Evaluation of four clinical laboratory parameters for the diagnosis of myalgic encephalomyelitis.

[Murph]

J Transl Med. 2018 Nov 21;16(1):322. doi: 10.1186/s12967-018-1696-z.
Evaluation of four clinical laboratory parameters for the diagnosis of myalgic encephalomyelitis.
De Meirleir KL1, Mijatovic T2, Subramanian K3, Schlauch KA4, Lombardi VC5.
Author information
Abstract
BACKGROUND:
Myalgic encephalomyelitis (ME) is a complex and debilitating disease that often initially presents with flu-like symptoms, accompanied by incapacitating fatigue. Currently, there are no objective biomarkers or laboratory tests that can be used to unequivocally diagnosis ME; therefore, a diagnosis is made when a patient meets series of a costly and subjective inclusion and exclusion criteria. The purpose of the present study was to evaluate the utility of four clinical parameters in diagnosing ME.

METHODS:
In the present study, we utilized logistic regression and classification and regression tree analysis to conduct a retrospective investigation of four clinical laboratory in 140 ME cases and 140 healthy controls.

RESULTS:
Correlations between the covariates ranged between [- 0.26, 0.61]. The best model included the serum levels of the soluble form of CD14 (sCD14), serum levels of prostaglandin E2 (PGE2), and serum levels of interleukin 8, with coefficients 0.002, 0.249, and 0.005, respectively, and p-values of 3 × 10-7, 1 × 10-5, and 3 × 10-3, respectively.

CONCLUSIONS:
Our findings show that these parameters may help physicians in their diagnosis of ME and may additionally shed light on the pathophysiology of this disease.

KEYWORDS:
Chronic fatigue; Diagnostic; IL-8, PGE2; ME/CFS; sCD14, CD57

PMID:
30463572
DOI:
10.1186/s12967-018-1696-z

 

[ljimbo423]

RESULTS:
Correlations between the covariates ranged between [- 0.26, 0.61]. The best model included the serum levels of the soluble form of CD14 (sCD14), serum levels of prostaglandin E2 (PGE2), and serum levels of interleukin 8, with coefficients 0.002, 0.249, and 0.005, respectively, and p-values of 3 × 10-7, 1 × 10-5, and 3 × 10-3, respectively.

Also from the same study (full paper)-

CD14, along with Toll-like receptor (TLR)-4 and lymphocyte antigen 96 (MD-2), forms the receptor complex that bind lipopolysaccharides (LPS) [59], which are found in the outer membrane of Gram-negative bacteria.

Previous reports have identified sCD14 as a nonspecific marker of monocyte activation [60] as well as a surrogate marker of bacterial translocation in the gut [61].

Link to full paper

 

[ljimbo423]

This quote is from the #61 reference, from the original paper. It basically says that the degree of microbial translocation(MT) or "leaky gut", is directly related to "physical function" in healthy older adults.

Lipopolysaccharide-Binding Protein, a Surrogate Marker of Microbial Translocation, Is Associated With Physical Function in Healthy Older Adults

Methods.
We assessed cross-sectional relationships among two plasma biomarkers of MT (sCD14 and LBP), physical function (hand grip strength, short physical performance battery [SPPB], gait speed, walking distance, and disability questionnaire),

and biomarkers of inflammation (C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), TNF-α soluble receptor 1 [TNFsR1]) in 59 older (60–89 years), healthy (no evidence of acute or chronic illness) men and women.

Results.
LBP was inversely correlated with SPPB score and grip strength (p = .02 and p < .01, respectively) and positively correlated with CRP (p = 0.04) after adjusting for age, gender, and body mass index.

sCD14 correlated with IL-6 (p = .01), TNF-α (p = .05), and TNFsR1 (p < .0001). Furthermore, the correlations between LBP and SPPB and grip strength remained significant after adjusting for each inflammatory biomarker.

Conclusions.
In healthy older individuals, LBP, a surrogate marker of MT, is associated with worse physical function and inflammation. Additional study is needed to determine whether MT is a marker for or a cause of inflammation and the associated functional impairments.

Link to paper

 

[Aubry]

Problem with these type of markers is that they come along with many neurodegenerative diseases (I think). So not specific for ME?

 

[Belbyr]

Problem with these type of markers is that they come along with many neurodegenerative diseases (I think). So not specific for ME?

Not trying to be rude at all, but could you expound on this for me? Trying to learn something.

