Sunday, 23 September 2012

Research: Cells making cytokines in MS

BACKGROUND: Numerous cytokines are implicated in the immunopathogenesis of multiple sclerosis (MS), but studies are often limited to whole blood (WB) or peripheral blood mononuclear cells (PBMCs), thereby omitting important information about the cellular origin of the cytokines. Knowledge about the relation between blood and cerebrospinal fluid (CSF) cell expression of cytokines and the cellular source of CSF cytokines is even more scarce.
METHODS: We studied gene expression of a broad panel of cytokines in WB from relapsing-remitting multiple sclerosis (RRMS) patients in remission and healthy controls (HCs). Subsequently we determined the gene expression of the dysregulated cytokines in isolated PBMC subsets (CD4+, CD8+T-cells, NK-cells, B-cells, monocytes and dendritic cells) from RRMS patients and HCs and in CSF-cells from RRMS patients in clinical relapse and non-inflammatory neurological controls (NIND).
RESULTS: RRMS patients had increased expression of IFN-gamma (IFNG), interleukin (IL) 1-beta (IL1B), IL7, IL10, IL12A, IL15, IL23, IL27, lymphotoxin-alpha (LTA) and lymphotoxin-beta (LTB) in WB. In PBMC subsets the main sources of pro-inflammatory cytokines were T- and B-cells, whereas monocytes were the most prominent source of immunoregulatory cytokines. In CSF-cells, RRMS patients had increased expression of IFNG and CD19 and decreased expression of IL10 and CD14 compared to NINDs. CD19 expression correlated with expression of IL7, IL12A, IL15 and LTA whereas CD14 expression correlated with IL10 expression.
CONCLUSIONS: Using a systematic approach, we show that expression of pro-inflammatory cytokines in peripheral blood primarily originates from T- and B-cells, with an important exception of IFNG which is most strongly expressed by NK-cells. In CSF-cell studies, B-cells appear to be enriched in RRMS and associated with expression of pro-inflammatory cytokines; contrarily, monocytes are relatively scarce in CSF from RRMS patients and are associated with IL10 expression. Thus, our findings suggest a pathogenetic role of B-cells and an immunoregulatory role of monocytes in RRMS.

You can read the conclusions. Interferon gamma is a macrophage activator and in tissues is not considered good news as it can help macrophages destroy myelin. This comes from mainly natural killers celles rather than T cells as the immunologists would have us believe. Dacluzimab is thought have a major impact on NK cells and this maybe how it works rathher than attacking T cells. However when we look in the CSF there are more active B cells, is this because of EBV?,  They make IL-7 (remember the receptor for this confers increased risk to MS, which is an immune growth factor, IL-12 which activates macrophages and is also involved in growth of certain B cells and IL-15 is a factor that helps T cells and importasntly NK cell grow. Whilst IL-10 is consisdered to be be an anti-inflammatory cytokine it is also a B cell growth factor and may be there as part of the B cell response.

1 comment:

  1. EBV is a strong candidate for a pathogenic cause of MS. It's pathway in auto-reactive B cells, that lay dormant in Lymphoid organs to its passage through the BBB in CD4+ T cells, Can it inject its genome into the Oligodendrocytes enabling them to go through a conformational change thereby showing a decrease in number. Perhaps due to the cell cycle arrest phase G1/G2 and then a commitment to apoptosis which is highly expressed? The interesting point with EBV is what happens that causes this latent form to awaken? In the older age group there maybe an immune dysfunction or exhaustion? What about the rarer type of infantile MS? Can there be a genetic malfunction? Can a gene which expresses a dysfunctional protein be the cause of an increased occurrence of P53 which can commit a cell to death; say in the oligodendrocytes?


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