#ResearchSpeak: it's the B-cells again

How soon will it be before we can clear the MS brain of plasma cells? Not soon enough. #ResearchSpeak #MSBlog

The study below confirms what we already know that even early in the course of MS B-cells and plasma cells are up to no good. Gray matter, or cortical, atrophy correlates with an inflammatory chemokine (CXCL13) responsible for attracting B-cells into the CNS. 

Interestingly, the authors interpret the lower BAFF (a B-cell survival and growth factor) to indicate that it must be plasma cells that have entered the CNS from the periphery and not matured centrally. I don't agree with this interpretation, what is the evidence for this? If it was the case then peripheral clones would result in matched OCBs. In the MS the majority of OCBs are unmatched, in other words are due to local synthesis. Surely the low BAFF levels could be due to local consumption? 

Despite these subtleties in relation to the interpretation of the data this study suggest that intrathecal B-cell and their products are associated with gray matter atrophy; this is part of the brain that is responsible for cognition. If this is the case we will need to clear the CNS of pathogenic B-cells and plasma cells if we want to prevent long-term damage from occurring. This is why anti-CD20 therapies may not be good enough to prevent delayed worsening of MS. If you haven't read our previous posts on this you may find the most recent one on rituximab failing to prevent delayed worsening or in the old terminology non-relapsing SPMS.  

The intrathecal plasma cell; is this the new enemy from within?

Puthenparampil et al. BAFF Index and CXCL13 levels in the cerebrospinal fluid associate respectively with intrathecal IgG synthesis and cortical atrophy in multiple sclerosis at clinical onset. J Neuroinflammation. 2017 Jan 17;14(1):11. doi: 10.1186/s12974-016-0785-2.

BACKGROUND: B lymphocytes are thought to play a relevant role in multiple sclerosis (MS) pathology. The in vivo analysis of intrathecally produced B cell-related cytokines may help to clarify the mechanisms of B cell recruitment and immunoglobulin production within the central nervous system (CNS) in MS.

METHODS: Paired cerebrospinal fluid (CSF) and serum specimens from 40 clinically isolated syndrome suggestive of MS or early-onset relapsing-remitting MS patients (CIS/eRRMS) and 17 healthy controls (HC) were analyzed for the intrathecal synthesis of IgG (quantitative formulae and IgG oligoclonal bands, IgGOB), CXCL13, BAFF, and IL-21. 3D-FLAIR, 3D-DIR, and 3D-T1 MRI sequences were applied to evaluate white matter (WM) and gray matter (GM) lesions and global cortical thickness (gCTh).

RESULTS: Compared to HC, CIS/eRRMS having IgGOB (IgGOB+, 26 patients) had higher intrathecal IgG indexes (p < 0.01), lower values of BAFF Index (11.9 ± 6.1 vs 17.5 ± 5.2, p < 0.01), and higher CSF CXCL13 levels (27.7 ± 33.5 vs 0.9 ± 1.5, p < 0.005). In these patients, BAFF Index but not CSF CXCL13 levels inversely correlated with the intrathecal IgG synthesis (r > 0.5 and p < 0.05 for all correlations). CSF leukocyte counts were significantly higher in IgGOB+ compared to IgGOB- (p < 0.05) and HC (p < 0.01), and correlated to CSF CXCL13 concentrations (r 0.77, p < 0.001). The gCTh was significantly lower in patients with higher CSF CXCL13 levels (2.41 ± 0.1 vs 2.49 ± 0.1 mm, p < 0.05), while no difference in MRI parameters of WM and GM pathology was observed between IgGOB+ and IgGOB-.

CONCLUSIONS: The intrathecal IgG synthesis inversely correlated with BAFF Index and showed no correlation with CSF CXCL13. These findings seem to indicate that intrathecally synthesized IgG are produced by long-term PCs that have entered the CNS from the peripheral blood, rather than produced by PCs developed in the meningeal follicle-like structures (FLS). In this study, CXCL13 identifies a subgroup of MS patients characterized by higher leukocyte counts in the CSF and early evidence of cortical thinning, further suggesting a role for this chemokine as a possible marker of disease severity.

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