Mutations in Ets1 Gene Tied to Autoimmunity and Lupus in Mice via T-cells, Study Reports

Mutations in Ets1 Gene Tied to Autoimmunity and Lupus in Mice via T-cells, Study Reports

Defects in the Ets1 gene in T-cells, immune system cells with known links to inflammation, caused the uncontrolled expansion of some of these cells in mice and induced systemic lupus erythematosus (SLE) autoimmunity in the animals, researchers report.

Blocking a cytokine known as interleukin (IL)-4 suppressed this cellular expansion and eased disease symptoms. (Cytokines are small proteins important in cell signaling.)

Their study “The Transcription Factor Ets1 Suppresses T Follicular Helper Type 2 Cell Differentiation to Halt the Onset of Systemic Lupus Erythematosus” was published in Immunity.

SLE, the most prevalent form of lupus, is a chronic autoimmune disease characterized by symptoms, depending on its severity, that can include tissue inflammation, skin rash, pain, fatigue, depression, and impaired cognition.

Previous studies have shown that SLE is highly influenced by genetic factors, and more than 60 genes are linked to the condition. None have yet been fully characterized.

Researchers at the Academy of Immunology and Microbiology in South Korea investigated the role of the Ets1 gene — a transcription factor that regulates the body’s immune response, and one of the four genes most often linked linked to SLE in Asian populations.

“A vast number of SLE patients have mutations in Ets1, but the reason why a faulty Ets1 is connected with autoimmunity was unknown. We wanted to solve this mystery,” the research team’s leader, Sin-Hyeog Im, said in a press release.

Through manipulation, they removed the Ets1 gene from different types of immune cells in a mouse model of lupus. The researchers found that removing Ets1 from T-cells — but not B-cells or dendritic cells — was sufficient to induce SLE autoimmunity.

This process was also associated with the expansion of another type of immune cell, called T follicular helper type 2 cells, or Tfh2 cells – a type of T-cell that control other types of immune cells.

In the absence of Ets1, Tfh2 cells produced high amounts of GATA-3 and IL-4, promoting the production and release by B-cells of auto-antibodies — those targeting a patient’s own tissues and cells. Interestingly, researchers observed the same interplay between Tfh2 cell expansion and auto-antibody production by B-cells in immune cells from SLE patients.

Based on these observations, the scientists believe that Ets1 works as an autoimmunity gatekeeper gene that is able to restrict the production of key Tfh2 genes, thereby preventing their expansion and the production of harmful auto-antibodies associated with SLE.

When researchers treated mice with an antibody that blocked the activity of IL-4, a key molecule driving the production of auto-antibodies, they observed a significant reduction in the animal’s spleen size and in the number of auto-antibody producing B-cells.

“SLE is a heterogeneous disease, making it difficult to tackle from a clinician’s perspective. Nevertheless, our data strongly suggests the use of IL-4 blocking therapy for patients with low Ets1 expressions and expanded Tfh2 populations,” Im commented.

“IL-4 is a promising target for specific inhibition of Tfh2 cells. However, to use IL-4 as a target for immunotherapy, further studies will be needed to determine whether IL-4 acts on B-cells, T-cells, or both,” the researchers added.

Joana is currently completing her PhD in Biomedicine and Clinical Research at Universidade de Lisboa. She also holds a BSc in Biology and an MSc in Evolutionary and Developmental Biology from Universidade de Lisboa. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that make up the lining of blood vessels — found in the umbilical cord of newborns.
×
Joana is currently completing her PhD in Biomedicine and Clinical Research at Universidade de Lisboa. She also holds a BSc in Biology and an MSc in Evolutionary and Developmental Biology from Universidade de Lisboa. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that make up the lining of blood vessels — found in the umbilical cord of newborns.
Latest Posts
  • autoantibodies
  • Alpha project, lupus
  • Biomarkers
  • Gazyva

Leave a Comment

Your email address will not be published. Required fields are marked *