Causal Effect of Blood Cell Perturbation Phenotypes on Multiple Sclerosis via Immune Mediation: A Mendelian...

Area of Science:

• Neuroimmunology
• Genetics
• Hematology

Background:

• Multiple sclerosis (MS) is a central nervous system inflammatory disease.
• The precise role of peripheral blood and immune cells in MS pathogenesis is not fully understood.
• Genetic factors and immune dysfunction contribute to MS, but peripheral influences require further definition.

Purpose of the Study:

• To investigate the causal relationships between blood cell perturbations, immune cell traits, and multiple sclerosis risk using a Mendelian randomization approach.
• To identify specific blood and immune cell phenotypes associated with increased MS risk.
• To explore potential mediating pathways, such as the role of HLA-DR expression on B cells in the neutrophil-MS association.

Main Methods:

• A two-sample Mendelian randomization (MR) analysis was performed.
• Data from 91 blood cell perturbation phenotypes and 731 immune cell traits were analyzed.
• Robust MR techniques, mediation analysis, and sensitivity tests (Cochran's Q, MR-Egger intercept, leave-one-out) were employed for causal inference and validation.

Main Results:

• Significant associations were found between 9 blood cell perturbation phenotypes and 34 immune cell traits with MS risk.
• Neutrophil disturbances showed a partial mediation effect on MS risk through HLA-DR expression on B cells (approx. 16.38% mediation).
• Sensitivity analyses confirmed the reliability and robustness of the identified associations.

Conclusions:

• Specific blood cell perturbations are genetically associated with an increased risk of developing multiple sclerosis.
• Immune cells, particularly B cells expressing HLA-DR, may mediate the link between peripheral blood disturbances and central nervous system pathology in MS.
• These findings offer genetic insights into MS immune mechanisms and may inform the development of novel immunotherapies.