Contributions
Abstract: P1751
Type: Poster Sessions
Abstract Category: N/A
Introduction: Intrathecal synthesis of immunoglobulin G (IgG) can often be observed in patients with multiple sclerosis (MS) and clinically isolated syndrome (CIS). We could previously show that genetic markers in the immunoglobulin heavy chain (IGHC) locus on chromosome 14 and the major histocompatibility complex (MHC) region on chromosome 6 are associated with the amount of intrathecal IgG in MS and CIS patients. To investigate how these markers influence the humoral immune response in the central nervous system (CNS) we analysed associations of these variants with B cells and plasma blasts in the cerebrospinal fluid (CSF).
Methods: CSF cells of 440 CIS and MS patients were analysed by fluorescence-activated cell scanning (FACS). Genotyping was performed by the iPlex Gold method. Associations of the rank transformed absolute numbers of CD19+ B cells and CD19+CD138+ plasma blasts and four genetic variants on chromosome 6 (rs6457617, rs9271353, rs2858312, rs2157051) and three variants in the IGHC locus (rs11160868, rs2753571 and rs8009156) were analysed by linear regression with adjustments made for gender, sequencing plate and age at lumbar puncture. A Bonferroni procedure was used to correct for multiple testing.
Results: Of the 440 patients 296 (67%) were female, the mean age at lumbar puncture was 33 years. There was no significant association of the genetic variants on chromosome 14 with absolute numbers of CSF B cells or plasma blasts. The minor allele T of rs9271353 was associated with higher absolute numbers of CSF B cells (p = 0.003) and plasma blasts (p = 0.001). rs6457617, rs2858312, rs2157051 did not show any significant associations with CSF B cell subpopulations.
Discussion: Our findings suggest differential mechanisms how genetic factors impact on intrathecal IgG synthesis in MS. The minor allele of rs9271353, which is strongly linked to HLA-DRB1*15:01, is associated with increased B cell and plasma blast numbers in the CSF indicating that the HLA locus primarily drives the extent of humoral immune responses in the CNS. By contrast genetic variants in the IGHC locus are not associated with absolute numbers of B cells or plasma blasts in the CSF suggesting that the association of these variants with intrathecal IgG synthesis is not due to increased CNS B cell inflammation but rather other mechanisms such as altered CSF immunoglobulin homeostasis.
Disclosure: CG reports no conflicts of interest
ATK reports no conflicts of interest
VG reports no conflicts of interest
BK reports grants from the Bundesministerium für Bildung und Forschung (Kompetenznetz Multiple Sklerose KKNMS), intramural funding from the Technical University of Munich (KKF program) and a grant from Novartis unrelated to this study.
AB reports personal fees from Biogen, Merck Serono, Mylan, Novartis, Roche, Sanofi Genzyme, and Teva, and compensations for clinical trials from Alexion Pharmaceuticals, Biogen, Novartis, Genzyme, Roche, and Teva - all outside the submitted work.
BH has served on scientific advisory boards for F. Hoffmann-La Roche Ltd, Novartis, Bayer AG, and Genentech; he has served as DMSC member for AllergyCare and TG therapeutics; he or his institution have received speaker honoraria from Biogen Idec, Teva Neuroscience, Merck Serono, Medimmune, Novartis, Desitin, and F. Hoffmann-La Roche Ltd; his institution has received research support from Chugai Pharmaceuticals and Biogen; holds part of two patents; one for the detection of antibodies against KIR4.1 in a subpopulation of MS patients and one for genetic determinants of neutralizing antibodies to interferon β.
Abstract: P1751
Type: Poster Sessions
Abstract Category: N/A
Introduction: Intrathecal synthesis of immunoglobulin G (IgG) can often be observed in patients with multiple sclerosis (MS) and clinically isolated syndrome (CIS). We could previously show that genetic markers in the immunoglobulin heavy chain (IGHC) locus on chromosome 14 and the major histocompatibility complex (MHC) region on chromosome 6 are associated with the amount of intrathecal IgG in MS and CIS patients. To investigate how these markers influence the humoral immune response in the central nervous system (CNS) we analysed associations of these variants with B cells and plasma blasts in the cerebrospinal fluid (CSF).
Methods: CSF cells of 440 CIS and MS patients were analysed by fluorescence-activated cell scanning (FACS). Genotyping was performed by the iPlex Gold method. Associations of the rank transformed absolute numbers of CD19+ B cells and CD19+CD138+ plasma blasts and four genetic variants on chromosome 6 (rs6457617, rs9271353, rs2858312, rs2157051) and three variants in the IGHC locus (rs11160868, rs2753571 and rs8009156) were analysed by linear regression with adjustments made for gender, sequencing plate and age at lumbar puncture. A Bonferroni procedure was used to correct for multiple testing.
Results: Of the 440 patients 296 (67%) were female, the mean age at lumbar puncture was 33 years. There was no significant association of the genetic variants on chromosome 14 with absolute numbers of CSF B cells or plasma blasts. The minor allele T of rs9271353 was associated with higher absolute numbers of CSF B cells (p = 0.003) and plasma blasts (p = 0.001). rs6457617, rs2858312, rs2157051 did not show any significant associations with CSF B cell subpopulations.
Discussion: Our findings suggest differential mechanisms how genetic factors impact on intrathecal IgG synthesis in MS. The minor allele of rs9271353, which is strongly linked to HLA-DRB1*15:01, is associated with increased B cell and plasma blast numbers in the CSF indicating that the HLA locus primarily drives the extent of humoral immune responses in the CNS. By contrast genetic variants in the IGHC locus are not associated with absolute numbers of B cells or plasma blasts in the CSF suggesting that the association of these variants with intrathecal IgG synthesis is not due to increased CNS B cell inflammation but rather other mechanisms such as altered CSF immunoglobulin homeostasis.
Disclosure: CG reports no conflicts of interest
ATK reports no conflicts of interest
VG reports no conflicts of interest
BK reports grants from the Bundesministerium für Bildung und Forschung (Kompetenznetz Multiple Sklerose KKNMS), intramural funding from the Technical University of Munich (KKF program) and a grant from Novartis unrelated to this study.
AB reports personal fees from Biogen, Merck Serono, Mylan, Novartis, Roche, Sanofi Genzyme, and Teva, and compensations for clinical trials from Alexion Pharmaceuticals, Biogen, Novartis, Genzyme, Roche, and Teva - all outside the submitted work.
BH has served on scientific advisory boards for F. Hoffmann-La Roche Ltd, Novartis, Bayer AG, and Genentech; he has served as DMSC member for AllergyCare and TG therapeutics; he or his institution have received speaker honoraria from Biogen Idec, Teva Neuroscience, Merck Serono, Medimmune, Novartis, Desitin, and F. Hoffmann-La Roche Ltd; his institution has received research support from Chugai Pharmaceuticals and Biogen; holds part of two patents; one for the detection of antibodies against KIR4.1 in a subpopulation of MS patients and one for genetic determinants of neutralizing antibodies to interferon β.