Hornig, Lipkin and chronic fatigue syndrome again

Drs Mady Hornig and Ian Lipkin once again provide some fodder for this blog, continuing one of their important research themes on how chronic fatigue syndrome (CFS) (sometimes also referred to as myalgic encephalomyelitis, ME) might show some important immune-related issues [1].

This research tag-team and the teams of dedicated scientists who surround them are making some real progress with regards to the idea that ME/CFS is a physical condition (not psychosomatic and not 'biopsychosocial') with some readily identifiable biological features potentially accompanying cases. Of course we're not there just yet when it comes to a biological test for ME/CFS but science has at least started down that particular research path...

With accompanying media attention in tow (see here), the focus of the most recent results were on how disease sub-types might be important to CFS and specifically, how: "Immune signatures in the central nervous system of ME/CFS patients with atypical features may be distinct from those with more typical clinical presentations."

Authors described how cerebrospinal fluid (CSF) samples from "32 ME/CFS cases with classical features and presentations and 27 ME/CFS cases with atypical features or clinical presentations" were included for analysis. On what basis was 'typical' and 'atypical' described? Well: "The ‘classical’ (C-ME/CFS) group had acute onset of disease marked by a prodrome consistent with infection; ‘atypical’ (A-ME/CFS) ME/CFS patients met full diagnostic criteria for ME/CFS at onset of their illness, but had a less standard onset of ME/CFS and/or developed other disorders after illness onset of ME/CFS." Interestingly one person included in the A-ME/CFS group was described as having Gulf-War Illness (another important condition talked about on this blog).

The results: various cytokines (chemical messengers of the immune system) were assayed for and with some nifty statistical 'corrections' authors reported some potentially important differences between the groups. So: "We found discrete differences in immune signatures of the CNS in ME/CFS subjects with atypical presentations that included sparse inter-cytokine networks and lower levels of two inflammatory mediators, the Th17 cytokine, IL17A, and the IFNγ- and TLR4-induced chemokine, CXCL9." All-in-all results suggested a "less robust CNS immune activation in A-ME/CFS."

Much more research is required in this area for sure. But these results are interesting and pertinent to the idea that within the heterogeneity (where have a I heard that before?) of CFS/ME, there may be quite a few phenotypes and subgroups that might be readily separable with a little biological research effort. Does this therefore mean when we talk about the pluralisation of lots of labels (the autisms, the schizophrenias, the depressions, etc), we might also one day called it 'the chronic fatigue syndromes'? Well, I've kinda speculated about this before in the peer-reviewed domain...

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[1] Hornig M. et al. Immune network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome with atypical and classical presentations. Transl Psychiatry. 2017 Apr 4;7(4):e1080.

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Hornig M, Gottschalk CG, Eddy ML, Che X, Ukaigwe JE, Peterson DL, & Lipkin WI (2017). Immune network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome with atypical and classical presentations. Translational psychiatry, 7 (4) PMID: 28375204

On (pre)pregnancy obesity and inflammation and offspring autism risk

At the time of writing this [long read] post there has been a flurry of autism research articles making news.

The headline: 'Scientists create the first ever autistic monkeys' referring to the work published by Liu and colleagues [1] who reported on "lentivirus-based transgenic cynomolgus monkeys (Macaca fascicularis) expressing human MeCP2 in the brain exhibit autism-like behaviours and show germline transmission of the transgene" started the ball rolling. Anyone who knows a little bit about autism will realise that mutations in the MeCP2 gene generally refers to Rett syndrome. Whilst linked to the expression of certain autistic-like behaviours, Rett syndrome is but one part of the very heterogeneous spectrum called autism. I'd also suggest that other primate research had previously 'modelled' autism, or at least, certain facets of autism (see here).

Next up was the headline: 'Autism Diets: Can Nutrition Have An Impact On Autism Risk?' portraying the findings reported by Xie and colleagues [2] (open-access) who talked about inborn errors of carnitine metabolism potentially being linked to some autism. This follows some important research history in this area (see here) specifically linked to a gene called trimethyllysine hydroxylase, epsilon (TMLHE) (see here). Inborn errors of metabolism potentially linked to autism (some autism) is a woefully under-researched and under-screened area (see here).

