The MRZ reaction

[frodo]

It seems that to have antibodies at the same time against Measles, Rubella and Varizella-Zoster viruses (MRZ viruses) is highly specific for MS (97% of positives vs. 3% of false positives)

The MRZ reaction as a highly specific marker of multiple sclerosis: re-evaluation and structured review of the literature

http://link.springer.com/article/10.100 ... 016-8360-4

It has long been known that the majority of patients with multiple sclerosis (MS) display an intrathecal, polyspecific humoral immune response to a broad panel of neurotropic viruses. This response has measles virus, rubella virus and varicella zoster virus as its most frequent constituents and is thus referred to as the MRZ reaction (MRZR).

Re-evaluation of the specificity of MRZR as a marker of MS. Structured review of the existing English-, German- and Spanish-language literature on MRZR testing, with evaluation of MRZR in a cohort of 43 unselected patients with MS and other neurological diseases as a proof of principle. A positive MRZ reaction, defined as a positive intrathecal response to at least two of the three viral agents, was found in 78% of MS patients but only in 3% of the controls (p < 0.00001), corresponding to specificity of 97%.

Median antibody index values were significantly lower in non-MS patients (measles, p < 0.0001; rubella, p < 0.006; varicella zoster, p < 0.02). The 30 identified original studies on MRZR reported results from 1478 individual MRZR tests. A positive MRZR was reported for 458/724 (63.3%) tests in patients with MS but only for 19/754 (2.5%) tests in control patients (p < 0.000001), corresponding to cumulative specificity of 97.5% (CI 95% 96–98.4), cumulative sensitivity of 63.3% (CI 95% 59.6–66.8) (or 67.4% [CI 95% 63.5–71.1] in the adult MS subgroup), a positive likelihood ratio of 25.1 (CI 95% 16–39.3) and a negative likelihood ratio of 0.38 (CI 95% 0.34–0.41).

Of particular note, MRZR was absent in 52/53 (98.1%) patients with neuromyelitis optica or MOG-IgG-positive encephalomyelitis, two important differential diagnoses of MS. MRZR is the most specific laboratory marker of MS reported to date. If present, MRZR substantially increases the likelihood of the diagnosis of MS. Prospective and systematic studies on the diagnostic and prognostic impact of MRZR testing are highly warranted.

[frodo]

Just for having news about viral theories together, I will post this one here

In a previous study, researchers identified antibodies against a specific non-human molecule, half carbohidrate, half protein. Later they found that a strain of influenza related bacteria could produce it. Finally they found that this molecule was targeted by antibodies from the sera of an MS patient subpopulation


MS antibodies recognise protein of common respiratory tract bacteria

http://www.ms-uk.org/ms-antibodies-reco ... nds-100117

Researchers have found a microbial protein from the Haemophilus influenza pathogen that is recognised by antibodies in a subpopulation of multiple sclerosis patients. The finding supports the idea of a link between microbial infections and neurodegenerative diseases like MS, whose causes are uncertain.

.....

They found a hyperglucosylated protein domain, based on the cell-surface adhesin HMW1A, that was targeted by antibodies from the sera of an MS patient subpopulation. Researchers performed further experiments and found that the purified antibodies cross-reacted with myelin of the spinal cord tissue in an experimental animal model of MS.

“H. influenzae hyperglucosylated adhesin I (Glc) is the first example of an N-glucosylated antigen that can be considered a relevant candidate for triggering pathogenic antibodies in multiple sclerosis,” the researchers wrote.

[centenarian100]

Interesting. anti MOG is also quite common in multiple sclerosis. Also, people with MS tend to lose varicella zoster IgG as they get older just like people without MS.

It is hard to know if this phenomenon represents non-specific antibody production or if it is a specific response to these viruses. There are many myelin specific autoantibodies in MS CSF like anti-MOG, anti MAG, anti PLP and so forth

-C

[1eye]

Forget myelin-specific antibodies. There are plenty of way to get those. There is only one way to get this combination, and if you do you, are certain to get MS, and certain not to have "neuromyelitis optica or MOG-IgG-positive encephalomyelitis, two important differential diagnoses of MS". Have you any better test?

[centenarian100]

Forget myelin-specific antibodies. There are plenty of way to get those. There is only one way to get this combination, and if you do you, are certain to get MS, and certain not to have "neuromyelitis optica or MOG-IgG-positive encephalomyelitis, two important differential diagnoses of MS". Have you any better test?

According to his post, the MRZ reaction is present in 78% of MS patients but only in 3% of the controls, so it is not correct to talk about "certainty."

Of note, 78% sensitivity would be much worse than routine clinical assessment and MRI scans which are much more sensitive. So, there is actually a better test for MS. However, the data are quite impressive.

-C

[1eye]

Forget myelin-specific antibodies. There are plenty of way to get those. There is only one way to get this combination, and if you do you, are certain to get MS, and certain not to have "neuromyelitis optica or MOG-IgG-positive encephalomyelitis, two important differential diagnoses of MS". Have you any better test?

According to his post, the MRZ reaction is present in 78% of MS patients but only in 3% of the controls, so it is not correct to talk about "certainty."

Of note, 78% sensitivity would be much worse than routine clinical assessment and MRI scans which are much more sensitive. So, there is actually a better test for MS. However, the data are quite impressive.

-C

If you go by convention the neurologist makes a lot more bucks making the patient wait for "time and space" to show up. Maybe some new "routines" ought to be tried. One thing I know is my time is more important than your money, or anyone's, for that matter. Cumulative specificity of 97.5% (CI 95% 96–98.4) sounds pretty accurate to me. I'd worry about MS.

[frodo]

More evidence about the viral theory. This time published in "Nature". The authors state that is not the EBV infection per se the culprit, but infected B-cells instead, and they link it to the action of anti-CD20 like Rituxan and Ocrevus.


http://www.nature.com/cti/journal/v6/n1 ... 1687a.html

Abstract

Mounting evidence indicates that infection with Epstein–Barr virus (EBV) has a major role in the pathogenesis of multiple sclerosis (MS). Defective elimination of EBV-infected B cells by CD8+ T cells might cause MS by allowing EBV-infected autoreactive B cells to accumulate in the brain.

Here we undertake a comprehensive analysis of the T-cell response to EBV in MS, using flow cytometry and intracellular IFN-γ staining to measure T-cell responses to EBV-infected autologous lymphoblastoid cell lines and pools of human leukocyte antigen (HLA)-class-I-restricted peptides from EBV lytic or latent proteins and cytomegalovirus (CMV), in 95 patients and 56 EBV-seropositive healthy subjects.

In 20 HLA-A2+ healthy subjects and 20 HLA-A2+ patients we also analysed CD8+ T cells specific for individual peptides, measured by binding to HLA-peptide complexes and production of IFN-γ, TNF-α and IL-2. We found a decreased CD8+ T-cell response to EBV lytic, but not CMV lytic, antigens at the onset of MS and at all subsequent disease stages.

CD8+ T cells directed against EBV latent antigens were increased but had reduced cytokine polyfunctionality indicating T-cell exhaustion. During attacks the EBV-specific CD4+ and CD8+ T-cell populations expanded, with increased functionality of latent-specific CD8+ T cells. With increasing disease duration, EBV-specific CD4+ and CD8+ T cells progressively declined, consistent with T-cell exhaustion. The anti-EBNA1 IgG titre correlated inversely with the EBV-specific CD8+ T-cell frequency.

We postulate that defective CD8+ T-cell control of EBV reactivation leads to an expanded population of latently infected cells, including autoreactive B cells.