Thursday, 3 December 2015

Activated B cells and more lesions

Comabella M, Cantó E, Nurtdinov R, Río J, Villar LM, Picón C, Castilló J, Fissolo N, Aymerich X, Auger C, Rovira A, Montalban X. MRI phenotypes with high neurodegeneration are associated with peripheral blood B-cell changes. Hum Mol Genet. 2015. pii: ddv473. [Epub ahead of print]

Little is known about the mechanisms leading to neurodegeneration in multiple sclerosis (MS) and the role of peripheral blood cells on this neurodegenerative component. We aimed to correlate brain radiological phenotypes defined by high and low neurodegeneration with gene expression profiling of peripheral blood mononuclear cells (PBMC) from MS patients. MRI scans from 64 patients with relapsing-remitting MS (RRMS) were classified into radiological phenotypes characterized by low (N=27) and high (N=37) neurodegeneration according to the number of contrast enhancing lesions, the relative volume of non-enhancing black holes on T1-weighted images, and the brain parenchymal fraction. Gene expression profiling was determined in PBMC using microarrays, and validation of selected genes was performed by PCR. B-cell immunophenotyping was conducted by flow cytometry. Microarray analysis revealed the B-cell specific genes FCRL1, FCRL2, FCRL5 (Fc receptor-like 1, 2, and 5 respectively), and CD22 as the top differentially expressed genes between patients with high and low neurodegeneration. Levels for these genes were significantly down-regulated in PBMC from patients with MRI phenotypes characterized by high neurodegeneration and microarray findings were validated by PCR. In patients with high neurodegeneration, immunophenotyping showed a significant increase in the expression of the B-cell activation markers CD80 in naïve B cells (CD45+/CD19+/CD27-/IgD+), unswitched memory B cells (CD45+/CD19+/CD27+/IgD+), and switched memory B cells (CD45+/CD19+/CD27+/ IgD-), and CD86 in naïve and switched memory B cells. These results suggest that RRMS patients with radiological phenotypes showing high neurodegeneration have changes in B cells characterized by down-regulation of B-cell specific genes and increased activation status.

So as MS becomes a B cell mediated because we see that rituximab and ocrelizumab inhibit relapsing disease. Some people think that B cell follicles within the brain are causing grey matter lesions. In this study they looked at MRI scans and looked at markers of activity and them looked in the blood and found that they were associated with B cell activation in the blood. CD80 (B7-1) and CD86 (B7-2) are co-stimulator molecules involved in antigen presenetation via binding to CD28. on T cell but they were more activated. When you look in the blood you are looking a needle in a haystack, the damaging cell are in the brain and if you are trawling the genome by chance some are going to be significance. However if there is active antigen presentation then you can have more T cell activity and more active lesions and so more nerve damage and there you have it. It this how ocrelizumab is working?

2 comments:

  1. What is the explanation for people being NEDA on Tysabri? I believe that Natalizumab stops the T cells getting into the CNS; are we not looking hard enough for evidence of disease activity? Or is it that without the T cells in the CNS the B cells can't do any damage on their own? Or something else or all of the above?

    ReplyDelete
  2. So could the B cells remain uninterrupted in the Central Nervous System? A virus could cause this?

    ReplyDelete

Please note that all comments are moderated and any personal or marketing-related submissions will not be shown.