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Biomarkers and microRNA

 

Biomarker identified to measure MS severity(19/06/15)

In a study published in the journal Nature Communications, researchers have clarified the lifespan of antibody-producing cells and have also identified a novel biomarker that could be used to monitor autoimmune conditions such as multiple sclerosis and lupus erythematous.

The humoral immune response is mediated by cells in plasma and is responsible for fighting infections. Plasma cells secrete antibodies, proteins that are able to identify pathogens and destroy them. However, antibodies with specific characteristics sometimes attack their host tissues causing autoimmune conditions like multiple sclerosis (MS) or lupus erythematosus(SLE).

“Balanced regulation of the production and activity of plasma cells is therefore vital,” Professor Edgar Meinl of the LMU Medical Centre said.

The researchers were able to identify a mechanism of action involved in the regulation of these antibody producing cells’ lifespan. Specifically, the researchers found a cell-surface receptor, called BCMA, can be a useful biomarker for monitoring the severity of autoimmune diseases.

The cells in the plasma are produced by B-cells, which carry certain membrane-bound receptors that are able to identify antigens. When B-cells recognize an antigen, they are able to differentiate it into a clone of plasma cells that secrete the antigen-binding protein in soluble form as antibody. But the life-span of these antibodies is dependent on the BCMA receptor survival.

The extension of the lifespan of the plasma cells is activated by the BAFF and APRIL survival factors, BCMA ligands.. “However, the lifetime of plasma cells cannot be prolonged indefinitely. Otherwise the organism would become swamped with antibodies, increasing the risk of an autoimmune reaction,” Meinl explained.

“We have now shown, in cooperation with colleagues in Munich, Berlin and Stockholm, that the membrane-bound enzyme gamma-secretase acts as a brake on immune reactions by fragmenting BCMA.”

BCMA extended the cell’s membrane and is projected in the extracellular medium. Gamma-secretase removes the exposed portion by cutting the protein inside of the plasma membrane. That this enzyme cleaves the receptor directly was a surprise: “Up to now, it was only known to be involved in the degradation of membrane proteins that had already been cleaved by other enzymes.

“BCMA is the first natural substrate of gamma-secretase to be identified that is directly cleaved by the enzyme,” said Meinl, “and probably reflects the fact that the extracellular segment of the receptor is unusually short.”

The cleaved fragment is constant, and can be detected in fluid of the body as soluble BCMA (sBCMA). The evidence from this new study showed that in patients with Lupus, the sBCMA levels in the blood are high and associated correlated with the disease severity.

“In MS patients sBCMA levels were increased specifically in the cerebrospinal fluid, which bathes the brain and the spinal cord,” said Meinl. “So, sBCMA is an indicator of the intensity of ongoing immune reactions. sBCMA is therefore well suited to serve as an informative clinical parameter for the assessment of the therapeutic effects of different treatment regimes on plasma cells.”

Results from this study could trigger the development of treatments, with both B cells and the BCMA/BAFF/APRIL mechanism being targets for lupus and multiple sclerosis, treatment.

Soure: Multiple Sclerosis News Today © BioNews Services 2015 (19/06/15)

Uric acid correlated with multiple sclerosis disease activity(18/02/15)

In a study published in the journal Clinical Chemistry and Laboratory Medicine, investigators Moccia et al identified uric acid as a potential biomarker in the progression of multiple sclerosis-related disability.

Uric acid, which has activity as a natural scavenger of oxygen radicals, is present in the bloodstream as a breakdown product of purines (adenine and guanine). In animal studies, uric acid has been shown to have some potential as a treatment for MS. Results of these studies led investigators in the CCLM study to search for a relationship between MS severity and levels of uric acid. In the case-control study, using propensity score matching, investigators paired 362 patients with MS and 181 control individuals without MS.

To reduce variation between populations, investigators corrected data for patient age, gender, and kidney function. Upon regression analysis, investigators identified a significant association between low levels of serum uric acid among patients with MS compared with controls, with an R-squared value of 30.4 per cent and significance determined at a P value level of 1.4 per cent.

Longer disease duration was associated with a longer time from diagnosis and a higher Expanded Disability Status Scale (EDSS) score (P < .001, all comparisons). These findings suggest that uric acid levels may be a biomarker of MS disability and progression, even though previous studies suggest that uric acid may have a limited role as a disease marker and as a therapeutic target in MS.

For example, a 2006 analysis, published in the journal Clinical Neurology and Neurosurgery, found that uric acid levels did not change as a result of immunomodulatory or immunosuppressive drug treatment in patients with MS.

