Cerebrospinal Fluid B Cells Correlate with Early Brain Inflammation in Multiple Sclerosis

Background: There is accumulating evidence from immunological, pathological and therapeutic studies that B cells are key components in the pathophysiology of multiple sclerosis (MS). Methodology/Principal Findings: In this prospective study we have for the first time investigated the differences in the inflammatory response between relapsing and progressive MS by comparing cerebrospinal fluid (CSF) cell profiles from patients at the onset of the disease (clinically isolated syndrome, CIS), relapsing-remitting (RR) and chronic progressive (CP) MS by flow cytometry. As controls we have used patients with other neurological diseases. We have found a statistically significant accumulation of CSF mature B cells (CD19+CD1382) and plasma blasts (CD19+CD138+) in CIS and RRMS. Both B cell populations were, however, not significantly increased in CPMS. Further, this accumulation of B cells correlated with acute brain inflammation measured by magnetic resonance imaging and with inflammatory CSF parameters such as the number of CSF leukocytes, intrathecal immunoglobulin M and G synthesis and intrathecal production of matri

Percentages of CD3+ T cells (A), CD19+CD138− mature B cells (B) and CD19+CD138+ plasma blasts (C) in the CSF of patients with a CIS, RRMS, CPMS and OND.

<p>Individual data points are shown as circles and horizontal bars indicate means. Data were compared using the Kruskal-Wallis test and Dunn's multiple comparison post-hoc test and overall p-values are shown in each figure. # = significant differences to the OND group.</p

CSF B cell subsets.

<p>(A) Dot plots of CSF leucocytes according to their CD45-PerCP versus side scatter properties (left panel) and forward versus side scatter properties (right panel). Region 1 (R1, left panel) was used for acquisition of a minimum number of 1000 events and region 2 (R2, right panel) was used for analysis. CSF analysis of representative patients with a CIS (B), RRMS (C), CPMS (D) and OND (E) for the presence of CD3+ T cells and CD19+ B cells (left panel), and CD19+CD138− mature B cells, CD19+CD138+ plasma blasts and CD19−CD138+ plasma cells (right panel). The numbers represent the relative percentages of these cell populations.</p

Correlation of CSF B cells with other inflammatory parameters.

<p><b>1</b> data are shown as median (range), p-value: groups were compared using <b>2</b> Mann-Whitney U test or <b>3</b> Spearmans nonparametric correlations.</p><p>Abbreviations: MRI Gd+ lesions = presence of gadolinium-enhancing lesions on T1-weighted MRI (neg = negative, pos = positive), MRI T2 lesions = number of lesions on T2-weighted MRI, Q-Alb = albumin quotient, OCB = oligoclonal bands, MMP = matrix metalloproteinase, R = Spearman's correlation coefficient, ns = statistically not significant.</p

Demographic, clinical and CSF data of analyzed patients.

<p><b>1</b> data are shown as median (range), p-value: groups were compared using <b>2</b> Qui-Square test or <b>3</b> Kruskal-Wallis test and Dunn's multiple comparison post-hoc test, # statistically significant different from OND control group.</p><p>Abbreviations: n = number of patients, y = years, EDSS = expanded disability status score, acute relapse = number of patients with an acute relapse, MRI Gd+ lesions = presence of gadolinium-enhancing lesions on T1-weighted MRI (neg = negative, pos = positive), ≥9 T2 MRI lesions = ≥9 lesions on T2-weighted MRI, OCB = oligoclonal bands, Q-Alb = albumin quotient, MMP = matrix metalloproteinase, ratio = CSF∶serum ratio, ns = statistically not significant.</p