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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.
3 papers on the board
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.