|I'm the big eater @ Wikipedia|
Macrophages. It all begins with monocytes, white blood cells produced in bone marrow from hematopoietic stem cells. Monocytes grow into different types of macrophages.
Macrophages, known as the big eaters of the immune system, are present in every cell of the body and include microglia (in the brain).
As part of their big eating duties, macrophages enjoy dining out on the odd invading pathogen or cell programmed for destruction as well as telling other immune cells what to do. A sort of Mr Creosote if you will (without the bucket). If you want the Star Wars version of macrophages (I'm not kidding) ... here you go (open-access).
Macrophages are activated by Gc-MAF (Gc Macrophage Activating Factor). The production of Gc-MAF is affected by nagalase (alpha-N-acetylgalactosaminidase) encoded by the gene NAGA. Nagalase affects the Gc protein (vitamin D3 binding protein) which has a knock-on effect blocking the production of Gc-MAF. The more nagalase activity, the less Gc-MAF is a rough-and-ready way to look at it. Less Gc-MAF equates as less macrophage activation according to this logic and some potential onward effects for immune function.
Why is it important? Well in cancer research, there is some preliminary chatter that tumors might be able to affect Gc-MAF function by way of altering nagalase activity (open-access)**. Such is the effect of increased nagalase and depressed Gc-MAF function that this has been put forward as a potential explanation of why cancers are able to 'avoid' the immune system and so develop unchecked. There is also some very preliminary evidence that giving supplemental Gc-MAF as an injection might affect cancer growth in animal models*** and human participants**** although this is still an area of some controversy given that one lab seems to be producing all the research.
So what's the logic of this area with autism in mind? I can't claim to be able to provide a definitive answer but one suggestion from press releases such as this one, are the reports of high levels of nagalase activity to be present in quite a few of the cohorts with autism looked at. Remember, nagalase negatively affects levels of Gc-MAF so potentially disrupting the activation of macrophages. Outside of malignant cells, there is a suggestion that elevated nagalase activity might be part and parcel of issues with immune function in cases of autism onwards to things like the presence of some kind of viral activity. Indeed this last point on viruses and nagalase I assume comes from other results on the use of Gc-MAF in the clearance of HIV infection***** bearing in mind replication is still required for this area of work.
So eventually we get back to the paper from Bradstreet and colleagues and in more detail:
- Described as a chart review, 40 participants with autism who sought testing for nagalase activity, pre- and post assessment of nagalase following Gc-MAF injections were followed.
- Diagnosis of participants was determined by having already received a DSM-IV diagnosis of autism independent of the study together with some in-house assessments on the severity of presentation.
- Blood draws signalled the start of the nagalase activity assessment which was shipped to a lab already versed in looking for the enzymatic activity.
- Gc-MAF was injected on a weekly basis covering an average of 14 injections to get those macrophages stimulated, and nagalase activity assessed again.
- Results: nagalase activity was generally higher in the autism group than the various reference ranges cited by the assaying laboratory.
- Nagalase activity levels dropped in quite a few participants following Gc-MAF administration (24 of 40 decreased to within laboratory reference ranges) and "uncontrolled observations of GcMAF therapy indicated substantial improvements in language, socialization and cognition". Before we get too carried away though, lets remember those words "uncontrolled observations".
- Importantly (very importantly) no significant side-effects were reported, bearing in mind reports of elevated body temperature occurred post infusion and words like "By the second month, no patients experienced significant febrile events" were used.
- The authors conclude that more research is required in this area.
OK. With the science hat on, one reiterates that this was a very, very preliminary case review and although Gc-MAF was "checked for sterility in-house and externally by the UK Health Protection Agency" apparently, this is still a compound under investigation and is still very experimental. I've not specifically made mention of Gc-MAF on this blog before this post. That being said, I have talked about nagalase in relation to some speculations on the now de-discovered work on XMRV and chronic fatigue syndrome (CFS).
There are some obvious questions raised from the findings reported by Bradstreet. So, assuming all that Gc-MAF does and how it apparently does it, the whole 'underactive immunity' side of autism comes into play. Indeed I'm immediately drawn back to the work by Harumi Jyonouchi and colleagues on SPAD and immunodeficiency detected in their cohort and the possible link with gastrointestinal (GI) dysfunction. That and the low IgA findings also observed on more than one occasion in cases of autism. Of course balancing all that with other findings indicative of other issues with immune function in cases of autism such as an overactive immune system and the whole autoimmunity side of things. I should perhaps also stress that I am not equating autism with HIV or cancer or anything else based on the description of these findings.
Perhaps just as important is the whole viral infection link being implied in some cases of autism by this work. I know this starts to take us into some quite uncomfortable territory with autism in mind as per the study by Mady Hornig and colleagues****** (including virus hunter Ian Lipkin) on a (mostly) lack of measles virus in reply to studies like the one from Kawashima and colleagues*******. I'm not really in a position to offer an expert opinion as to whether this is proof positive that specific viruses are or aren't involved in autism, over an above the multitude of viruses everyone comes across in a lifetime, albeit with an immune response in full working order and the focus being on autisms not autism. Think also back to that most classical autism-viral connection which looked at rubella******** quite a few years back. And then all those ancient remnants of viruses which we all carry in our genome and have been recently looked at with autism in mind and whether there are any connections to be made or not.
Irrespective of any controversy this might unearth - which I assume it probably will - the Bradstreet results are peer-reviewed results and hence worthy of further independent analysis. Perhaps Prof. Lipkin might once again step up to this task?
[Update: you may also want to have a look at the second time Gc-MAF has cropped up on the autism research circuit too.]
* Bradstreet JJ. et al. Initial observations of elevated alpha-N-acetylgalactosaminidase activity associated with autism and observed reductions from GC protein—macrophage activating factor injections. Autism Insights. 2012. 4: 31-38.
** Korbelik M. et al. The value of serum alpha-N-acetylgalactosaminidase measurement for the assessment of tumour response to radio- and photodynamic therapy. Br J Cancer. 1998; 77: 1009-1014.
*** Yamamoto N. & Nataparaju VR. Immunotherapy of BALB/c mice bearing Ehrlich ascites tumor with vitamin D-binding protein-derived macrophage activating factor. Cancer Res. 1997 Jun 1;57(11):2187-92.
**** Yamamoto N. et al. Immunotherapy of metastatic breast cancer patients with vitamin D-binding protein-derived macrophage activating factor (GcMAF). Int J Cancer. 2008; 122: 461-467.
***** Yamamoto N. et al. Immunotherapy of HIV-infected patients with Gc protein-derived macrophage activating factor (GcMAF). J Med Virol. 2009; 81: 16-26.
****** Hornig M. et al. Lack of association between measles virus vaccine and autism with enteropathy: a case-control study. PLoS ONE. 2008; 3: e3140.
******* Kawshima H. et al. Detection and sequencing of measles virus from peripheral mononuclear cells from patients with inflammatory bowel disease and autism. Dig Dis Sci. 2000; 45: 723-729.
******** Chess S. Follow-up report on autism in congenital rubella. J Autism Child Schizophr. 1977; 7: 69-81.
James Jeffrey Bradstreet, Emar Vogelaar, & Lynda Thyer (2012). Initial observations of elevated alpha-N-acetylgalactosaminidase activity associated with autism and observed reductions from GC protein—macrophage activating factor injections Autism Insights