And then we have two papers that make up the core of today's post. The first by Mengying Li and colleagues [3] continues something of an important theme in autism research circles these days on how mum's weight and risk of diabetes during pregnancy might have a bearing on offspring development [4], and specifically the risk of autism and comorbid learning disability. This time around researchers "examined the independent and combined effects of maternal prepregnancy obesity and maternal diabetes on the risk of autism spectrum disorder (ASD) in parallel with other developmental disorders (DDs)." They did this by analysing data - "a subset of the Boston Birth Cohort who completed at least 1 postnatal study visit at Boston Medical Center between 1998 and 2014" - and comparing rates of autism ("based on physician diagnoses as documented in electronic medical records") and other diagnoses "among 6 groups defined by maternal prepregnancy obesity and diabetes status." They found that yes, those mums who were obese and presented with pregestational diabetes (PGDM) had a [significantly] increased risk of offspring autism as were those with both obesity and gestational diabetes. Interestingly: "This pattern of risk was mostly accounted for by cases with co-occurring ASD and ID."

Before heading further into the potential whys and wherefores to account for the Li results, I want to bring in another paper making news. Gloria Choi and colleagues [5] report results that have created headlines such as: 'Autism caused by immune response to viral infection during pregnancy?' Accepting that again, the use of the singular term 'autism' in that media piece does little to accentuate the degree of diversity that the label includes and the various 'routes' that might bring someone to a diagnosis (see here for example), I found this to be an interesting paper.

Building on the idea that viral infection during pregnancy might be able to affect offspring risk of autism or other behavioural outcomes (see here), researchers set about looking at some of the possible mechanisms involved in this process. The work of the late Paul Patterson (see here) gets a mention in the Choi study write-up and the concept of maternal immune activation (MIA). Pregnant mice were initially artificially 'immune stimulated' and offspring were found to display the sorts of behaviours that had previously been mentioned in the science literature in this area. Researchers then took out some key elements of the cells involved in the inflammatory response to immune activation - specifically Th17 cells - and repeated the artificial immune activation procedure. Offspring mice did not appear to show the same behavioural issues as those whose mother mice possessed their Th17 cells intact. Further, when pregnant mother mice were given an antibody that blocks interleukin-17 (IL-17) (produced by Th17 cells), offspring mice also showed behavioural differences compared with those offspring whose mother mice received immune stimulation but nothing else. Ergo, the suggestion that: "therapeutic targeting of TH17 cells in susceptible pregnant mothers may reduce the likelihood of bearing children with inflammation-induced ASD-like phenotypes." The idea of an 'inflammation-induced autism phenotype' by the way is not a new one (see here).

Whilst remembering that mice are mice (and monkeys are monkeys) and so not necessarily able to model all of the complexity of human autism (and its important comorbidities), these are potentially important findings. I've covered the idea that immune function and inflammatory processes might be part and parcel of some autism previously on this blog (see here for example) as part of a larger shift in psychiatry circles (see here). Indeed, some of that research has specifically talked about IL-17 and at least some autism (see here for example) and the idea that levels might be increased compared to other groups. Insofar as the notion of blocking the effects of IL-17 (or Th17), I'm minded to suggest that we need a lot more data first before specific interventions are discussed or attempted including looking at compounds linked to the maturation of Th17 cells [6] as possible targets.

What the Li and Choi papers share in common are several variables. First is the idea that 'the nine months that made us' might indeed be an important time insofar as future behavioural outcome. Indeed the Li results also suggest that what happens prepregnancy might also exert a significant effect. Second is the notion that inflammation (or response to inflammation) in-utero might be an important concept for at least some 'types' of autism and indeed other future diagnoses (see here). If you're wondering what obesity might have to do with inflammation, well, let's just say that quite a few researchers/research groups believe there is an important link [7] and certainly some write-up on the Li paper makes that point. I say this acknowledging that Li and colleagues also noted the children with autism in their cohort were also more likely to be born preterm and with a low birth weight. Finally, is the question of whether disrupting inflammatory processes or responses particularly during critical times of prepregnancy and/or pregnancy might be something to look at with a view to altering any 'programmed' offspring autism or other risk. Appreciating that not everyone might receive this question the same way, I do think we need to have some frank discussions about this option. That Li and colleagues reported on prepregnancy obesity/diabetes as being particularly associated with autism and learning (intellectual) disability perhaps provides an important detail pertinent to the idea of improving child outcomes and quality of life (particularly if pregnancy inflammation translates into offspring inflammation and where that could lead).

Some important future research directions are indicated.

Music, and what else but Terry Wogan and The Floral Dance. Rest in peace Sir Terry and not forgetting your best quotes...

