn't interesting enough (don't even ask about the other interferons).

There are a few other small details to add to the work in progress that is the interferons and autism.


As you will probably have noted, examination of the interferons has, in the majority of studies, been done alongside other biological parameters of the immune system, specifically other cytokines such as the various interleukins (those compounds prefaced by IL). What this perhaps implies is that the various findings on the interferons is part and parcel of a wider set of immune-related functions and parameters. The trick is determining which ones might be core to autism, and which ones are just after-effects.


Inflammation also features quite a bit in this story as it seems to have done based on other autism research. As with many cytokines and the blurring which comes with regards to (a) inflammation being universally a bad thing - it's not, (b) the black or white issue of being pro- or anti-inflammatory - it's not so simple, the relationship between interferons and inflammation is just as complicated. So for example, there is evidence that as well as being pro-inflammatory, interferons might also limit the inflammatory response as per this article by Sauer and colleagues***** (full-text). Just think Anakin Skywalker and his 'mixed' relationship with the Force as a kind of template.


Finally, I stumbled across this interesting paper by Barker and colleagues****** just to throw into the mix, and their suggestion that IFN-γ may be able to influence vitamin D levels. I'm interested in this paper on so many levels: the IFN-γ levels noted in cases of autism, vitamin D potentially being related to autism (and a few other things), etc. Accepting that Barker looked at a specific condition associated with 'inflammatory stress' and the old adage about correlation not being the same as causation, one has to wonder whether this may also impact on the interferon findings noted in autism. Indeed whether chronic activation of interferons and other immue parameters towards inflammation, may have much more far-reaching consequences than just immune involvement in autism. Gut permeability perhaps?


To close, preaching is what Papas do best so why should we stop? (and we do it oh so well).


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* Schroder K. et al. Interferon-γ: an overview of signals, mechanisms and functions. Journal of Leukocyte Biology. 2004; 75: 163-189.


** Singh VK. Plasma increase of interleukin-12 and interferon-gamma. Pathological significance in autism. Journal of Neuroimmunology. 1996; 66: 143-145.


*** Croonenberghs J. et al. Activation of the inflammatory response system in autism. Neuropsychobiology. 2002; 45: 1-6.


**** Stubbs G. Interferonemia and autism. JADD. 1995; 25: 71-73.


***** Sauer I. et al. Interferons limit inflammatory responses by induction of tristetraprolin. Blood. 2006; 107: 4790-4797.

****** Barker T. et al. Circulating interferon-γ correlates with 1,25(OH)D and the 1,25(OH)D-to-25(OH)D ratio. Cytokine. June 2012.