What genes are active in MS?
In this study they looked at lesions and surrounding white matter and found a load of CD8 T cells, a lot of CD20 B cells and a few CD4 T cells and plasma cells (antibody making cells).
The B cells contained EBV
In this study they take brain tissue and then cut it into very thin slices (eg. a 100th of a mm) and then you look to see if you can find a lesion. You use a laser to cut out the cells from the section (laser capture) and then you remove the nucleus to see what proteins the cells were making.
There were CD4 T cells in all the lesions, CD8 T cells in all of the lesions and CD19 B cells in all the lesions. Not many CD4 T cells and only 1-3% lesions contained IL-17/IL-22 (Th17 cytokines). If if there is more IL-17 in the blood (see beleow) how come there
So are these few cells causing autoimmunity as the EAEers would have us believe There were 70% of lesions with gamma interferon, which could be Th1 derived or could come from CD8.
There was about 70-95% of lesions with clear B cell growth and differentiation factors like IL-6, IL-10 (yes it is a B cell factor and IL-10 does not have to be a regulatory cytokine), BAFF, lymphotoxin etc etc.
There are CXCR3 and CXCL12 chemokines in most lesions ,which recruit B cells
However the paper is open access and they do vastly different association for these products
One or more EBV genes were detected in immune infiltrates from 9 of 11 MS cases and in 41.3% of the samples.
EBV genes were detected more frequently in meningeal than in WM perivascular infiltrates (55.6 vs 28% of the samples) and genes expressed during viral latency were detected more frequently (i.e. present in memory cells) than genes associated with the viral lytic which is where the virus kills the cell and releases the cells contents which is live virus).
LMP1 and LMP2A are viral genes, deliver surrogate B cell survival and differentiation signals (CD40 and B cell receptor, LMP1 was detected more commonly than LMP2 suggest that the B cells may be more T cell-independent .
The authors suggests that “EBV could be the main antigenic trigger of an immunopathological, CD8+ T cell-mediated response that damages the brain/spinal cord in MS. This model is consistent with the notion that CD8+ T cells are the main drivers of bystander tissue damage in EBV-associated immunopathologic diseases“
So are CD8 cells in the brain to destroy EBV infected B cells?
The authors suggest that “the use of drugs that, by directly targeting the virus and its cellular reservoir, could be more effective in normalizing an altered EBV-host interaction in MS. For example, B cell-depleting therapies could lower EBV load and hence the burden of EBV-induced immunopathology in MS more efficiently than other drugs“.
Is this what we are doing?
BACKGROUND:It is debated whether multiple sclerosis (MS) might result from an immunopathological response toward an active Epstein-Barr virus (EBV) infection brought into the central nervous system (CNS) by immigrating B cells. Based on this model, a relationship should exist between the local immune milieu and EBV infection status in the MS brain. To test this hypothesis, we analyzed expression of viral and cellular genes in brain-infiltrating immune cells.
METHODS:Twenty-three postmortem snap-frozen brain tissue blocks from 11 patients with progressive MS were selected based on good RNA quality and prominent immune cell infiltration. White matter perivascular and intrameningeal immune infiltrates, including B cell follicle-like structures, were isolated from brain sections using laser capture microdissection. Enhanced PCR-based methods were used to investigate expression of 75 immune-related genes and 6 EBV genes associated with latent and lytic infection. Data were analyzed using univariate and multivariate statistical methods.
RESULTS: Genes related to T cell activation, cytotoxic cell-mediated (or type 1) immunity, B cell growth and differentiation, pathogen recognition, myeloid cell function, type I interferon pathway activation, and leukocyte recruitment were found expressed at different levels in most or all MS brain immune infiltrates. EBV genes were detected in brain samples from 9 of 11 MS patients with expression patterns suggestive of in situ activation of latent infection and, less frequently, entry into the lytic cycle. Comparison of data obtained in meningeal and white matter infiltrates revealed higher expression of genes related to interferonγ production, B cell differentiation, cell proliferation, lipid antigen presentation, and T cell and myeloid cell recruitment, as well as more widespread EBV infection in the meningeal samples. Multivariate analysis grouped genes expressed in meningeal and white matter immune infiltrates into artificial factors that were characterized primarily by genes involved in type 1 immunity effector mechanisms and type I interferon pathway activation.
