TY - JOUR

T1 - IL-6, IL-12, and IL-23 STAT-Pathway Genetic Risk and Responsiveness of Lymphocytes in Patients with Multiple Sclerosis

AU - von Essen, Marina R

AU - Søndergaard, Helle B

AU - Petersen, Eva R S

AU - Sellebjerg, Finn

PY - 2019

Y1 - 2019

N2 - Multiple sclerosis (MS) is an immune-mediated demyelinating disease characterized by central nervous system (CNS) lymphocyte infiltration, abundant production of pro-inflammatory cytokines, and inappropriate activation of Th1 and Th17 cells, B cells, and innate immune cells. The etiology of MS is complex, and genetic factors contribute to disease susceptibility. Genome-wide association studies (GWAS) have revealed numerous MS-risk alleles in the IL-6/STAT3, IL-12/STAT4, and IL-23/STAT3-pathways implicated in the differentiation of Th1 and Th17 cells. In this study, we investigated the signaling properties of these pathways in T, B, and NK cells from patients with relapsing-remitting MS (RRMS) and healthy controls, and assessed the genetic contribution to the activity of the pathways. This revealed a great variability in the level of STAT-pathway molecules and STAT activation between the cell types investigated. We also found a strong donor variation in IL-6, IL-12, and IL-23 responsiveness of primed CD4+ T cells. This variation could not be explained by a single MS-risk variant in a pathway component, or by an accumulation of multiple STAT-pathway MS-risk SNPs. The data of this study suggests that other factors in cohesion with the genetic background contribute to the responsiveness of the IL-6/STAT3, IL-12/STAT4, and IL-23/STAT3-pathways.

AB - Multiple sclerosis (MS) is an immune-mediated demyelinating disease characterized by central nervous system (CNS) lymphocyte infiltration, abundant production of pro-inflammatory cytokines, and inappropriate activation of Th1 and Th17 cells, B cells, and innate immune cells. The etiology of MS is complex, and genetic factors contribute to disease susceptibility. Genome-wide association studies (GWAS) have revealed numerous MS-risk alleles in the IL-6/STAT3, IL-12/STAT4, and IL-23/STAT3-pathways implicated in the differentiation of Th1 and Th17 cells. In this study, we investigated the signaling properties of these pathways in T, B, and NK cells from patients with relapsing-remitting MS (RRMS) and healthy controls, and assessed the genetic contribution to the activity of the pathways. This revealed a great variability in the level of STAT-pathway molecules and STAT activation between the cell types investigated. We also found a strong donor variation in IL-6, IL-12, and IL-23 responsiveness of primed CD4+ T cells. This variation could not be explained by a single MS-risk variant in a pathway component, or by an accumulation of multiple STAT-pathway MS-risk SNPs. The data of this study suggests that other factors in cohesion with the genetic background contribute to the responsiveness of the IL-6/STAT3, IL-12/STAT4, and IL-23/STAT3-pathways.

KW - Adult

KW - Alleles

KW - Case-Control Studies

KW - Cross-Priming/immunology

KW - Female

KW - Genetic Predisposition to Disease

KW - Humans

KW - Interleukin-12/metabolism

KW - Interleukin-23/metabolism

KW - Interleukin-6/metabolism

KW - Interleukins/metabolism

KW - Lymphocytes/immunology

KW - Male

KW - Middle Aged

KW - Multiple Sclerosis/genetics

KW - Receptors, Interleukin/metabolism

KW - Risk Factors

KW - STAT Transcription Factors/metabolism

KW - Signal Transduction

U2 - 10.3390/cells8030285

DO - 10.3390/cells8030285

M3 - Journal article

C2 - 30917537

VL - 8

JO - Cells

JF - Cells

SN - 2073-4409

IS - 3

M1 - 285

ER -