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[1] Liu Z. et al. Autism-like behaviours and germline transmission in transgenic monkeys overexpressing MeCP2. Nature. 2016 Jan 25.

[2] Xie Z. et al. Inborn Errors of Long-Chain Fatty Acid β-Oxidation Link Neural Stem Cell Self-Renewal to Autism. Cell Reports. 2016. Jan 28.

[3] Li M. et al.  The Association of Maternal Obesity and Diabetes With Autism and Other Developmental Disabilities. Pediatrics. 2016. Jan 29.

[4] Connolly N. et al. Maternal metabolic risk factors for autism spectrum disorder-An analysis of electronic medical records and linked birth data. Autism Res. 2016 Jan 29.

[5] Choi GB. et al. The maternal interleukin-17a pathway in mice promotes autism like phenotypes in offspring. Science. 2016. 28 Jan.

[6] Huang W. et al. DDX5 and its associated lncRNA Rmrp modulate TH17 cell effector functions. Nature. 2015 Dec 24;528(7583):517-22.

[7] Lumeng CN. & Saltiel AR. Inflammatory links between obesity and metabolic disease. J Clin Invest. 2011 Jun;121(6):2111-7.

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Li, M., Fallin, M., Riley, A., Landa, R., Walker, S., Silverstein, M., Caruso, D., Pearson, C., Kiang, S., Dahm, J., Hong, X., Wang, G., Wang, M., Zuckerman, B., & Wang, X. (2016). The Association of Maternal Obesity and Diabetes With Autism and Other Developmental Disabilities PEDIATRICS, 137 (2), 1-10 DOI: 10.1542/peds.2015-2206



Choi GB, Yim YS, Wong H, Kim S, Kim H, Kim SV, Hoeffer CA, Littman DR, & Huh JR (2016). The maternal interleukin-17a pathway in mice promotes autismlike phenotypes in offspring. Science (New York, N.Y.) PMID: 26822608

Autism, asthma and IL-17

"IL-17 was increased in ASD [autism spectrum disorder] children with co-morbid asthma compared to controls with the same condition."

That was the conclusion reached by Marjannie Eloi Akintunde and colleagues [1] including some notable names on the authorship list from the University of California, Davis. IL-17 (Interleukin 17) by the way, refers to a group of cytokines - chemical messengers of the immune system - linked to various processes centred on inflammation. Jin & Dong [2] provide quite a good overview of the complexities of IL-17 with respect to immune function and inflammation.

Asthma crops up yet again on this blog. Based on the idea that overlapping diagnoses of autism and asthma might be more frequent than one would perhaps anticipate (see here and see here), researchers looked at the production of various cytokines including IL-17 in biological samples provided by a group of young children with ASD compared to asymptomatic controls "following ex vivo mitogen stimulation." They reported that levels of IL-17 were elevated in samples from the group with ASD compared to controls and for those with ASD and comorbid asthma, levels of IL-17 were elevated compared with those diagnosed with ASD minus asthma.

This is not the first time that IL-17 has cropped up on the autism research radar as per the findings reported by Al-Ayadhi & Mostafa [3] also covered on this blog (see here). Other, more case report data has also hinted that IL-17 as part of a "proinflammatory, autoimmune-polarized cytokine profile" [4] might also show some connection with [some] autism. Even some of the co-authors on the Akintunde paper have previously reported on IL-17 in relation to autism [5] albeit not necessarily central to the cytokine 'profile' of autism.

It is important to note that whilst there were group differences noted between autism and controls, the idea that IL-17 might distinguish autism + asthma from autism alone is not an entirely unexpected finding. Elevated levels of IL-17 have been reported in cases of asthma [6] and in some quarters, has been touted as a possible 'therapeutic target' specifically in those cases of steroid-insensitive asthma [7]. Questions do however remain about the hows and whys of the association between autism and asthma and importantly, whether there may be overlapping aetiological factors leading to both conditions developing alongside the idea that other comorbidity might be also implicated (see here).

Music: MGMT - Time To Pretend.

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[1] Akintunde ME. et al. Increased production of IL-17 in children with autism spectrum disorders and co-morbid asthma. Journal of Neuroimmunology. 2015. July 11.

[2] Jin W. & Dong C. IL-17 cytokines in immunity and inflammation. Emerging Microbes & Infections. 2013; 2: e60.

[3] Al-Ayadhi LY. & Mostafa GA. Elevated serum levels of interleukin-17A in children with autism. J Neuroinflammation. 2012 Jul 2;9:158.

