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.
P1121 - Effector T cells are selectively controlled and related to postpartum relapses during pregnancy in MS (ID 1610)
Abstract
Background
Women with multiple sclerosis (MS) experience limited relapses during pregnancy, while an increased relapse risk is observed within the first period after delivery. How extensive pregnancy-associated fluctuations of serum proteins correspond to brain-homing effector T cells and whether this differs between pregnant MS patients and healthy controls is currently unknown.
Objectives
Here, we aimed to assess the effector phenotype and outgrowth of T-cell subsets in relation to pregnancy, pregnancy-related serum factors and postpartum relapses in MS.
Methods
Paired third trimester and 4-8 weeks postpartum blood samples from pregnant MS patients with and without a postpartum relapse (n=21) were compared to age-matched pregnant healthy controls (n=12) for memory phenotype, skewing and activation of T cells. Memory T cells were sorted, activated and analyzed for production of inflammatory cytokines (multiplex assay). Third trimester and postpartum sera were added to CFSE-labeled, proliferating T cells for 72 hours. Serum cortisol, estradiol and progesterone levels were determined using liquid chromatography-mass spectrometry.
Results
Frequencies of effector memory (CCR7-CD45RA-) CD4+ and not CD8+ T cells were selectively increased in postpartum versus third trimester blood of 15 MS patients without a postpartum relapse. This was not seen for 6 patients experiencing a postpartum relapse or in pregnant healthy controls. Brain-homing markers CCR6 and CXCR3 were enriched on memory CD4+ T cells derived from postpartum samples, except for patients with a postpartum relapse. These differences in effector T-cell phenotypes were also found in vitro using paired third trimester and postpartum sera from pregnant MS patients and controls, suggesting that this is at least partly regulated by soluble factors. Serum cortisol, estradiol and progesterone levels did not differ or correlate to outcome measures in third trimester samples. In sharp contrast to non-relapsing patients, memory CD4+ T cells were activated (HLA-DR+) and showed an overall increase in inflammatory cytokine production in third trimester samples from MS patients who experienced a postpartum relapse.
Conclusions
These data demonstrate that effector CD4+ T cells are alternatively controlled in pregnant MS patients, which is influenced by serum-derived factors. Moreover, we found first indications that the activation state of these cells during pregnancy may be used to predict a postpartum relapse in MS.