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Intrathecal B Cells in MS Have Significantly Greater Lymphangiogenic Potential Compared to B Cells Derived From Non-MS Subjects.

ABSTRACT: Although B cell depletion is an effective therapy of multiple sclerosis (MS), the pathogenic functions of B cells in MS remain incompletely understood. We asked whether cerebrospinal fluid (CSF) B cells in MS secrete different cytokines than control-subject B cells and whether cytokine secretion affects MS phenotype. We blindly studied CSF B cells after their immortalization by Epstein-Barr Virus (EBV) in prospectively-collected MS patients and control subjects with other inflammatory-(OIND) or non-inflammatory neurological diseases (NIND) and healthy volunteers (HV). The pilot cohort (n = 80) was analyzed using intracellular cytokine staining (n = 101 B cell lines [BCL] derived from 35 out of 80 subjects). We validated differences in cytokine production in newly-generated CSF BCL (n = 207 BCL derived from subsequent 112 prospectively-recruited subjects representing validation cohort), using ELISA enhanced by objective, flow-cytometry-based B cell counting. After unblinding the pilot cohort, the immortalization efficiency was almost 5 times higher in MS patients compared to controls (p < 0.001). MS subjects' BCLs produced significantly more vascular endothelial growth factor (VEGF) compared to control BCLs. Progressive MS patients BCLs produced significantly more tumor necrosis factor (TNF)-? and lymphotoxin (LT)-? than BCL from relapsing-remitting MS (RRMS) patients. In the validation cohort, we observed lower secretion of IL-1? in RRMS patients, compared to all other diagnostic categories. The validation cohort validated enhanced VEGF-C production by BCL from RRMS patients and higher TNF-? and LT-? secretion by BCL from progressive MS. No significant differences among diagnostic categories were observed in secretion of IL-6 or GM-CSF. However, B cell secretion of IL-1?, TNF-?, and GM-CSF correlated significantly with the rate of accumulation of disability measured by MS disease severity scale (MS-DSS). Finally, all three cytokines with increased secretion in different stages of MS (i.e., VEGF-C, TNF-?, and LT-?) enhance lymphangiogenesis, suggesting that intrathecal B cells directly facilitate the formation of tertiary lymphoid follicles, thus compartmentalizing inflammation to the central nervous system.

SUBMITTER: Stein J

PROVIDER: S-EPMC6062589 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Intrathecal B Cells in MS Have Significantly Greater Lymphangiogenic Potential Compared to B Cells Derived From Non-MS Subjects.

Stein Jason J Xu Quangang Q Jackson Kayla C KC Romm Elena E Wuest Simone C SC Kosa Peter P Wu Tianxia T Bielekova Bibiana B

Frontiers in neurology 20180720

Although B cell depletion is an effective therapy of multiple sclerosis (MS), the pathogenic functions of B cells in MS remain incompletely understood. We asked whether cerebrospinal fluid (CSF) B cells in MS secrete different cytokines than control-subject B cells and whether cytokine secretion affects MS phenotype. We blindly studied CSF B cells after their immortalization by Epstein-Barr Virus (EBV) in prospectively-collected MS patients and control subjects with other inflammatory-(OIND) or ...[more]

PMID: 30079049

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Project description:BackgroundBlack African (BA) populations are losing the cardio-protective lipid profile they historically exhibited, which may be linked with increasing fructose intakes. The metabolic effects of high fructose diets and how they relate to blood lipids are documented for Caucasians, but have not been described in BA individuals.ObjectiveThe principle objective of this pilot study was to assess the independent impacts of high glucose and fructose feeding in men of BA ancestry compared to men of White European (WE) ancestry on circulating triglyceride (TG) concentrations.MethodsHealthy males, aged 25-60 years, of BA (n = 9) and WE (n = 11) ethnicity were randomly assigned to 2 feeding days in a crossover design, providing mixed nutrient meals with 20 % total daily caloric requirements from either added glucose or fructose. Circulating TG, non-esterified fatty acids (NEFA), glucose, insulin and C-peptide were measured over two 24-h periods.ResultsFasting TGs were lower in BAs than WEs on the fructose feeding day (p < 0.05). There was a trend for fasting TG concentrations 24 h following fructose feeding to increase in both BA (baseline median fasting: 0.80, IQR 0.6-1.1 vs 24-h median post-fructose: 1.09, 0.8-1.4 mmol/L; p = 0.06) and WE (baseline median fasting 1.10, IQR 0.9-1.5 vs 24-h median post-fructose: 1.16, IQR 0.96-1.73 mmol/L; p = 0.06). Analysis within ethnic group demonstrated that in TG iAUC was significantly higher in BA compared to WE on both glucose (35, IQR 11-56 vs -4, IQR -10-1 mmol/L/min; p = 0.004) and fructose (48, IQR 15-68 vs 13, IQR -7-38 mmol/L/min; p = 0.04). Greater suppression of postprandial NEFA was evident in WE than BA after glucose feeding (-73, IQR -81- -52 vs -26, IQR -48- -3 nmol/L/min; p = 0.001) but there was no ethnic difference following fructose feeding.ConclusionsUnderstanding the metabolic effects of dietary acculturation and Westernisation that occurs in Black communities is important for developing prevention strategies for chronic disease development. These data show postprandial hypertriglyceridemia following acute feeding of high added fructose and glucose in BA men, compared to WE men, may contribute to metabolic changes observed during dietary acculturation and Westernisation.Trial registrationThe study was retrospectively registered on clinicaltrials.gov: NCT02533817 .

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Intrathecal B Cells in MS Have Significantly Greater Lymphangiogenic Potential Compared to B Cells Derived From Non-MS Subjects.

Publications

Intrathecal B Cells in MS Have Significantly Greater Lymphangiogenic Potential Compared to B Cells Derived From Non-MS Subjects.

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