[4] Magid-Bernstein J. et al. Case report: cytokine and CD4+ T-cell profiles of monozygotic twins with autism and divergent comorbidities and drug treatment. J Child Neurol. 2015 Mar;30(3):386-90.

[5] Onore C. et al. Decreased cellular IL-23 but not IL-17 production in children with autism spectrum disorders. J Neuroimmunol. 2009 Nov 30;216(1-2):126-9.

[6] Chesné J. et al. IL-17 in severe asthma. Where do we stand? Am J Respir Crit Care Med. 2014 Nov 15;190(10):1094-101.

[7] Morishima Y. et al. Th17-associated cytokines as a therapeutic target for steroid-insensitive asthma. Clin Dev Immunol. 2013;2013:609395.

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Akintunde, M., Rose, M., Krakowiak, P., Heuer, L., Ashwood, P., Hansen, R., Hertz-Picciotto, I., & Van de Water, J. (2015). Increased production of IL-17 in children with autism spectrum disorders and co-morbid asthma Journal of Neuroimmunology DOI: 10.1016/j.jneuroim.2015.07.003

Hookworm infection and microchallenge for coeliac disease?

I'm getting rather baffled by some of the literature appearing with the autoimmune condition coeliac (celiac) disease in mind. The paper by Kalliokoski and colleagues [1] started the bafflement ball rolling with their suggestion that: "administration of IgA-deficient celiac disease patient serum or total IgG induces both deterioration of the intestinal mucosa and clinical features of celiac disease in mice". Then came the paper from Namatovu and colleagues [2] who concluded that: "Neighborhood composition influences CD [coeliac disease] risk". Such discussions were based on a condition which science seemed to be getting a handle on in terms of the genetic and biological processes involved... or maybe not.

"Klaatu Barada N... Necktie... Neckturn... Nickel"

Enter also the findings reported by John Croese and colleages [3] observing that: "Necator americanus and gluten microchallenge promoted tolerance and stabilized or improved all tested indices of gluten toxicity in CeD [coeliac disease] subjects" and the bafflement ball starts to roll away yet faster and further.

A few points from the Croese paper are worth noting:

• This was a year long study looking at a small number of adults with "diet-managed" CD (N=12). In case you might not know, the diet in question is a gluten-free diet.
• Said participants were "inoculated" with 20 hookworm larvae (see here for a picture if you really wish) and subsequently fed increasing doses of gluten - consumed as pasta - ranging from micrograms to grams over the course of some weeks. 
• "Symptomatic, serologic, and histological outcomes evaluated gluten toxicity. Regulatory and inflammatory T cell populations in blood and mucosa were examined".
• Results: Not all the participants went the distance with the gluten challenge; two of which were labelled 'gluten intolerant' (which is a little odd because intolerance of gluten is I presume a hallmark of all CD). That being said, there were some interesting findings observed such as: "the mean IgA-tissue transglutaminase titers declined". I'm not an expert on CD but elevated IgA-tissue transglutaminase is closely associated with CD and I believe levels should fall when a person adopts a gluten-free diet [4]. The fact that levels declined when a gluten challenge (ingesting gluten) was in place was, in the words of the authors, "contrary to the predicted rise".
• Researchers also described how: "Intestinal T cells expressing IFNγ were reduced following hookworm infection". Again with my non-expert hat on, these are some interesting results. The interferons have been previously discussed on this blog with autism in mind (see here) but with CD in focus, are thought to be part of the destructive immune system processes which describe the condition (see here). The suggestion that hookworm infection might be somehow placating such immune processes is intriguing.

Obviously, there is a lot more to do in this area before anyone decides that hookworm infection is a panacea for CD. I've already mentioned the small participant number and attrition rate but given also that CD is usually described as a lifelong condition, one year of experimental study is not nearly enough to discuss any long-term effects. That other studies from the authors have reported less eventful results [5] is also worth mentioning.

But, I'm also minded to discuss another paper from this research group [6] which was covered on a sister blog (see here). On that occasion, authors talked about how hookworm infection seemed to influence production of the TH-17 cytokine, IL-17A too: "Hookworm infection suppressed basal production of the inflammatory cytokines IFN-γ and IL-17A". I've become quite interested in IL-17 over the years, again with the autism research connection in mind (see here) and a possible link with autoimmunity. The fact that IL-17 might also represent one way of distinguishing subgroups with CD [7] is likewise intriguing and offer something in the way of a variable on response to such helminthic therapy...

