Identical Genes, Different Outcomes: How Environment Shapes the Immune System in Multiple Sclerosis

Multiple sclerosis is a chronic autoimmune disease in which the body’s own immune system attacks the central nervous system (CNS). Despite decades of research, its exact cause remains elusive. Scientists know that both genetic risk and environmental triggers (like viral infections, vitamin D deficiency, and smoking) contribute — but how these forces interact inside the immune system has been hard to pin down.

The Perfect Experiment: Identical Twins
To untangle genes from environment, the researchers studied 61 pairs of monozygotic (identical) twins where one twin had MS and the other did not. This “natural experiment” allows scientists to hold genetics and early-life environment constant, highlighting immune changes that arise purely from non-heritable, environmental factors.

Using cutting-edge tools — mass cytometry (CyTOF) and CITE-seq (single-cell RNA + protein sequencing) — the team profiled millions of immune cells from both twins, analyzing not only what types of cells were present but also which genes and surface markers they expressed.

Key Discovery 1: Subtle But Crucial Immune Shifts
Surprisingly, most immune cell types looked similar between affected and unaffected twins — indicating that MS isn’t caused by broad immune disruption. Instead, specific changes stood out in two cell groups:

Myeloid cells (monocytes)

Twins with MS had more inflammatory monocytes expressing the receptors CCR2 and CD116 (GM-CSF receptor).

These cells are known to migrate into the brain and drive inflammation in MS lesions.

Helper T cells (CD4⁺ T cells)

A population of “transitional naive” helper T cells in MS twins showed abnormally high CD25 expression — the alpha chain of the IL-2 receptor, crucial for T cell activation and proliferation.

These findings highlight that even among genetically identical individuals, the immune system can diverge in key regulatory pathways linked to inflammation.

Key Discovery 2: A Misfiring IL-2 Signaling Axis
The overexpression of CD25 suggests a hyper-responsiveness to IL-2, a cytokine that promotes T cell growth. In MS twins, these T cells:

Were overly reactive to IL-2.

Produced more IL-2 and IL-17, cytokines associated with autoimmune inflammation.

Expressed brain-homing receptors (like VLA4 and CXCR4), which help immune cells infiltrate the CNS.

Importantly, the degree of IL-2 overproduction correlated with MS severity, linking this immune misfire directly to disease progression.

Key Discovery 3: Genes Set the Stage, Environment Pulls the Trigger
To determine whether these immune changes were heritable, the researchers compared their MS twin data with healthy identical and fraternal twin pairs.

They found that:

The baseline expression of CD25 in naive helper T cells is largely genetically determined (≈50%), with early environmental factors (like childhood infections) also playing a role.

However, the increase in CD25 seen in MS twins was non-heritable, meaning it arose from later-life environmental triggers.

In other words: Genes may load the gun, but environment pulls the trigger.

Why This Matters
This study reframes how we think about MS and autoimmunity in general. It suggests:

MS may stem from environmentally induced immune dysregulation on a genetically primed background.

A dysregulated IL-2–CD25–GM-CSF pathway could be a central mechanism driving disease.

Future therapies might aim to restore balance in this signaling loop rather than suppress the entire immune system.

The Bigger Picture
The twin model provides a uniquely powerful lens for studying autoimmune diseases — stripping away genetic noise to expose the impact of environment, infection, and epigenetics. By showing that immune dysfunction in MS can arise without genetic differences, this study underscores the potential for reversing or preventing disease through modifiable factors and targeted immune interventions.

Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.

References:
Barro C., Healy B.C., Liu Y., Saxena S., Paul A., Polgar-Turcsanyi M., et al. Serum GFAP and NfL Levels Differentiate Subsequent Progression and Disease Activity in Patients with Progressive Multiple Sclerosis. Neurol Neuroimmunol Neuroinflamm. 2023;10:e200052. doi:10.1212/NXI.0000000000200052