In addition, in the Association of Inosine and Interferon beta in relapsing- remitting Multiple Sclerosis (ASIIMS) trial, investigators administered a precursor of uric acid — inosine — to patients with MS in conjunction with interferon-beta over the course of two years. The results of this trial were negative, and uric acid did not have any additional benefit on disability outcomes versus interferon-beta alone.

Despite the negative result of the ASIIMS trial, antioxidative drugs may have a future in treatment of MS. However, uric acid may be a biomarker — not a treatment modality. Studying uric acid may help physicians predict the progression of MS in patients, although previous research indicates that uric acid levels do not predict response to treatment, and supplementation with uric acid does not alter the progression of disability in MS. Further study will be necessary to determine whether or not drugs that mimic the effects of uric acid are of any value.

Source: HCPLive Copyright HCPLive 2006-2013 Intellisphere, LLC (18/02/15)

The effects of microparticles on endothelial barrier function in MS and clinically isolated syndrome highlighted(22/09/14)

Microparticles in multiple sclerosis and clinically isolated syndrome: effect on endothelial barrier function.

Cell-derived microparticles are secreted in response to cell damage or dysfunction. Endothelial and platelet dysfunction are thought to contribute to the development of multiple sclerosis (MS).

Our aim here is, first, to compare the presence of microparticles of endothelial and platelet origin in plasma from patients with different clinical forms of MS and with clinically isolated syndrome. Second, to investigate the effect of microparticles on endothelial barrier function.

Results: Platelet-poor plasma from 95 patients (12 with clinically isolated syndrome, 51 relapsing-remitting, 23 secondary progressive, 9 primary progressive) and 49 healthy controls were analyzed for the presence of platelet-derived and endothelium-derived microparticles by flow cytometry.

The plasma concentration of platelet-derived and endothelium-derived microparticles increased in all clinical forms of MS and in clinically isolated syndrome versus controls. The response of endothelial barriers to purified microparticles was measured by electric cell-substrate impedance sensing.

Microparticles from relapsing-remitting MS patients induced, at equivalent concentrations, a stronger disruption of endothelial barriers than those from healthy donors or from patients with clinically isolated syndrome. MS microparticles acted synergistically with the inflammatory mediator thrombin to disrupt the endothelial barrier function.

Conclusions: Plasma microparticles should be considered not only as markers of early stages of MS, but also as pathological factors with the potential to increase endothelial permeability and leukocyte infiltration.

Source: 7thSpace Interactive © 2014 7thSpace Interactive (22/09/14)

Molecule linked to neurological dysfunctions identified(06/08/14)

A team of researchers has pinpointed a small molecule responsible for nerve cell damage and other symptoms tied to neurological diseases, including multiple sclerosis (MS).

In a study published in the June 2014 issue of The Federation of American Societies for Experimental Biology Journal, investigators at The Open University (OU) in the United Kingdom and colleagues from Sheffield, London, and Amsterdam highlighted the behavior of MicroRNA-155 (miR-155) and its activity during inflammation.

According to a statement released by the OU, inflammation in the molecule creates gaps in tissue cells, leading to toxins entering the brain from the bloodstream. In comparison, unaffected individuals’ cells create a barrier that prevents molecules from invading the brain.

“We have identified miR-155 as a critical miRNA in neuroinflammation at the blood-brain barrier (BBB),” the authors noted. “miR-155 is expressed at the neurovascular unit of individuals with MS and of mice with experimental autoimmune encephalomyelitis.”

The statement also noted that cells that line blood vessels and control molecules’ brain access when inflamed become “leaky” due to neurological immunity. This inflammation, the study noted, has been observed with several conditions such as MS, HIV, dementia, and bacterial infections of the blood.

The investigators said that while BBB dysfunction was recognised in MS and stroke patients, molecular activity behind the dysfunction is still a mystery.

"This research has helped us to gain a better understanding of how toxins and other blood-borne molecules are leaked into the brain in inflammatory conditions,” lead author Ignacio Romero, MD, senior lecturer in Cellular Neuroscience in Open University’s Department of Life, Health and Chemical Sciences, said in a statement.“This is crucial, not only for helping to explain the molecular underpinnings of neurological diseases such as Alzheimer’s and MS, but also for opening up new possibilities for developing treatments to reduce the flow of these unwanted molecules to the brain and also for delivering life-saving drugs.”

Source: HCP Live Copyright HCPLive 2006-2014 (06/08/14)

KIR4.1 ruled out as possible antigen for MS(15/07/14)

Investigation of the KIR4.1 potassium channel as a putative antigen in patients with multiple sclerosis: a comparative study.

Brickshawana A, Hinson SR, Romero MF, Lucchinetti CF, Guo Y, Buttmann M, McKeon A, Pittock SJ, Chang MH, Chen AP, Kryzer TJ, Fryer JP, Jenkins SM, Cabre P, Lennon VA.