Music to close. How about some bluegrass... The Grascals and Bugle Call Rag?

And since, I have your attention, here's a link to my latest paper [8] on the potential use of gluten and casein-free diets for autism (shameless self-publicity I know).

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[1] Kalliokoski S. et al. Injection of celiac disease patient sera or immunoglobulins to mice reproduces a condition mimicking early developing celiac disease. J Mol Med (Berl). 2014 Sep 12.

[2] Namatovu F. et al. Neighborhood conditions and celiac disease risk among children in Sweden. Scand J Public Health. 2014 Sep 23. pii: 1403494814550173.

[3] Croese J. et al. Experimental hookworm infection and gluten microchallenge promote tolerance in celiac disease. J Allergy Clin Immunol. 2014 Aug 29. pii: S0091-6749(14)01010-0.

[4] Dahele AV. et al. Serum IgA tissue transglutaminase antibodies in coeliac disease and other gastrointestinal diseases. QJM. 2001 Apr;94(4):195-205.

[5] Daveson AJ. et al. Effect of hookworm infection on wheat challenge in celiac disease--a randomised double-blinded placebo controlled trial. PLoS One. 2011 Mar 8;6(3):e17366.

[6] McSorley HJ. et al. Suppression of inflammatory immune responses in celiac disease by experimental hookworm infection. PLoS One. 2011;6(9):e24092.

[7] Sapone A. et al. Differential mucosal IL-17 expression in two gliadin-induced disorders: gluten sensitivity and the autoimmune enteropathy celiac disease. Int Arch Allergy Immunol. 2010;152(1):75-80.

[8] Whiteley P. Nutritional management of (some) autism: a case for gluten- and casein-free diets? Proc Nutr Soc. 2014 Oct 14:1-6.

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Croese J, Giacomin P, Navarro S, Clouston A, McCann L, Dougall A, Ferreira I, Susianto A, O'Rourke P, Howlett M, McCarthy J, Engwerda C, Jones D, & Loukas A (2014). Experimental hookworm infection and gluten microchallenge promote tolerance in celiac disease. The Journal of allergy and clinical immunology PMID: 25248819

sPECAM pie and school-aged autism

I've talked about adhesion molecules with autism in mind before on this blog (see here). In that entry it was some interesting data out of the MIND Institute which caught my attention; specifically the selectins and their sticky siblings being 'generally' suggested to be lower in case of autism than control samples. Without repeating my previous post, it's all about the binding of leukocytes to the walls of blood vessels to begin their rolling journey towards the site of an injury and then inflammation, yadda, yadda...

Rolling stone & moss @ Wikipedia  

Anyhow, a new addition joins the voices suggesting issues with adhesion in cases of autism in the form of the paper by Yosuke Kameno and colleagues* (open-access paper available here).

The Kameno paper fills a bit of a gap in the literature in this area by looking at levels of platelet-endothelial adhesion molecule-1 (PECAM-1), platelet selectin (P-selectin), endothelial selectin (E-selectin), intracellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in serum samples from school-aged children (5-17 years old) diagnosed with autism compared with asymptomatic controls. The reasoning being that very young infants and young adults have been examined with these adhesion molecules in mind but not the intervening age group.

The results: well probably unsurprisingly, levels of at least some of the adhesion molecules were lower in cases of autism compared with the control group. So: "The serum levels of sPECAM-1 in subjects with high-functioning ASD were significantly lower than those of controls (U = 91.0, P<0.0001) (Table 1). Subjects with high-functioning ASD also had significantly decreased levels of sVCAM-1 compared with those in controls (U= 168.0, P = 0.0042)". The U by the way refers to the statistical test used (Mann-Whitney U test) to analyse results. That and the fact that attempts to correlate the biological findings with things like scores on the Autism Diagnostic Interview-Revised (ADI-R) didn't reveal any significant correlations.

There are also a few hidden gems in this paper not readily discussed too much. So for example: "To exclude inflammatory disease, serum C-reactive protein (CRP) levels were determined". CRP is another interesting compound which I've talked about before with regards to inflammation and autism or risk of autism (see here and here). Kameno didn't seem to find anything specific in their autism cohort aside from: "The CRP measurement of one subject with ASD was 2.30 mg/dl (this individual did not have subjective symptoms or a history of inflammatory disease)".

