Researchers have investigated the overlapping origins of certain blood cancers and autoimmune disease.
Some leukaemia patients have an increased chance of developing autoimmune disease. For example, in T cell large granular lymphocytic leukaemia (T-LGL), half of patients have expanded CD8+ T cell clones bearing 'gain-of-function' somatic mutation in the STAT3 gene. 43% of patients harbouring these mutations have the autoimmune disease rheumatoid arthritis.
However, the association between cancer and autoimmune disease remains unexplained. So a research team led by Dr Etienne Masle-Farquhar, from the Garvan Institute of Medical Research in Darlinghurst, Australia, set out to investigate whether these STAT3 mutations cause autoimmune disease, or are simply a by-product of it.
In tests on human and mouse cells with STAT3 mutations, normally associated with leukaemia, they found evidence that the mutations were the driver of the build-up of ‘rogue’ CD8+ T cell clones.
They report: “These results demonstrate that STAT3 gain-of-function mutations cause effector CD8+ T cell accumulation, and that these rogue cells contribute to autoimmune pathology, supporting the hypothesis that somatic mutations in leukaemia-driving genes contribute to autoimmune disease.”
Dr Masle-Farquhar said: “We showed that these rogue killer T cells are driving the autoimmunity. They’re probably one of the cell types most directly contributing to autoimmune disease."
He added: “Our research also narrows down a few pathways that might be helpful in targeting these cells for future treatments.”
Masle-Farquhar E, Jackson KJL, Peters TJ, Al-Eryani G, Singh M, Payne KJ, Rao G, Avery DT, Apps G, Kingham J, Jara CJ, Skvortsova K, Swarbrick A, Ma CS, Suan D, Uzel G, Chua I, Leiding JW, Heiskanen K, Preece K, Kainulainen L, O'Sullivan M, Cooper MA, Seppänen MRJ, Mustjoki S, Brothers S, Vogel TP, Brink R, Tangye SG, Reed JH, Goodnow CC. (2022) “STAT3 gain-of-function mutations connect leukemia with autoimmune disease by pathological dysregulation and accumulation of NKG2Dhi CD8+ T cells.” Immunity, doi: 10.1016/j.immuni.2022.11.001
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