Using Plasma Autoantibodies of Central Nervous System Proteins to Distinguish Veterans with GWI from ... Controls. Abou-Donia, Klimas 2020 RETRACTED

[John Mac]

RETRACTED - link to post
Full Title:
Using Plasma Autoantibodies of Central Nervous System Proteins to Distinguish Veterans with Gulf War Illness from Healthy and Symptomatic Controls

Gulf War Illness the main focus of the study but they had a control group of 50 people with ME/CFS

Abstract: For the past 30 years, there has been a lack of objective tools for diagnosing Gulf War
Illness (GWI), which is largely characterized by central nervous system (CNS) symptoms emerging from 1991 Gulf War (GW) veterans.

In a recent preliminary study, we reported the presence of autoantibodies against CNS proteins in the blood of veterans with GWI, suggesting a potential objective biomarker for the disorder.

Now, we report the results of a larger, confirmatory study of these objective biomarkers in 171 veterans with GWI compared to 60 healthy GW veteran controls and 85 symptomatic civilian controls (n = 50 myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and n = 35 irritable bowel syndrome (IBS)).

Specifically, we compared plasma markers ofCNS autoantibodies for diagnostic characteristics of the four groups (GWI, GW controls, ME/CFS, IBS).

For veterans with GWI, the results showed statistically increased levels of nine of the ten
autoantibodies against neuronal “tubulin, neurofilament protein (NFP), Microtubule Associated
Protein-2 (MAP-2), Microtubule Associated Protein-Tau (Tau), alpha synuclein (-syn), calcium
calmodulin kinase II (CaMKII)” and glial proteins “Glial Fibrillary Acidic Protein (GFAP), Myelin
Associated Glycoprotein (MAG), Myelin Basic Protein (MBP), S100B” compared to healthy GW
controls as well as civilians with ME/CFS and IBS.

Next, we summed all of the means of the CNS autoantibodies for each group into a new index score called the Neurodegeneration Index (NDI). The NDI was calculated for each tested group and showed veterans with GWI had statistically significantly higher NDI values than all three control groups.

The present study confirmed the utility of the use of plasma autoantibodies for CNS proteins to distinguish among veterans with GWI and other healthy and symptomatic control groups.

My bolding

https://www.mdpi.com/2076-3425/10/9/610

 

[Forbin]

Furthermore, ME/CFS symptomatic controls exhibited levels of autoantibodies against neural proteins that were intermediate between veterans with GWI and controls with IBS. ME/CFS is characterized by body and muscle pains as well as some CNS symptoms, including debilitating fatigue. GWI cases had higher levels of all autoantibodies except for GFAP when compared with ME/CFS controls. The increased GFAP levels in ME/CFS suggest a potential marker and pathobiology for that disorder. Recent studies from other groups have shown increased antibodies against ß2-adrenergic receptors in ME/CFS patients [50,51]. This suggests that ME/CFS is more similar to GWI than IBS based on these autoantibody biomarkers, but GWI still clearly represents a unique disorder based on different autoantibody patterns.

 

[Ravn]

The increased GFAP levels in ME/CFS suggest a potential marker and pathobiology for that disorder.

Question 1: what is GFAP?
Question 2: what relevance would elevated GFAP autoantibodies have & could that really be a biomarker (if the finding stacks up)?

Have only read the abstracts of the following.

Glial fibrillary acidic protein (GFAP) is the hallmark intermediate filament (IF; also known as nanofilament) protein in astrocytes, a main type of glial cells in the central nervous system (CNS). Astrocytes have a range of control and homeostatic functions in health and disease. Astrocytes assume a reactive phenotype in acute CNS trauma, ischemia, and in neurodegenerative diseases. This coincides with an upregulation and rearrangement of the IFs, which form a highly complex system composed of GFAP (10 isoforms), vimentin, synemin, and nestin. We begin to unravel the function of the IF system of astrocytes and in this review we discuss its role as an important crisis-command center coordinating cell responses in situations connected to cellular stress, which is a central component of many neurological diseases.