They also looked at a number of cytokines in their participant group and concluded: "We determined that plasma concentrations of IL-1β, IL-1RA, IL-5, IL-8, IL-12(p70), IL-13, IL-17 and GRO-α were 
significantly higher in subjects with ASD compared with the corresponding values of the matched controls, after correcting for multiple comparisons". I'm particularly interested in their observations on IL-17 given some previous work in this area (see here) and its [proposed] link to various autoimmune conditions.

So Kameno and colleagues have filled the age group gap in the work looking at adhesion molecules with autism in mind. Given the increasing strength of the evidence coming out of this area of autism research, one could make a good argument for quite a bit more detailed investigation?

To finish, there are potentially lots of rolling linked songs I could offer. But instead I'll go for burning....

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* Kameno Y. et al. Serum levels of soluble platelet endothelial cell adhesion molecule-1 and vascular cell adhesion molecule-1 are decreased in subjects with autism spectrum disorder. Mol Autism. 2013 Jun 17;4(1):19.

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Kameno Y, Iwata K, Matsuzaki H, Miyachi T, Tsuchiya KJ, Matsumoto K, Iwata Y, Suzuki K, Nakamura K, Maekawa M, Tsujii M, Sugiyama T, & Mori N (2013). Serum levels of soluble platelet endothelial cell adhesion molecule-1 and vascular cell adhesion molecule-1 are decreased in subjects with autism spectrum disorder. Molecular autism, 4 (1) PMID: 23773279

Mouse modeling, immune function and autism

Contrary to the title of this post and any images that it may conjure up of mice parading down a runway in this season's 'hottest looks' whilst pouting to the clicks and flashes of multiple cameras, I'm back to mouse models and autism again(!) and an interesting piece of research by Hsiao and colleagues*.

I am kinda standing on the shoulders of giants with this paper given that it comes from the laboratory of Paul Patterson who has already run with a short description about it on his blog (see here). Whilst not pinning my colours to any mast, Prof. Patterson's blog is one I enjoy reading, not least because of the various links being made between the immune system and the brain (at least in mice). I assume most people would recognise by now that the brain does not run independent of the rest of the body despite our implicit need to compartmentalise anything and everything (see this post on labels).

Drawing heavily on Prof. Patterson's latest blog entry and the paper in question - hopefully without plagiarising - a few factoids:

• The Patterson team have previously published results based on a mouse model of stimulated immune activation during pregnancy and the resultant behavioural effects on offspring which seemed to overlap with the core symptoms of autism (see this paper by Malkova and colleagues**).
• In the latest study* the authors report on the profile of immune function in offspring mice of immune-stimulated mothers, suggesting some interesting effects in the area of T regulatory cells and cytokine production. I have recently talked about T-cells in this post on pristine cysteine so will perhaps put that to one side for now. Of just as much interest are elevations in that old favourite IL-6 and similar suggestions for IL-17, again the source of some interest recently on the topic of autoimmunity and autism (here). Roads toward inflammation seemed to be a key part of their findings.
• Coincidental to these findings is the report of "altered myeloid lineage potential and differentiation" in offspring. I'm not even going to profess to begin to know what this actually means, aside from referring you to quite a nice overview of hematopoietic stem cells (here) showing the distinction between myeloid and lymphoid progenitors. 
• Then to the big findings and please don't shoot the messenger: irradiating and transplanting "immunologically normal" bone marrow from both affected and non-affected control mice offspring into the offspring of immune stimulated mother mice seemed to correct some of the autism-type behaviours that were exhibited. So repetitive- and anxiety-like behaviours seemed to be reduced bearing in mind that anxiety is not (yet) a core symptom of autism (see here).
• That and some suggestion that timing might be everything when it comes to programming for immune dysfunction as a result of very few effects being seen when transplanting bone marrow from affected offspring to non-affected offspring over being born into a stimulated maternal immune system environment.

I note that on quite a few sites analysing these latest results, the authors have gone to great lengths to stress that (a) these were mouse findings - I'll say again, these were mouse findings, and (b) at the moment, no-one is suggesting that a bone marrow / stem cell transplant is any kind of 'treatment' for autism given questions for example, about whether the 'irradiation' bit of the procedure might have shown any effect alongside the actual bone marrow transplant. I would most definitely support these statements given both the preliminary nature of this research and also the complications and risks attached to bone marrow transplants (see here).

Having said that this is not the first time that bone marrow transplants and conditions like autism have appeared in the research literature. This paper by Akaho and colleagues*** talks about such transplants in cases of autism (and schizophrenia) occurring alongside leukaemia with a specific focus on maintaining treatment regimes and the anxiety related to the treatment process. Sharma and colleagues**** discussed some rather more direct observations following administration of "autologous bone marrow-derived mononuclear cells" in their quite varied patient group including cases of autism, bearing in mind one tree does not a forest make.

