Characterizing the T-cell receptor repertroire in FSHD

Investigator: Matthew Cowley PhD

Category: Research - Basic

People with FSHD differ widely in how fast their disease progresses and which muscles it affects, even within the same family. Many FSHD muscles go through a phase of inflammation, visible on MRI, before they start to break down faster and are replaced by fat. Immune cells called T cells are among the cells that move into these inflamed muscles. What they are doing there, and why the response differs so much from person to person, is not known.

Each T cell carries a receptor that recognizes a specific target. Every person’s set of T-cell receptors, called their repertoire, is shaped partly by chance and partly by what their immune system has encountered, so even identical twins have different repertoires. That makes the T-cell repertoire a possible source of the variation seen in FSHD. Some people may have T cells that react to abnormal proteins made by FSHD muscle. Others may differ in their regulatory T cells, which help muscle repair itself.

The lab has adapted its receptor-sequencing method to work on muscle biopsies, and has completed a pilot in four people with FSHD and three healthy volunteers. Inflamed FSHD muscle held more distinct T cells than healthy muscle. A small number of those T cells had multiplied far beyond the rest, which is what happens when the immune system responds to a specific target. These T cells also differed from the ones circulating in the same person’s blood, which suggests the response is specific to the muscle. Because the pilot was small, these findings are preliminary.

This grant will fund sequencing of stored samples from 22 people with FSHD and one more healthy volunteer, all donated through Radboud University Medical Center in the Netherlands. For most of the participants with FSHD, the samples include inflamed muscle, non-inflamed muscle and blood. With the larger group, the team can test the pilot findings statistically, compare inflamed with non-inflamed muscle, and look for similar receptors in different people. If FSHD muscle consistently draws in an expanded, muscle-specific group of T cells, those cells could become a new target for FSHD therapies.