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Causal Relationship Between Circulating Leukocyte Characteristics and Immune Cell Traits With Multiple Sclerosis
Jia-Jia Yun1, Ya-Lei Li1, Jing-Man Qiu2
1School of Special Education and Rehabilitation, Binzhou Medical University, Yantai, 264003, China.
Cellular and Molecular Neurobiology
|July 13, 2026
Summary
Increased white blood cell and lymphocyte counts are linked to a higher risk of multiple sclerosis (MS). Certain immune cell traits may decrease MS risk, but MS does not appear to cause changes in these blood cell counts.
Area of Science:
- Immunology
- Genetics
- Neurology
Background:
- Multiple sclerosis (MS) is a chronic autoimmune disease affecting the central nervous system.
- The role of circulating immune cells and their traits in MS etiology remains incompletely understood.
- Genetic factors influencing immune cell populations may contribute to MS susceptibility.
Purpose of the Study:
- To investigate potential causal relationships between circulating leukocytes, immune cell traits, and multiple sclerosis (MS) using a bidirectional Mendelian randomization (MR) approach.
- To determine if genetic predisposition to specific immune cell profiles increases or decreases MS risk.
- To assess whether MS influences circulating immune cell counts or traits.
Main Methods:
- Utilized a two-sample, bidirectional Mendelian randomization (MR) analysis with summary-level data from large genome-wide association studies.
- Employed multiple MR methods including Inverse Variance Weighted (IVW), weighted mode, weighted median, simple mode, and MR-Egger.
- Assessed horizontal pleiotropy using MR-Egger intercept, genetic heterogeneity with Cochran's Q test, and result sensitivity with leave-one-out procedures, adjusting for multiple comparisons using False Discovery Rate (FDR).
Main Results:
- Forward MR indicated that genetically predicted higher white blood cell count (OR=1.16) and lymphocyte count (OR=1.18) are associated with increased MS risk.
- Specific immune cell traits, including CD25hi CD45RA-CD4 not Treg %CD4+ (OR=0.87) and CD16-CD56 on HLA DR+ NK (OR=0.85), were associated with reduced MS risk.
- Reverse MR analyses found no robust evidence for MS causally affecting white blood cell or lymphocyte counts, with one potential association for B-cell counts deemed unreliable due to sensitivity analysis.
Conclusions:
- Genetic predisposition to elevated white blood cell and lymphocyte counts is a risk factor for developing multiple sclerosis.
- Certain immune cell phenotypes are associated with a protective effect against MS.
- Evidence does not support a causal role for MS in altering circulating white blood cell or lymphocyte levels.
