Saturday, 22 June 2013

CSF OCBs are associated with genetic markers in MS

OCB negative MS is not MS. This is why diagnostic lumbar punctures need to be done. #MSBlog #MSresearch

Leone et al. Association of Genetic Markers with CSF Oligoclonal Bands in Multiple Sclerosis Patients. PLoS One. 2013 Jun 13;8(6):e64408. 


OBJECTIVE: to explore the association between genetic markers and Oligoclonal Bands (OCB) in the Cerebro Spinal Fluid (CSF) of Italian MSers.

METHODS: They genotyped 1115 Italian patients for HLA-DRB1*15 and HLA-A*02. In a subset of 925 MSers they tested association with 52 non-HLA SNPs associated with MS susceptibility and we calculated a weighted Genetic Risk Score. Finally, they performed a Genome Wide Association Study (GWAS) with OCB status on a subset of 562 MSers. The best associated SNPs of the Italian GWAS were replicated in silico in Scandinavian and Belgian populations, and meta-analyzed.

RESULTS: HLA-DRB1*15 is associated with OCB+: p = 0.03, Odds Ratio (OR) = 1.6, 95% Confidence Limits (CL) = 1.1-2.4. None of the 52 non-HLA MS susceptibility loci was associated with OCB, except one SNP (rs2546890) near IL12B gene (OR: 1.45; 1.09-1.92). The weighted Genetic Risk Score mean was significantly (p = 0.0008) higher in OCB+ (7.668) than in OCB- (7.412) MSers. After meta-analysis on the three datasets (Italian, Scandinavian and Belgian) for the best associated signals resulted from the Italian GWAS, the strongest signal was a SNP (rs9320598) on chromosome 6q (p = 9.4×10(-7)) outside the HLA region (65 Mb).

DISCUSSION: Genetic factors predispose to the development of OCB.


"I am not sure if you realise the implications of  this study? This study supports OCB-ve MS as being a different disease, which is something I have been saying for 20 years."

"OCB-positive and OCB-negative MS differ in a characteristic that was not used to select the cohort. This is one of the criteria I use when making a call on whether the two populations have the same disease or not."

"I always feel uncomfortable labelling someone as having MS who has a normal CSF study. Firstly, their clinical course is more benign and they often feel very different to classic MS. There is one caveat that MSers who were chosen for this study were chosen on the basis of having a diagnosis of MS. As CSF is not essential for making the diagnosis, but is included in the diagnostic criteria, some MSers who should have been included in this study may have been excluded for having a normal CSF; in other words the study may be biased against people fulfilling contemporary criteria for MS (dissemination in time and space) but having a negative CSF study."

"The implications of this study are no insignificant. OCBs from a biological perspective mean the presence of clonal B-cells in the brain and CSF; possibly the presence of B-cell follicles. Their absence means no B-cell follicles. What drives clonal B-cells? Almost certainly a specific-antigen or pathogen. In other words OCB-positive and OCB-negative MS differ biologically in terms of the type of immune response that is occurring within the CNS."
"There is one caveat that needs to be borne in mind when labelling OCB-ve MS as a different disease. Firstly  the assay we use  to detect OCBs is not perfect, no assay is perfect. And if the lumbar puncture is done very early in the course of the disease it may be OCB-negative at first and may become OCB-positive over the next 6-12 months."

"Are the treatment implications from this study? Possibly. I would predict that OCB-negative MS may not respond to therapies that target B-cells, for example rituximab and ocrelizumab."

6 comments:

  1. How variable is the OCB pattern same from one MSer to another? What does this represent? Different proteins/immunoglobulins, and therefore different antigens?

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  2. I am OCB negative and respond poorly if at all to Methylprednisolon and Interferon.
    Mitoxantron was the first drug which has shown a positive effect in my progression.

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  3. Nope, we need CD19 monoclonal therapies to combat PPMS because then it will work on the plasmablast component driving the disease. I fear that rituximab and ocrelizumab will fail in comparison to the former because they are CD20 monoclonal compounds.

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  4. And what infect and changes the behaviour of B cells and the immune cells about them, the Epstein Barr. Consider what it does to the immune system in Mixed Cellularity Hodgkin's Lymphoma

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  5. Dr. G as you mentioned "CSF is not essential for making a diagnosis but may be included in the diagnostic criterion..." If analysis of CSF is not deemed essential for diagnosis does that imply that dissemination in time and space is not adequate for determining MS? In other words, no clonal bands no MS. Is there a clinical disagreement in diagnosing MS?

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  6. Are other patterns than 2 and 3 are considered OCB+? type 4 for instance, there are bands in CSF, but they are produced non locally ?

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