 

[pattismith]

Interleukin 8 could be an interesting target. It seems to be induced by P2receptor activation, like P2X7, P2Y6 or P2Y2.

This cytokine is induced by LPS and Ambroxol was shown to inhibit IL8 release in vitro

https://www.ncbi.nlm.nih.gov/pubmed/25998443

 

[pattismith]

Also from the same study (full paper)-
CD14, along with Toll-like receptor (TLR)-4 and lymphocyte antigen 96 (MD-2), forms the receptor complex that bind lipopolysaccharides (LPS) [59], which are found in the outer membrane of Gram-negative bacteria.

Previous reports have identified sCD14 as a nonspecific marker of monocyte activation [60] as well as a surrogate marker of bacterial translocation in the gut

Link to full paper

LPS is not the only possible trigger for CD14/TLR4 activation, this study points ENV-SU (long but very well explained):

"Multiple sclerosis-associated retroviral element (MSRV) is a retroviral element, the sequence of which served to define the W family of human endogenous retroviruses. MSRV viral particles display proinflammatory activities both in vitro in human mononuclear cell cultures and in vivo in a humanized SCID mice model. To understand the molecular basis of such properties, we have investigated the inflammatory potential of the surface unit of the MSRV envelope protein (ENV-SU), the fraction that is poised to naturally interact with host cells."

"Human endogenous retroviruses (HERV)6 represent ∼8% of the human genome and result from integration of exogenous retroviruses that have infected the germline of their host during primate evolution (1). Although most HERV elements are partly or completely deleted following integration, the human genome does contain HERV sequences with open reading frames encoding functional proteins (2)."

"In the present study, we have investigated the mechanisms of the proinflammatory properties of the surface unit (ENV-SU) of MSRV envelope protein. This fraction contains the binding site to the cellular receptor and allows the virus to naturally interact with host cells. We report that ENV-SU is able to specifically activate cells of the innate immune system, such as monocytes, through PRR CD14 and TLR4. This activation is associated with the production of major proinflammatory cytokines such as IL-1β, IL-6, or TNF-α. Moreover, we also show that ENV-SU can activate DC and promote the development of Th1-like responses."

"Thus, CD14 and TLR4 are PRR that cooperate for the activation of innate immunity in response to both bacteria and viruses. Our observations that CD14 and TLR4 are involved in mediating the proinflammatory effect of the MSRV envelope protein identify proteins of HERV-W family as a putative new class of viral ligand for these PRR. As DC do not express CD14 at their surface, their capacity to react to MSRV ENV-SU most certainly relies on the recruitment of soluble CD14 that is present in the serum, as it is known to be the case for the response of DC to LPS stimulation (32, 33)."

"The activation of the innate immune system might contribute to the development of neurodegenerative diseases, and a possible role for CD14 and TLR4 in autoimmune/proinflammatory disorders has been evoked. It was thus shown that the level of soluble CD14 naturally present in plasma was elevated in diseases such as multiple sclerosis (34), rheumatoid arthritis (35), or systemic lupus erythematosus (36). Moreover, specific activation of CNS innate immunity through TLR4 can lead to neurodegenerative phenomena (37) via activation of brain-resident macrophages (microgliocytes), which are the only glial cells with TLR4 expression. Finally, TLR4 is necessary for LPS-induced oligodendrocyte injury in the CNS (38). These results indicate that the engagement of TLR4 expressed on CNS resident, and/or perivascular, macrophages by its ligands might contribute to oligodendrocyte damage and neurodegeneration.

Because MSRV was first isolated in choroid plexus/leptomeningeal cell cultures from multiple sclerosis patients (12, 13), and virion-associated MSRV RNA can be detected in sera and/or cerebrospinal fluids of such patients (39, 40), it is plausible that its envelope protein can exert its CD14/TLR4-dependent proinflammatory effect within the CNS, and therefore initiates and/or substantially exacerbates the disorder. This idea is in line with the findings that: 1) HERV-W ENV and GAG glycoproteins are expressed in the white matter of patients with multiple sclerosis (41, 42, 43), and that 2) the virus load detected in the CSF increases with MS progression and thus may have prognosis value (38). HERV-W 7q ENV expression is enhanced relative to tissues from healthy controls or patients with other neurological disorders and has the potential to cause inflammation and oligodendrocyte death through the induction of redox reactants in astrocytes (41)."