Indeed the concept of stem cell therapy, words which still seem to create quite an emotional response in many people, seems to be occurring more and more often in the research literature on autism as per this review by Siniscalco and colleagues***** (full-text) including a familiar name (Anna Sapone). I know many people might read 'stem cells and autism' and think back to those pop-up ads that seem to appear on various search engines offering some kind of James Bond style 'Die Another Day' rearrangement. Again, no endorsement is intended or given but perhaps what the Patterson lab study is suggesting is that a little more focused research is required in this area just before the door is entirely slammed shut. 

The Hsiao findings do represent another very important preliminary step into the immune-behaviour relationship with conditions like autism in mind. Assuming that the whole is greater than the sum of its parts, these moves towards a more whole body analysis of conditions like autism, where immune function, gut and gut bacterial function and brain function are examined in unison, offer the promise of some truly tantalising insights into autism.

And finally... just in case you are not convinced on the potential for an immune-behaviour link, cast your eye over this recent preliminary report on Alzheimer's disease and the use of IVIg as another area ripe for further inquiry.

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* Hsaio EY. et al. Modeling an autism risk factor in mice leads to permanent immune dysregulation. PNAS. July 2012.
DOI: 10.1073/pnas.1202556109

** Malkova NV. et al. Maternal immune activation yields offspring displaying mouse versions of the three core symptoms of autism. Brain, Behavior & Immunity. 2012; 26: 607-616.

*** Akaho R. et al. Bone marrow transplantation in subjects with mental disorders. Psychiatry & Clinical Neurosciences. 2003; 57: 311-315.

**** Sharma A. et al. Administration of autologous bone marrow-derived mononuclear cells in children with incurable neurological disorders and injury is safe and improves their quality of life. Cell Transplantation. 2012; 21: Suppl 1: S79-S90.

***** Siniscalco D. et al. Autism spectrum disorders: is mesenchymal stem cell personalized therapy the future? Journal of Biomedicine & Biotechnology. 2012; 480289.

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Hsiao EY, McBride SW, Chow J, Mazmanian SK, & Patterson PH (2012). Modeling an autism risk factor in mice leads to permanent immune dysregulation. Proceedings of the National Academy of Sciences of the United States of America PMID: 22802640

IL-17A elevated in cases of autism

"The converging evidence strongly argues that neurodevelopmental immune insults and genetic background critically interact and result in increased risk for either autism or schizophrenia". So say Max Michel and colleagues* in their recent paper reviewing the often intricate findings in this area of investigation. Personally, I have to say that I agree with their sentiments, after having read through quite a lot of the literature on this topic over the years. I hasten to add that both the genetic and environmental effects acting on the immune system, or any other system in cases of autism, is likely to be variable and not uniform across the condition. As far as we know...

Yet more evidence for a potential role for the immune system and certain cytokines in cases of autism has emerged from two very familiar names, Laila Yousef Al-Ayadhi & Gehan Ahmed Mostafa in this paper** (full-text) looking at levels of the proinflammatory cytokine IL-17A. I say that these are familiar names because this research tag-team have been pretty prolific in recent years as per their publication entries on autism (here) and various immune-related findings. I would perhaps also plug a few previous blog posts about their work (here, here and here).

Let's start with a description. I'm sure quite a few people who follow the immune system research in relation to autism will have heard about Th1 and Th2 (type 1 and 2 helper T-cells). As per their name, helper T-cells help; more specifically they are involved in the orchestra that this is the immune response and in particular, cytokines and their expression, different types of cytokines, depending on the type of helper T-cell. Balance seems to be quite an important concept when it comes to Th1 and Th2 as per this article by Berger*** (full-text).

For quite a long time, the concepts of Th1 and Th2 predominated. That is until another kind of helper T-cell came onto the scene: Th17 - T helper 17 cells. Th17 produces the IL-17 family of cytokines which play a role in host defence and inflammation. Th17 has also been tied to quite a few 'autoimmune' conditions such as psoriasis (here) and inflammatory bowel disease (here) among others. There is of course quite a lot of biochemistry behind Th17 cells and the counterbalance, Treg(s) (including an old friend, IL-6) but I have neither the will nor expertise to go too far into all that now.