https://www.sciencedirect.com/science/article/abs/pii/S0955067415000137

Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is an autoimmune disease of the nervous system first defined in 2016. GFAP autoantibody, especially IgG that binds to GFAPα, has been reported in the cerebrospinal fluid (CSF) and serum of patients with GFAP astrocytopathy. [...] GFAP astrocytopathy is accompanied by neoplasms, but the relationship between virus infection and GFAP astrocytopathy is unclear. GFAP antibody itself does not induce pathological changes; it is only a biomarker for the process of immune inflammation.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6290896/

So it looks like:

1. GFAP are rather important to health.
2. Autoantibodies to GFAP are elevated in at least some other conditions and are already being used as a biomarker for a type of autoimmune astrocytopathy - this would seem to complicate their use as biomarker for ME?
3. Autoantibodies to GFAP are not causing any problems themselves but are a marker of "immune inflammation" (whatever that is but given it implicates astrocytes maybe it's another take on the nebulous "neuroinflammation"?).

 

[Forbin]

Generally speaking, GWI sounds like it's mostly triggered by exposure to chemicals, whereas ME/CFS seems mostly triggered by infections, though it seems like there are some cases where the opposite has been true.

This makes me think that the thing that they may have in common is that something (not necessarily the same thing) is crossing the blood brain barrier and the illnesses are a result of the brain's immune system reacting to that.

Dr. Komaroff mentioned this possibility years ago when describing a 2005 study as showing:

"A whole group of proteins, in the brain, were found in a third to a half of patients with chronic fatigue syndrome versus none of the patients who were healthy - highly significant differences statistically. And what those molecules - and others that I haven't shown you - say is that there is a low grade inflammation going on in the brain. There is something in the brain that the immune system doesn't like - doesn't want to be there and wants to get rid of - and that's being reflected in these proteins in the spinal fluid."

He was referring to this 2005 study by James Baraniuk, et al.

Baraniuk, J.N., Casado, B., Maibach, H. et al. A chronic fatigue syndrome – related proteome in human cerebrospinal fluid. BMC Neurol 5, 22 (2005). https://doi.org/10.1186/1471-2377-5-22

https://bmcneurol.biomedcentral.com/articles/10.1186/1471-2377-5-22

Conclusion
This pilot study detected an identical set of central nervous system, innate immune and amyloidogenic proteins in cerebrospinal fluids from two independent cohorts of subjects with overlapping CFS, *PGI and fibromyalgia. Although syndrome names and definitions were different, the proteome and presumed pathological mechanism(s) may be shared.

*PGI stands for "Persian Gulf Illness."

 

[It's M.E. Linda]

Generally speaking, GWI sounds like it's mostly triggered by exposure to chemicals, whereas ME/CFS seems mostly triggered by infections, though it seems like there are some cases where the opposite has been true.

This makes a lot of sense. The Countess of Mar’s trigger was chemicals too, sheep dip, I believe.

 

[forestglip]

This paper has been retracted, 29 July 2024.

Pubpeer

Retraction notice

"The Brain Sciences Editorial Office retracts the article “Using Plasma Autoantibodies of Central Nervous System Proteins to Distinguish Veterans with Gulf War Illness from Healthy and Symptomatic Controls” [1], cited above.

Following publication, concerns were brought to the attention of the Editorial Office by a representative from Duke University regarding the validity of the Western blots presented in Figures 1–3 of this publication [1].

Adhering to our complaints procedure, an investigation was conducted by the Editorial Office and Editorial Board. Based on the review by Duke University of the article’s findings, the co-authors have requested a retraction due to concerns about their ability to rely on the Western blot images and produce verified, reliable results.

The Editorial Board evaluated the correspondence from the authors and the Institution and decided to retract this article [1], as per MDPI’s retraction policy (https://www.mdpi.com/ethics#_bookmark30, accessed on 28 May 2024) and in line with the Committee on Publication Ethics retraction guidelines (https://publicationethics.org/retraction-guidelines, accessed on 28 May 2024).

This retraction was approved by the Editor-in-Chief of the journal Brain Sciences.
The authors agreed to this retraction."