Contributions
Abstract: P862
Type: Poster Sessions
Abstract Category: Pathology and pathogenesis of MS - Biomarkers
Background: Fingolimod is a functional sphingosine-1-phosphate antagonist approved for the treatment of MS which exerts its effect through sequestration of CCR7+ cells into lymph nodes. However, this mechanism does not explain all changes in the composition of circulating B cells. The serum levels of BAFF, a survival factor for B cells, has been found elevated in response to fingolimod and it seems to be involved in the expansion of transitional B cells. In this study, we wanted to investigate the transcriptional effect of fingolimod on genes related to B cell differentiation and survival, as well as the differential regulation according to clinical response.
Materials and methods: Samples (PBMCs) from the biobank of Puerta de Hierro University Hospital of 10 RRMS patients obtained before and 6 months after starting fingolimod treatment were selected. Five patients had been classified as responders and five as non-responders according to NEDA-4 status at 2 years. Transcriptome sequencing by next-generation technologies was used to define the gene expression profiling in all samples, and the effect on B cell differentiation and survival pathways was determined in all patients.
Results: As expected, the genes coding for the mature B-cell markers and B cell receptor were down-regulated by the treatment: CD27 (log2FC=-2.3 p=9.6x10-17), CD19 (log2FC=-2.7 p=1.2x10-13) and CD79A (log2FC=-2.3 p=1.6x10-10). We also found a very significant reduction in the expression of the genes related to differentiation of naive B cells [IRF4 (log2FC=-1.2 p=3.6x10-40) and RELA (log2FC=-0.3 p=0.005)] and related to B survival [FOXO1(log2FC=-0.9 p=1.2x10-17), MYC (log2FC=-2.2 p=1.1x10-25) and NFKB1(log2FC=-1.3 p=0.003)]. The gene coding for BAFF (TNFSF13B) was up-regulated in response to fingolimod (log2FC=2.1 p=3.2x10-6) but the gene coding for APRIL (TNFSF13) and the MAPK3 gene were up-regulated only in responder patients (log2FC=0.9 p=0.02 and log2FC=0.83p=0.005) while the APRIL receptor BCMA (TNFRSF17) was down-regulated only in non-responders (log2FC=-2.9 p=0.03).
Interpretation: Fingolimod induces changes in the composition of circulating B cells not only through lymphocyte retention into lymph node but it also seems to interfere with biological processes as B cell differentiation and survival. In addition, the differential effect in this pathway could be related to clinical response and used in the search for new response biomarkers.
Disclosure: Antonio García-Merino: has received honoraria for lecturing, consulting or travel expenses from Bayer, Biogen-Idec, Merck, Teva, Novartis, Roche, Almirall and Genzyme, and research grants from Merck and Novartis.
Irene Moreno Torres: has received honoraria for lecturing and travel expenses from Merck, Teva, Novartis, and Genzyme.
Luis Rodríguez Esparragoza: has received honoraria for lecturing and travel expenses from Novartis.
Ruth García Hernández has received honoraria for travel expenses from Teva, Novartis, and Genzyme
The other authors do not have any conflicts of interest to report.
Abstract: P862
Type: Poster Sessions
Abstract Category: Pathology and pathogenesis of MS - Biomarkers
Background: Fingolimod is a functional sphingosine-1-phosphate antagonist approved for the treatment of MS which exerts its effect through sequestration of CCR7+ cells into lymph nodes. However, this mechanism does not explain all changes in the composition of circulating B cells. The serum levels of BAFF, a survival factor for B cells, has been found elevated in response to fingolimod and it seems to be involved in the expansion of transitional B cells. In this study, we wanted to investigate the transcriptional effect of fingolimod on genes related to B cell differentiation and survival, as well as the differential regulation according to clinical response.
Materials and methods: Samples (PBMCs) from the biobank of Puerta de Hierro University Hospital of 10 RRMS patients obtained before and 6 months after starting fingolimod treatment were selected. Five patients had been classified as responders and five as non-responders according to NEDA-4 status at 2 years. Transcriptome sequencing by next-generation technologies was used to define the gene expression profiling in all samples, and the effect on B cell differentiation and survival pathways was determined in all patients.
Results: As expected, the genes coding for the mature B-cell markers and B cell receptor were down-regulated by the treatment: CD27 (log2FC=-2.3 p=9.6x10-17), CD19 (log2FC=-2.7 p=1.2x10-13) and CD79A (log2FC=-2.3 p=1.6x10-10). We also found a very significant reduction in the expression of the genes related to differentiation of naive B cells [IRF4 (log2FC=-1.2 p=3.6x10-40) and RELA (log2FC=-0.3 p=0.005)] and related to B survival [FOXO1(log2FC=-0.9 p=1.2x10-17), MYC (log2FC=-2.2 p=1.1x10-25) and NFKB1(log2FC=-1.3 p=0.003)]. The gene coding for BAFF (TNFSF13B) was up-regulated in response to fingolimod (log2FC=2.1 p=3.2x10-6) but the gene coding for APRIL (TNFSF13) and the MAPK3 gene were up-regulated only in responder patients (log2FC=0.9 p=0.02 and log2FC=0.83p=0.005) while the APRIL receptor BCMA (TNFRSF17) was down-regulated only in non-responders (log2FC=-2.9 p=0.03).
Interpretation: Fingolimod induces changes in the composition of circulating B cells not only through lymphocyte retention into lymph node but it also seems to interfere with biological processes as B cell differentiation and survival. In addition, the differential effect in this pathway could be related to clinical response and used in the search for new response biomarkers.
Disclosure: Antonio García-Merino: has received honoraria for lecturing, consulting or travel expenses from Bayer, Biogen-Idec, Merck, Teva, Novartis, Roche, Almirall and Genzyme, and research grants from Merck and Novartis.
Irene Moreno Torres: has received honoraria for lecturing and travel expenses from Merck, Teva, Novartis, and Genzyme.
Luis Rodríguez Esparragoza: has received honoraria for lecturing and travel expenses from Novartis.
Ruth García Hernández has received honoraria for travel expenses from Teva, Novartis, and Genzyme
The other authors do not have any conflicts of interest to report.