Contributions
Abstract: P750
Type: Poster Sessions
Abstract Category: Pathology and pathogenesis of MS - Genetics/Epigenetics
Background and aims: Increasing evidences point towards a role of NK cells in Multiple Sclerosis (MS). Specifically, regulatory CD56bright NK cells are decreased in MS patients and daclizumab, that proved effective in MS treatment, is thought to act by increasing the proportion of this NK compartment. Here we investigate the possible role of NK cells in MS pathogenesis by analyzing the association between MS risk variants and NK cells markers expression.
Materials and methods: Blood samples from 93 Caucasian healthy subjects were collected and an extensive immune-phenotype profiling of NK cells was obtained by flow cytometric analysis. Two kinds of analysis were performed investigating the association of NK traits, under a linear regression model with: 1) a weighted genetic risk score (wGRS) obtained combining the effect size of 192 MS variants present in our dataset and of HLADRB1*1501; 2) 3514 SNPs in LD (r2>0.8) with the 200 MS variants. We also investigated whether the MS-associated region on chr1 that contains the KLRB1 gene is associated with its expression at protein level in NK cells, thus representing a protein quantitative trait locus (pQTL).
Results: wGRS positively correlates with the proportion of cells expressing KLRB1, a marker expressed on IL17-producing cells, when considering both total NK cells or CD56bright and dim cells. Moreover, we found that the MS-related alleles rs10951042C and rs4808488G are linked to a lower proportion of NK cells expressing CD8 while rs4916004G associates to a lower percentage of KIR3DL1+ cells, thus suggesting a decrease in NK function in presence of MS susceptibility variants. Likewise, rs1077667C and rs10790275C, are associated with a decrease in CD107a+ and MIP1beta+ NK cells upon stimulation with target cells. Finally, we found a variant, rs795947, showing a cis-pQTL effect on KLRB1 protein expression, but this variant does not colocalize with the previously reported MS signal in that region (rs7977720).
Conclusions: Although additional studies are warranted to confirm our findings and their NK cells specificity, the present results suggest that at least some genetic variants previously associated with MS susceptibility modulate NK cell markers expression and regulate NK cell functionality, highlighting molecular features that are involved in the onset of MS.
Disclosure: Laura Ferrè, Dr Tina Roostaei, Dr Daniel Felsky, Dr Hans-Ulrich Klein, Dr Zongqi Xia and Dr Galit Alter have nothing to disclose. Dr Philip De Jager served as a member of advisory board for Celgene, Roche, Sanofi/Genzyme, received grant funding from Eisai, Roche, Biogen, Lundbeck and speaker honorarium from GlaxoSmithKline.
Abstract: P750
Type: Poster Sessions
Abstract Category: Pathology and pathogenesis of MS - Genetics/Epigenetics
Background and aims: Increasing evidences point towards a role of NK cells in Multiple Sclerosis (MS). Specifically, regulatory CD56bright NK cells are decreased in MS patients and daclizumab, that proved effective in MS treatment, is thought to act by increasing the proportion of this NK compartment. Here we investigate the possible role of NK cells in MS pathogenesis by analyzing the association between MS risk variants and NK cells markers expression.
Materials and methods: Blood samples from 93 Caucasian healthy subjects were collected and an extensive immune-phenotype profiling of NK cells was obtained by flow cytometric analysis. Two kinds of analysis were performed investigating the association of NK traits, under a linear regression model with: 1) a weighted genetic risk score (wGRS) obtained combining the effect size of 192 MS variants present in our dataset and of HLADRB1*1501; 2) 3514 SNPs in LD (r2>0.8) with the 200 MS variants. We also investigated whether the MS-associated region on chr1 that contains the KLRB1 gene is associated with its expression at protein level in NK cells, thus representing a protein quantitative trait locus (pQTL).
Results: wGRS positively correlates with the proportion of cells expressing KLRB1, a marker expressed on IL17-producing cells, when considering both total NK cells or CD56bright and dim cells. Moreover, we found that the MS-related alleles rs10951042C and rs4808488G are linked to a lower proportion of NK cells expressing CD8 while rs4916004G associates to a lower percentage of KIR3DL1+ cells, thus suggesting a decrease in NK function in presence of MS susceptibility variants. Likewise, rs1077667C and rs10790275C, are associated with a decrease in CD107a+ and MIP1beta+ NK cells upon stimulation with target cells. Finally, we found a variant, rs795947, showing a cis-pQTL effect on KLRB1 protein expression, but this variant does not colocalize with the previously reported MS signal in that region (rs7977720).
Conclusions: Although additional studies are warranted to confirm our findings and their NK cells specificity, the present results suggest that at least some genetic variants previously associated with MS susceptibility modulate NK cell markers expression and regulate NK cell functionality, highlighting molecular features that are involved in the onset of MS.
Disclosure: Laura Ferrè, Dr Tina Roostaei, Dr Daniel Felsky, Dr Hans-Ulrich Klein, Dr Zongqi Xia and Dr Galit Alter have nothing to disclose. Dr Philip De Jager served as a member of advisory board for Celgene, Roche, Sanofi/Genzyme, received grant funding from Eisai, Roche, Biogen, Lundbeck and speaker honorarium from GlaxoSmithKline.