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....

----------

* 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.

----------

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

Stick with me kid: adhesion molecules and autism

Spider web by Luc Viatour / www.Lucnix.be

A paper by Charity Onore and colleagues* from the MIND Institute caught my eye quite recently. The topic was adhesion, and in particular cell adhesion related to immune function; and an analysis of some of the primary players in this sticky process such as the selectins and other interesting molecules including CD31 otherwise known as PECAM-1 (see here for an explanation) in relation to autism. From the outset, I should clarify that this is not a post on the neuronal cell adhesion research that has been undertaken on autism (see here). As if I would know where to start on that research area...

Regular readers of this blog might already understand that I have a continued interested in the output from the MIND Institute with autism in mind, much of which has been summarised in another paper from Dr Onore** on the role of the immune system in cases of autism. Indeed just reading the abstract to this summary paper makes me further realise how complex and 'real' the immune system findings are to autism - some cases of autism. These are not just funny abbreviations like IL-6 or INF but very real elements to what is a very complicated condition. An interesting opinion piece arrives at similar conclusions.

Anyway, back to the topic/paper at hand, cell adhesion, and probably best if I try and translate a few of the concepts outlined in the recent paper as well as summarising what was found, just so you know how the findings might fit in.

• 'leukocyte transendothelial migration' basically refers to the process of getting leukocytes (white blood cells) to the site of infection or injury. If you can bear some pretty heavy biochemistry, this paper by Liu and colleagues*** (full-text) offers quite a detailed description of what's potentially involved in the process.
• 'Levels of sPECAM-1 and sP-selectin were significantly reduced in the ASD group'. The selectins are kinda the first response in recruiting leukocytes to where they're needed. From what I can gather, they 'tether' white blood cells (leukocytes) to the endothelial cells to facilitate rolling to the site of injury and inflammation (see here). I suppose it's kinda like a velcro response although perhaps not so permanent (see here). Lower levels of [plasma soluble] sP-selectin might indicate some issue with the ability to perform these adhesive duties bearing in mind that the other selectins, L-selectin and E-selectin also play an important role. Given the link between elevations of sP-selectin as a marker for platelet / endothelial activation (among other things), one has to suggest that these results are perhaps reflective of hypo-activation compared with controls. Similar findings have been reported previously**** (full-text).
• Lower levels of platelet endothelial adhesion molecule-1 (PECAM-1) (see here for a good overview) were also reported. PECAM-1 seems to perform a similar role with regards to adhesion. Interestingly, this is again not the first time that lower levels of PECAM-1 have been reported in cases of autism*****. 
• "Soluble PECAM-1 levels were negatively associated with repetitive behavior and abnormal brain growth in children with ASD (p = .03)". In other words, low levels of PECAM-1 were linked to elevated levels of repetitive behaviours and unusual head growth (again as per the Tsuchuiya findings).

I can't claim to be a world's expert on this area of autism research so won't go to far further into the possible meaning. The authors conclude that these adhesion molecules "modulate the permeability and signaling at the blood-brain barrier". That is true as per reviews like this one from Kalinowska & Losy****** on PECAM-1 and neuroinflammation. Unless I'm reading this wrong, the only issue being that elevated levels of PECAM-1 seem to be related to such issues; the current results were kinda sailing against that tide at least in their cohort as a group.

Taken at face value, these results may suggest that the various ways and means that the body deals with inflammation may be perturbed in some cases of autism. Without actually knowing whether inflammation (acute or chronic) was present in the described cases of the current study, it is slightly difficult to make too much of the findings as they stand. Reiterating that the involvement of the immune system in cases of autism is far from simple - some say presentation of under-activation (as per this article on the immunoglobulins by the MIND Institute) others say over-activation (see here) - one has to be cautious about making sweeping generalisations. Realising also that the immune system is not just one system, as per the innate vs. adaptive classifications.

A final note. One added bonus to the current paper was the relationship with the Autism Phenome Project (APP) which very importantly realises that autism is an umbrella term to describe lots and lots of different presentations; not necessarily all the same thing however in terms of aetiology or trajectory (see the 'bloomers' post). Indeed based on the previous results reported for the APP looking at brain enlargement and regression in autism (see here), there is perhaps some overlap in participants taking part in the current study also.

To finish, the sad news of the death of a true icon of the age, Neil Armstrong, brings to mind an apt song, Man on the Moon by REM. Truly one small step, one giant leap.

----------

* Onore CE. et al. Levels of soluble platelet endothelial cell adhesion molecule-1 and P-selectin are decreased in children with autism spectrum disorder. Biological Psychiatry. June 2012.

** Onore CE. et al. The role of immune dysfunction in the pathophysiology of autism. Brain, Behavior & Immunity. 2012; 36: 383-392.

*** Liu Y. et al. Regulation of leukocyte transmigration: cell surface interactions and signaling events. Journal of Immunology. 2004; 172: 7-13.

**** Iwata Y. et al. Serum levels of P-selectin in men with high-functioning autism. British Journal of Psychiatry. 2008; 193: 338-339.

**** Tsuchuiya KJ. et al. Decreased serum levels of platelet-endothelial adhesion molecule (PECAM-1) in subjects with high-functioning autism: a negative correlation with head circumference at birth. Biological Psychiatry. 2007; 62: 1056-1058.

***** Kalinowska A. & Losy J. PECAM-1, a key player in neuroinflammation. European Journal of Neurology. 2006; 13: 1284-1290.

----------

Onore CE, Nordahl CW, Young GS, Van de Water JA, Rogers SJ, & Ashwood P (2012). Levels of Soluble Platelet Endothelial Cell Adhesion Molecule-1 and P-Selectin Are Decreased in Children with Autism Spectrum Disorder. Biological Psychiatry PMID: 22717029