IL-35 Genetic Variations and Serum Levels in Multiple Sclerosis

The Familial Risk and Heritability of Multiple Sclerosis: Insights from a Case-Control Study

Multiple Sclerosis (MS) is a chronic autoimmune disorder characterized by inflammation and demyelination of the central nervous system (CNS). It affects communication between the brain and the rest of the body, often resulting in significant disability. Despite substantial advances, the precise mechanisms contributing to MS remain unclear, though genetic and immunological factors are known to play key roles. In this context, IL-35, an anti-inflammatory cytokine produced by regulatory T (Treg) cells, B cells, and other immune cells, has emerged as a molecule of interest. This blog post will review a recent population-based case-control study that explores the association between IL-35 genetic variations and serum levels with MS susceptibility and disease severity.

Study Overview
The study recruited 186 MS patients and 195 sex- and age-matched healthy controls to investigate two key elements: (1) serum IL-35 levels, and (2) polymorphisms in genes encoding IL-35 subunits, specifically EBI3 (rs4740) and IL-12A (rs568408). The research sought to clarify whether genetic variations in IL-35 contribute to MS risk and progression, alongside measuring the cytokine’s levels in blood serum.

Key Findings
Serum IL-35 Levels in MS Patients
A significant finding was the reduced serum levels of IL-35 in MS patients compared to healthy controls. MS patients exhibited an average IL-35 level of 49.3 pg/ml, much lower than the 69.5 pg/ml observed in controls. Notably, this decline was most pronounced in patients with secondary progressive MS (SPMS), a more severe form of the disease. The study also established a reverse correlation between IL-35 levels and MS severity, as measured by the Expanded Disability Status Scale (EDSS). These results suggest that reduced IL-35 may be linked to increased disease severity.

EBI3 and IL-12A Polymorphisms and MS Susceptibility
Genetic analysis revealed that the EBI3 rs4740 polymorphism significantly increased the risk of developing MS. Patients with the AA genotype for this polymorphism were 2.23 times more likely to develop MS compared to those with the wild-type genotype. In contrast, the IL-12A rs568408 polymorphism showed no significant association with MS susceptibility, highlighting the stronger contribution of the EBI3 subunit to MS pathogenesis.

The Role of IL-35 in MS Pathogenesis
IL-35 is known for its immunosuppressive effects, particularly its ability to regulate Treg and Th17 cells, which are central to autoimmune responses. Th17 cells, associated with producing IL-17, are implicated in the inflammatory processes of MS, while Treg cells act to suppress such inflammation. The reduced levels of IL-35 in MS patients observed in this study align with its potential role in modulating immune responses, emphasizing its importance in maintaining the delicate balance between pro- and anti-inflammatory pathways.

Genetic Variants and Functional Predictions
Bioinformatics tools were employed to predict the functional impact of the EBI3 rs4740 and IL-12A rs568408 polymorphisms. The study suggests that the G-to-A substitution in EBI3 rs4740 may disrupt protein stability and influence the signaling pathways involved in immune regulation, including NF-κB and IFN-γ pathways. This disruption could explain the observed association between the EBI3 polymorphism and increased MS risk.

Implications for MS Treatment and Prognosis
These findings provide a clearer picture of IL-35’s role in MS and suggest potential clinical applications. Monitoring IL-35 serum levels may serve as a biomarker for MS severity, especially in tracking disease progression in SPMS. Furthermore, therapies aimed at restoring IL-35 levels or targeting its genetic pathways may represent a novel avenue for treatment, particularly in patients with genetic predispositions linked to the EBI3 polymorphism.

Implications for MS Treatment and Prognosis
Boles et al. (2023) provide robust evidence that familial risk is a significant factor in the development of MS, with no major differences in genetic liability between the two main MS phenotypes, ROMS and PPMS. The study highlights the importance of genetic factors in MS susceptibility and calls for continued research into the environmental and genetic contributors to different MS phenotypes. As our understanding of MS genetics evolves, so too will our ability to predict disease risk and develop targeted interventions for those at greatest risk.

Conclusion
This study is among the first to link IL-35 genetic variants and serum levels with MS susceptibility and severity, shedding light on the complex immunological landscape of the disease. The EBI3 rs4740 polymorphism, in particular, appears to play a crucial role in disease risk, while low IL-35 levels are associated with more severe forms of MS. These insights pave the way for further research into IL-35 as both a biomarker and potential therapeutic target in MS.

Reference:
Eslami, M., Rafiei, A., Baghbanian, S.M. et al. Serum levels and genetic variation of IL-35 are associated with multiple sclerosis: a population-based case–control study. Immunol Res 70, 75–85 (2022).