Author Of 2 Presentations
P0528 - T cell composition and polygenic multiple sclerosis risk: a population-based study in children (ID 943)
Abstract
Background
Multiple sclerosis (MS) is associated with extensive immunological alterations in adult patients. MS patients show changes in T cell composition, including increased CD4+/CD8+ ratios. However, it is unclear to which extent these changes in T cell composition are influenced by genetic risk for MS, and how this may precede a possible disease onset.
Objectives
In the current study we investigate the association between polygenic risk scores (PRSs) for MS and T cell subsets in a large population-based pediatric sample, to provide new understanding about the link between genetic risk for MS and disease pathophysiology.
Methods
We included participants from the population-based Generation R study who had genetic- and immunological data available. Children were sampled for immunological data around the age of 6 years (IQR: 5.9-6.2). Linear regression analyses were used to analyze the impact of MS-PRSs on absolute T cell numbers (n=1,261) and CD4+ and CD8+ T cell fractions (n=675) adjusted for important child- (age and sex) and environmental confounding factors (serum vitamin D levels and cytomegalovirus positivity).
Results
The MS-PRS showed a negative correlation with CD8+ T cell frequencies (β=-0.05, SE=0.015, ΔR2=0.020, p=2.88 × 10-4), which resulted in a positive association with CD4+/CD8+ ratios (β=0.07, SE=0.011, ΔR2=0.054, p=9.20 × 10-10). Interestingly, the latter was driven by 2 out of 196 genome-wide significant MS risk variants. Both from within the HLA class II region, risk variants rs3135388 and rs9271366 were positively associated with the CD4+/CD8+ ratio. No association was found with absolute total T cell numbers.
Conclusions
This study shows that higher genetic risk for MS is associated with T cell alterations at an early age. Our results show a possibility that MS genetics affect the T cell composition during childhood, which may contribute to increased risk of MS disease later in life.
P0973 - Impact of Epstein-Barr virus infection on CXCR3+ B-cell development: lessons learned from immunotherapies in MS (ID 751)
Abstract
Background
Epstein-Barr virus (EBV) infection of B cells is strongly associated with the onset of several chronic inflammatory and autoimmune diseases such as multiple sclerosis (MS). In MS, a subset of memory B cells infiltrates the central nervous system (CNS) and further differentiates into antibody-secreting cells to mediate local pathology.
Objectives
Here, we aimed to decipher whether and how EBV impacts the development of such CNS-homing memory B cells in MS patients.
Methods
Chemokine receptor profiles were analyzed for ex vivo B cells in single-cell suspensions obtained from paired CNS compartments of 10 MS patients (NBB) using multicolor flow cytometry. The CNS infiltration capacity of memory B-cell subsets was confirmed using confluent brain endothelial monolayers. Similar analyses were performed for distinct memory subsets in the blood from 16 untreated, 32 natalizumab-treated and 9 bone-marrow transplant (BMT)-treated MS patients as well as matched healthy controls. An IL-21-/CD40L-based germinal center-like culture system was used to compare naive and memory B-cell differentiation. EBV copy numbers were determined in total and memory B cells using a multiplex BALF5-related qPCR assay.
Results
CXCR3-expressing B cells were selectively enriched in paired CSF, meningeal and brain tissues versus blood of MS patients. Treatment of patients with natalizumab resulted in an accumulation of CXCR3high IgG+ B cells in the blood, corresponding to their increased ability to cross CNS barriers in vitro. Naive B cells developed into plasmablasts under IFN-γ-mediated germinal center-like conditions and required additional TLR9 signaling for differentiation into CXCR3+ switched memory cells. In 3-7 months post- vs pre-BMT blood samples, EBV DNA load was elevated and positively correlated to the frequency of CXCR3+, and not CXCR4+ or CXCR5+, switched memory B cells. High EBV load in memory B cells from natalizumab-treated MS patients corresponded to an increased potential to develop into anti-EBNA1 IgG-producing CXCR3+ plasma cells (CD38++CD27++CD138+) during IFN-γ-mediated germinal center-like cultures.
Conclusions
This study implicates that persistent viral infections such as EBV potentiate brain-homing and antibody-producing CXCR3(T-bet)+ B cells in MS patients. These findings may mechanistically link EBV infection to anti-EBNA1 IgG production as being a predictor of disease onset and to the massive B-cell influx into the CNS after natalizumab discontinuation in MS.