Scientists in South Korea have identified a switch that controls the expansion of a subset of immune cells involved in the development of systemic lupus erythematosus (SLE). Their findings are published in the journal Immunity.
SLE is a chronic disease where the immune system produces antibodies that erroneously attack multiple healthy organs and tissues, such as skin, kidneys, joints and blood vessels. Genetic factors strongly influence SLE development.
Currently, no cure is available for SLE. Steroid-based anti-inflammatory drugs are the main therapy choice, and although they alleviate acute symptoms, they are also accompanied by severe side effects. Other studies have focused on blocking the activation of B-cells that produce autoantibodies, but clinical trials have mostly failed to produce a sustained positive outcome for patients, emphasizing the need for alternative strategies.
In this study, a research team at the Institute for Basic Science (IBS) and Pohang University of Science and Technology (POSTECH) in South Korea investigated the Ets1 gene, one of the top four genes associated with SLE in Asian populations. The Ets1 gene is highly expressed in many subtypes of immune cells and is responsible for regulating the expression of other genes.
“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,” said Professor Im Sin-Hyeog of IBS, the corresponding author of this study.
The research team first deleted the Ets1 gene in major types of immune cells in mice, discovering that the removal of Ets1 in a specific subset of immune cells—CD4+ T-cells—was enough to cause the development of SLE-like autoimmunity. Upon further evaluation, the team found that Ets1 is involved in controlling the expansion of a newly-described class of immune cells, known as T follicular helper type 2 (Tfh2) cells.
Tfh2 cells interact with antibody-producing cells B-cells in lymph nodes and the spleen, causing them to produce autoantibodies that react against ‘friendly forces’—the body’s own cells. The scientists found that Ets1 halts the expression of key Tfh2 genes, thereby blocking the increase in the number of Tfh2 cells in the body.
Thus, when Ets1 is missing or mutated, like in SLE, Tfh2 cells are free to expand, leading to autoantibody production. The researchers observed this phenomenon in both mouse and human SLE cases.
The research team could also mitigate some SLE symptoms by blocking a key component in the autoantibody production pathway known as IL-4. After treating mice with anti-IL-4, the scientists observed a reduction in spleen size and the number of autoantibody-producing 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 expression and expanded Tfh2 populations,” said Im.