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ETS2 / Functional Genomics
A new master switch on chromosome 21 that turns immune cells inflammatory across AS, IBD, and other related conditions.
Why this is a thread
For decades, AS research has been a story about HLA-B27, a single gene that explains some of the risk but nowhere near all of it. ETS2 changes the picture. It's a different gene, on chromosome 21, and it acts like a master switch that decides whether immune cells called macrophages turn inflammatory. The same switch keeps showing up in IBD, primary sclerosing cholangitis, and a rare blood vessel condition called Takayasu's arteritis. No drug currently targets ETS2, which is what makes this thread interesting. It points to a treatment direction the existing AS toolkit doesn't already cover.
5 papers on the board
EXTL3 dysfunction identified as a driver of aberrant bone development in severe familial ankylosing spondylitis.
Annals of the rheumatic diseases
In a family with unusually severe ankylosing spondylitis, a rare change in a gene called EXTL3 was found, and mice carrying it developed early joint bridging and abnormal bone through a pathway involving heparan sulfate and Wnt signalling. It identifies a bone-formation mechanism separate from inflammation, which may explain why some people fuse despite well-controlled disease.
An Increased Circular RNA, circRNPS1, in T Cells of Ankylosing Spondylitis Patients Enhances the MEK/ERK Signaling and Inflammation Mediated by T Cell Activation via Stabilization of hnRNPK and VAV1.
International journal of molecular sciences
T cells from people with ankylosing spondylitis carry raised levels of a circular RNA called circRNPS1, which stabilises two proteins that push the cells to make IL-17 and other inflammatory signals; blocking it in the lab calmed those cells down. It is one explanation for why HLA-B27 alone does not cause AS, and a possible new drug target that works inside the T cell rather than on the cytokines it releases.
The role of ETS2 in macrophage inflammation
DNA and Cell Biology
Direct follow-up to the 2024 Nature paper. Shows that ETS2 turns on several inflammatory signals at once, TNF, IL-23, IL-1β, and TL1A, the same signals current biologic drugs target one at a time.
Macrophages: subtypes, distribution, polarization, immunomodulatory functions, and therapeutics
MedComm
Comprehensive review of macrophage subtypes, distribution, polarisation states, and therapeutic targeting. NF-κB and p38 MAPK pathway hijacking drives the maladaptive M1 shift, with links to DNA damage and senescence-associated secretory phenotype accumulation.
A disease-associated gene desert directs macrophage inflammation through ETS2
Nature
Identified a single 'switch' gene called ETS2, sitting on chromosome 21, that turns immune cells inflammatory across AS, IBD, and several other related diseases. Because no current drug targets ETS2, this points to a treatment direction beyond what's already available with TNF and IL-17 blockers.