Published on
Autoimmune diseases form a vast family of at least 80 pathologies including type 1 diabetes, rheumatoid arthritis, psoriasis, Crohn's disease... In total, nearly 5 million French people are affected by these diseases. What they have in common is a deregulation of the immune system which then attacks its own body. A multitude of causes, including genetic factors, can lead to this deregulation of the immune system, which explains the diversity of symptoms observed.
When the immune system attacks the self...
The immune system is regulated by many checkpoints. If one of these checkpoints fails, it can cause the body to lose immunological tolerance to its own constituents and result in autoimmunity. "More often than not, several genetic factors are involved in autoimmune diseases, which makes the development of a curative treatment complicated," says Frédéric Rieux-Laucat, Inserm research director and head of the Immunogenetics of Pediatric Autoimmune Diseases team at the Imagine Institute. However, single-gene causes leading to a breakdown in immune tolerance and autoimmunity have been identified, facilitating the development of targeted treatments to stop their effect.
And this is what Frédéric Rieux-Laucat and Alexandre Belot from the Centre International de Recherche en Infectiologie (Inserm, Claude Bernard University) and the Hospices Civils de Lyon have just highlighted: They describe in a publication in the journal Nature Communications the first SOCS1 gene deficiency in ten patients from five unrelated families with a variety of early-onset autoimmune diseases. Five patients had autoimmune cytopenia - quantitative deficiency of certain types of blood cells -, four others had organ-specific autoimmunity - thyroiditis, celiac disease, psoriasis, spondyloarthritis and hepatitis -, and two patients had systemic lupus erythematosus with skin and kidney involvement.
Blocking the JAK/STAT pathway
The SOCS1 protein regulates the response to cytokines, proteins produced by immune cells to control the immune system's response to an attack. "The SOCS1 protein acts on cytokines by repressing the JAK/STAT signaling pathway, which is essential for the activation of the immune response," describes Frédéric Rieux-Laucat. Due to a genetic mutation, SOCS1 is less active and can no longer fulfill its role as an inhibitor of the JAK/STAT pathway. This results in hyper-sensitivity of immune system cells in response to certain cytokines (IL2, Interferon gamma, IL4). In this context of genetic deficiency, the immune system's response to an infectious agent can lead to a runaway response and the development of autoimmunity.
JAK inhibitors are already used to treat rheumatoid arthritis, for example. "In the short term, this discovery could lead to targeted therapy with JAK inhibitors. One SOCS1-deficient patient is currently being treated," concludes the researcher. In the longer term, it also opens up possibilities for patients who develop post-infectious autoimmunity as a result of hyper-sensitivity to these cytokines.