Abstract

BACKGROUND: Antibodies have been implicated in the pathogenicity of multiple sclerosis by findings of immunoglobulins in patients' CSF and often IgG and complement in lesions, and by a 2012 report that nearly half of patients' serum samples contain IgG specific for a glial potassium-channel, KIR4.1. We aimed to establish the frequency of KIR4.1-binding IgG in serum and CSF of patients with multiple sclerosis, and whether KIR4.1 immunoreactivity is retained or lost in demyelinating lesions.

METHODS: Using ELISA with a KIR4.1 peptide, we tested archival serum from 229 population-based and 57 clinic-based patients with multiple sclerosis, 99 healthy controls, and 109 disease controls, and CSF from 25 patients with multiple sclerosis and 22 disease controls. We tested all CSF and serum samples from 50 of the clinic-based patients with multiple sclerosis on cells expressing functional KIR4.1, using cell-based immunofluorescence and immunoprecipitation (solubilised recombinant human KIR4.1). We assessed KIR4.1 immunoreactivity in archival brain samples from 15 patients with histopathologically confirmed multiple sclerosis (22 plaques [eight early active, eight inactive, and six remyelinated], 13 periplaque regions and eight normal-appearing white-matter and grey-matter regions) and from three controls with non-neurological diseases.

FINDINGS: Three of 286 serum samples from patients with multiple sclerosis and two of 208 serum samples from controls showed KIR4.1 reactivity on ELISA; none of the CSF samples from patients or controls showed KIR4.1 reactivity. IgG in none of the 50 serum samples from clinic-based patients immunoprecipitated KIR4.1, but a commercial KIR4.1-specific control IgG did. By immunofluorescence, one of 50 serum samples from patients with multiple sclerosis yielded faint plasmalemmal staining on both KIR4.1-expressing and non-expressing cells; 16 bound faintly to intracellular components. In all cases, IgG binding was quenched by absorption with liver powder or lysates from non-transfected cells. Binding by the KIR4.1-specific control IgG was quenched only by lysates containing KIR4.1. IgG in none of the 25 CSF samples from patients with multiple sclerosis bound to KIR4.1-transfected cells. Glial KIR4.1 immunoreactivity was increased relative to expression in healthy control brain in all active demyelinating lesions, remyelinated lesions, and periplaque white matter regions.

INTERPRETATION: We did not detect KIR4.1-specific IgG in serum or CSF from patients with multiple sclerosis or KIR4.1 loss from glia in multiple sclerosis lesions. Serological testing for KIR4.1-specific IgG is unlikely to aid diagnosis of multiple sclerosis. The target antigen of multiple sclerosis remains elusive.

FUNDING: The National Institutes of Health, the National Multiple Sclerosis Society, and the Mayo Clinic Robert and Arlene Kogod Center on Aging.

Source: Lancet Neurol. 2014 Jul 4. pii: S1474-4422(14)70141-3. doi: 10.1016/S1474-4422(14)70141-3. [Epub ahead of print] & Pubmed PMID: 25008548 (15/07/14)

Cytokine signature patterns provide insights into immunomodulatory drug effects(07/07/14)

The use of cytokine signature patterns: separating drug naïve, interferon and natalizumab-treated multiple sclerosis patients.

O'Connell KE1, Mok T, Sweeney B, Ryan AM, Dev KK.

Abstract

Multiple sclerosis (MS) is an inflammatory illness characterised by demyelination and axonal neurodegeneration. Here, we used serum samples from MS patients to demonstrate if "cytokine signature" patterns can separate different patient groups better than using single cytokines.

In this case, we used cytokine profiling to demonstrate if "cytokine signature" patterns can separate MS patients treated with interferon or natalizumab from drug naïve patients.

Serum levels of eight individual cytokines (TNFα, IFNγ, S100B, IL-1β, IL-6, IL-8, IL-17 and IL-23) in MS patients treated with interferons (n = 11) and natalizumab (n = 14) were measured and, in general, showed reduced levels compared to drug naïve MS patients (n = 12).

More evident changes were seen when analyzing "cytokine signatures" (i.e. summed value of all eight cytokines), which showed that patients treated with natalizumab and interferons showed significantly reduced cytokine signature levels than drug naïve MS patients.

Moreover, patients treated with natalizumab were separated from drug naïve patients by almost 100% fidelity and that patients treated with natalizumab also had reduced levels of pro-inflammatory cytokines compared to patients treated with interferon.

Overall, this study provides an example showing that the use of "cytokine signatures" may provide benefits over the analysis of single cytokines for the development of potential biomarkers.

Source: Autoimmunity. 2014 Jun 30:1-7. [Epub ahead of print] & Pubmed PMID: 24974887 (07/07/14)