Causal association between the peripheral immunity and the risk and disease severity of multiple sclerosis

Lian Chen; Li-Fang Zhu; Lu-Yang Zhang; Yun-Hui Chu; Ming-Hao Dong; Xiao-Wei Pang; Sheng Yang; Luo-Qi Zhou; Ke Shang; Jun Xiao; Wei Wang; Chuan Qin; Dai-Shi Tian

doi:10.3389/fimmu.2024.1325938

Causal association between the peripheral immunity and the risk and disease severity of multiple sclerosis

Front Immunol. 2024 Feb 8:15:1325938. doi: 10.3389/fimmu.2024.1325938. eCollection 2024.

Authors

Lian Chen^#^{1

2}, Li-Fang Zhu^#^{1

2}, Lu-Yang Zhang^{1

2}, Yun-Hui Chu^{1

2}, Ming-Hao Dong^{1

2}, Xiao-Wei Pang^{1

2}, Sheng Yang^{1

2}, Luo-Qi Zhou^{1

2}, Ke Shang^{1

2}, Jun Xiao^{1

2}, Wei Wang^{1

2}, Chuan Qin^{1

2}, Dai-Shi Tian^{1

2}

Affiliations

¹ Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
² Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, China.

^# Contributed equally.

Abstract

Background: Growing evidence links immunological responses to Multiple sclerosis (MS), but specific immune factors are still unclear.

Methods: Mendelian randomization (MR) was performed to investigate the association between peripheral hematological traits, MS risk, and its severity. Then, further subgroup analysis of immune counts and circulating cytokines and growth factors were performed.

Results: MR revealed higher white blood cell count (OR [95%CI] = 1.26 [1.10,1.44], P = 1.12E-03, P adjust = 3.35E-03) and lymphocyte count (OR [95%CI] = 1.31 [1.15,1.50], P = 5.37E-05, P adjust = 3.22E-04) increased the risk of MS. In further analysis, higher T cell absolute count (OR [95%CI] = 2.04 [1.36,3.08], P = 6.37E-04, P adjust = 2.19E-02) and CD4⁺ T cell absolute count (OR [95%CI] = 2.11 [1.37,3.24], P = 6.37E-04, P adjust = 2.19E-02), could increase MS risk. While increasing CD25⁺⁺CD4⁺ T cell absolute count (OR [95%CI] = 0.75 [0.66,0.86], P = 2.12E-05, P adjust = 1.72E-03), CD25⁺⁺CD4⁺ T cell in T cell (OR [95%CI] = 0.79[0.70,0.89], P = 8.54E-05, P adjust = 5.29E-03), CD25⁺⁺CD4⁺ T cell in CD4⁺ T cell (OR [95%CI] = 0.80[0.72,0.89], P = 1.85E-05, P adjust = 1.72E-03), and CD25⁺⁺CD8⁺ T cell in T cell (OR [95%CI] = 0.68[0.57,0.81], P = 2.22E-05, P adjust = 1.72E-03), were proved to be causally defensive for MS. For the disease severity, the suggestive association between some traits related to CD4⁺ T cell, Tregs and MS severity were demonstrated. Moreover, elevated levels of IL-2Ra had a detrimental effect on the risk of MS (OR [95%CI] = 1.22 [1.12,1.32], P = 3.20E-06, P adjust = 1.34E-04).

Conclusions: This study demonstrated a genetically predicted causal relationship between elevated peripheral immune cell counts and MS. Subgroup analysis revealed a specific contribution of peripheral immune cells, holding potential for further investigations into the underlying mechanisms of MS and its severity.

Keywords: Mendelian randomization (MR); cytokines; genome wide association study (GWAS); multiple sclerosis; peripheral immune cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

CD8-Positive T-Lymphocytes
Causality
Cell Count
Humans
Multiple Sclerosis* / genetics
Patient Acuity

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was supported by Ministry of Science and Technology China Brain Initiative Grant (2022ZD0204704), National Natural Science Foundation of China (Grants: 82071380, 81873743, 82271341), Knowledge Innovation Program of Wuhan Shuguang Project (2022020801020454), and Tongji Hospital (HUST) Foundation for Excellent Young Scientist (Grant No. 2020YQ06). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.