Multiple Sclerosis-Like Mouse Model Gains Greater Validation

Mouse models are incredibly valuable to scientists studying human diseases like the neurodegenerative autoimmune condition multiple sclerosis (MS).

There’s only one problem: Mice don’t develop MS. Instead, researchers mimic the symptoms of the condition, in which the immune system attacks the myelin sheath, which normally coats nerve cells and allows brain signals to travel at speed. Researchers induce a similar disease process in mice called experimental autoimmune encephalomyelitis (EAE). This lab-made condition is far from a perfect model of MS, but it has helped researchers better understand the disease.

Researchers have now clarified how immune cells drive EAE in a new paper published in Science Immunology. ¹ They showed that EAE, like MS, involves T helper 17 (T_h17) cells and that B cells play an important role in kickstarting EAE. These findings dispel doubts held by some scientists on whether the EAE disease processes were actually relevant to MS and provide new insight into the condition.

What Causes EAE?

Scientists induce EAE in mice by exposing them to bacterial components that drive the immune system to attack myelin. The disease begins in the gut and then spreads to the brain. But researchers studying EAE have cast doubt on whether T_h17 cells drive the autoimmune attack. This skepticism was based on studies of mice genetically modified to lack IL-17F, a key cytokine released by T_h17 cells.² Researchers at the University of Zurich had exposed these mice to antibodies that blocked a related immune molecule also released by T_h17 cells, IL-17A. In the absence of these key T_h17 molecules, mice still developed EAE.

These scientists suggested that a poorly understood group of T cells that produce the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) were the true instigators of EAE. If confirmed, these findings would have turned the field’s understanding of the lab-made condition on its head and called into question its relevance to MS, in which T_h17 are widely understood to drive disease.

But in this new study, immunologist Vijay Kuchroo and his team at Brigham and Women's Hospital, reported that T_h17 cells do in fact play an important role in EAE.

Modified Mice

The team studied mice genetically modified to lack both IL-17A and IL-17F. They transferred T_h17 cells that target myelin into these mice as well as control mice lacking these mutations. Adding these cytokines induced EAE in both groups. But T_h17 cells that couldn’t produce these chemical signals couldn’t cause disease in the mutant mice.

To work out why, the team used RNA sequencing to study what made T_h17 cells lacking IL-17A and IL-17F different. They saw that without these chemicals, signaling pathways kick-started by another chemical, IL-23, failed to fire. This prevented T_h17 cells from turning into a disease-linked form that can move from the gut into the central nervous system.

However, these altered T_h17 cells could still cause disease if B cells were present. The researchers hypothesize that B cells may release IL-17A and IL-17F to activate disease-linked signaling in T_h17 cells. It is still not clear which gut cell population is producing the chemicals that activate EAE. Still, the study answers some key questions about this important model condition.