CONCLUSION: These results confirm profound in situ EBV deregulation and suggest orchestration of local antiviral function in the MS brain, lending support to a model of MS pathogenesis that involves EBV as possible antigenic stimulus of the persistent immune response in the central nervous system.
However, without wanting to upset the authors too much, they are the group that have proposed that B cell follicles ares associating with, and implicated in, the cause of progression. However as in their own words
“several groups have reported absence or paucity of EBV in postmortem MS brain samples”….whilst….
“we have repeatedly shown not only presence of EBVinfected B-lineage cells but also EBV latency disruption and reactivation in the MS brain”
“RNA/protein nor deregulated EBV infection was detected in brain tissues from patients with other infectious and non-infectious neuroinflammatory diseases”…”ruling out the possibility that an active EBV infection in the CNS is the general consequence of immune cell invasion and local activation.”
Therefore not all people agree on this and so requires replication by other groups who do not have a vested interest in this story.
What do others find?
Trenova AG, Slavov GS, Draganova-Filipova MN, Mateva NG, Manova MG, Miteva LD, Stanilova SA. Circulating levels of interleukin-17A, tumor necrosis factor-alpha, interleukin-18, interleukin-10, and cognitive performance of patients with relapsing-remitting multiple sclerosis. Neurol Res. 2018 Jan 3:1-7. doi: 10.1080/01616412.2017.1420522. [Epub ahead of print]
Multiple sclerosis (MS) is associated with cytokine imbalance and high rate (40-70%) of cognitive impairment. The objective of this study is to investigate the relationship between serum concentrations of tumor necrosis factor (TNF)-alpha, interleukin (IL)-17A, IL-18, IL-10, and cognitive performance in patients with relapsing-remitting MS (RRMS).
Methods The study comprised 159 patients with RRMS (mean age 40.08 ± 8.48 years) in remission phase and 86 age-, gender-, and education-matched healthy controls. Paced Auditory Serial Addition Test (PASAT), Symbol Digit Modalities test (SDMT), and Isaacs test were used for assessment of working memory, attention, visuo-perceptual abilities, information processing speed, and executive functions. Serum cytokine concentrations were measured by enzyme-linked immunosorbent assay (ELISA).
Results Patients had significantly increased serum concentrations of TNF-alpha and IL-17A and decreased levels of IL-10 compared to the controls (p < 0.05). Negative correlation was found between serum TNF-alpha and SDMT score in patients with disease evolution longer than 10 years (rxy = -0.258 p = 0.033); PASAT and SDMT scores were in negative correlation with concentration of IL-17A (rxy = -0.229 p = 0.004; rxy = -0.166 p = 0.041). Cognitive impairment was established in 46.5% (n = 74) of the patients. Cognitively impaired patients had significantly higher serum IL-17A than cognitively preserved individuals (p = 0.007). Multiple linear regression analysis revealed IL-17A as a significant predictor of cognitive performance in RRMS patients.
Conclusion The results from this study suggest that pro-inflammatory cytokines IL-17A and TNF-alpha simultaneously with decreased IL-10 are involved in cognitive deterioration in RRMS.
When I was rreally interested in cytokines, we looked for cytokines like TNF in the blood and didn’t find any. Now it could be sensitivity of the assay.Alternatively it mean what was produced was used, so that if excess is found, it suggests more is produced than needed.
However it had been reported that TNF levels in blood in MS, correlated with disease activity and the the results appeared to good. Indeed when the person writing the paper was asked to repeat the analysis with coded and blinded samples, so they wouldn’t know what was what…They ran a mile never to be heard off again.
So you can guess what I thought of the data. This report may suggest the neuro was correct. They find what you expect if you follow dogma…an increase in pro-inflammatory cytokines and a decrease in regulatory cytokines.