After that very brief overview, let's go through what Al-Ayadhi & Mostafa did and found:

• A sample of 45 children diagnosed with DSM-IV autism (mean age: 8.4 years) were included for study and compared with 40 age- and sex-matched 'apparently healthy' asymptomatic children. No comorbid autoimmune conditions were recorded in participants as far as the authors could tell.
• Participants with autism were also 'graded' on the severity of their autism presentation by way of the CARS; most fell into the severe category (n=28); the others (n=17) were described as having mild to moderate autism.
• Blood samples were drawn from all participants and serum levels of IL-17A determined by ELISA. Importantly, from an analytical perspective, all samples were run twice in independent experiments to confirm the results and rule out cross-reactivity (see here for a description).
• Results: as a group, the children with autism presented with significant elevations in IL-17A compared to controls. Individually, almost half of the children with autism presented with elevated IL-17A levels based on results on or above the 95th percentile of serum IL-17A noted in the control group.
• Severity of autistic symptoms seemed also to show some relationship with serum IL-17A levels in that the more severe presentation was associated with greater serum levels than those with a more moderate presentation. Age and gender did not seem to show effects.

There are a few things that can be taken from this study. IL-17 and inflammation. IL-17 and autism. Inflammation and autism. Need I say anything else? The association between Th17 and autoimmune disorders is something to bear in mind. I've talked before about autism and both features of autoimmunity seemingly present in some cases (here) or overlap with autoimmune comorbidity (here). The current results seem to suggest that there maybe something which might, at a biochemical level, relate autism and autoimmunity in at least some cases of autism; indeed quite a few cases judging by this latest paper. The question is: are IL-17A levels a core feature of autism or merely describing some hidden autoimmune comorbidity?

This is not the first time that a relationship between Th17 and autism has been suggested. Suzuki and colleagues**** (full-text) reported elevations in IL-17 and various other cytokines in their study of young adolescent boys with autism compared with control. Indeed the current authors also cited a potential role for IL-17 in other findings, specifically related to elevations in osteopontin levels previously discussed with parallel features according to things like symptom severity affecting results.

I suppose the final question should be: what can be done about elevated levels of IL-17? Reiterating my position about not giving medical advice or anything that could be construed as medical advice, the research literature contains a few options for further investigation. The therapeutic application of monoclonal antibodies against human IL-17A has already been mentioned in other areas of investigation. Leonardi and colleagues***** reported some initial success on the use of ixekizumab for a specific type of psoriasis, plaque psoriasis and improvement in clinical symptoms. Similar preliminary findings were also reported by Hueber and colleagues****** based the use of on another IL-17A human monoclonal antibody, AIN457 (secukinumab). Other compounds also seem to have the potential to affect IL-17 levels or production too. Lanzilli and colleagues******* for example, discussed the potential of resveratrol to affect IL-17 levels (at least in vitro).  Again, I reiterate the need for a lot more efficacy and safety research before these and other potential compounds go anywhere near people with autism.

There seems to be a rising tide of research coming through suggestive of links between at least some cases of autism and issues with the immune system and more precisely autoimmunity. Bearing in mind the 'correlation does not equal causation' motif, I think back to the post on Dr Kevin Becker's paper and the other work that has been done in this area and wonder whether we really should be making moves to more generalised screening for autoimmune markers and comorbidity where an autism diagnosis is given, if only to establish how deep the rabbit hole really goes?

To finish, and to coincide with the news about "detecting a particle consistent with the Higgs boson", the Galaxy song by Monty Python. Makes me feel quite insignificant really.

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* Michel M. et al. Immune system gene dysregulation in autism & schizophrenia. Developmental Neurobiology. June 2012.

** Al-Ayadhi LY. & Mostafa GA. Elevated serum levels of interleukin-17A in children with autism. Journal of Neuroinflammation. 2012; 9: 158.
DOI: 10.1186/1742-2094-9-158

*** Berger A. Th1 and Th2 responses: what are they? BMJ. 2000; 321: 424.1.

**** Suzuki K. et al. Plasma cytokine profiles in subjects with high-functioning autism spectrum disorders. PLoS ONE. 2011; 6: e20470.

***** Leonardi C. et al. Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. NEJM. 2012; 366: 1190-1199.

****** Heuber W. et al. Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. Science Translational Medicine. 2010; 2: 52ra72.

******* Lanzilli G. et al. Anti-inflammatory effect of resveratrol and polydatin by in vitro IL-17 modulation. Inflammation. 2012; 35: 240-248.