Interferon subverts an AHR–JUN axis to promote CXCL13+ T cells in lupus, 2024, Law et al.

Interferon subverts an AHR–JUN axis to promote CXCL13+ T cells in lupus
Law, Calvin; Wacleche, Vanessa Sue; Cao, Ye; Pillai, Arundhati; Sowerby, John; Hancock, Brandon; Horisberger, Alice; Bracero, Sabrina; Skidanova, Viktoriya; Li, Zhihan; Adejoorin, Ifeoluwakiisi; Dillon, Eilish; Benque, Isaac J.; Nunez, Diana Pena; Simmons, Daimon P.; Keegan, Joshua; Chen, Lin; Baker, Tina; Brohawn, Phillip Z.; Al-Mossawi, Hussein; Hao, Ling-Yang; Jones, Brian; Rao, Navin; Qu, Yujie; Alves, Stephen E.; Jonsson, A. Helena; Shaw, Katharina S.; Vleugels, Ruth Ann; Massarotti, Elena; Costenbader, Karen H.; Brenner, Michael B.; Lederer, James A.; Hultquist, Judd F.; Choi, Jaehyuk; Rao, Deepak A.

Systemic lupus erythematosus (SLE) is prototypical autoimmune disease driven by pathological T cell–B cell interactions. Expansion of T follicular helper (TFH) and T peripheral helper (TPH) cells, two T cell populations that provide help to B cells, is a prominent feature of SLE. Human TFH and TPH cells characteristically produce high levels of the B cell chemoattractant CXCL13 (refs. 5,6), yet regulation of T cell CXCL13 production and the relationship between CXCL13+ T cells and other T cell states remains unclear. Here, we identify an imbalance in CD4+ T cell phenotypes in patients with SLE, with expansion of PD-1+/ICOS+ CXCL13+ T cells and reduction of CD96hi IL-22+ T cells.

Using CRISPR screens, we identify the aryl hydrocarbon receptor (AHR) as a potent negative regulator of CXCL13 production by human CD4+ T cells. Transcriptomic, epigenetic and functional studies demonstrate that AHR coordinates with AP-1 family member JUN to prevent CXCL13+ TPH/TFH cell differentiation and promote an IL-22+ phenotype.

Type I interferon, a pathogenic driver of SLE, opposes AHR and JUN to promote T cell production of CXCL13. These results place CXCL13+ TPH/TFH cells on a polarization axis opposite from T helper 22 (TH22) cells and reveal AHR, JUN and interferon as key regulators of these divergent T cell states.

Link | PDF (Nature)

 

Northwestern Medicine: Scientists Discover a Cause of Lupus and a Possible Way to Reverse It

 

So this is opposite to what Lutter found? Lutter arguing for AHR antagonism whereas Lupus needs an AHR agonist? Interesting?

https://www.s4me.info/threads/prolo...of-sars-cov-2-infection-2023-guo-et-al.34402/

 

Another article here from Stat.

https://www.statnews.com/2024/07/10/lupus-research-molecular-switch-possible-new-treatments/

 

Subtitle : Researchers have identified a fundamental imbalance in the immune responses to lupus and defined specific mediators to correct it.

Link : https://www.thebrighterside.news/po...a-cure-helping-1-5-million-people-in-the-u-s/

Publication date : 11th July 2024

Article continues at LINK

 

I don’t have access to the paper but the story they are telling seems to be: Interferons cause a deficiency in AHR Receptor Ligands. Without as much AHR Receptor Ligands you then get more bad T cells that call for more bad B cells. Once they reintroduced the AHR-activating molecules to blood samples from lupus patients the blood starts to look normal. That is the blood starts to look normal, no experiments in patients were conducted. So I naturally wonder wouldn’t the interferons just start causing a deficiency again and what happens under continuous reintroduction of these AHR-activating molecules? They seem to argue that there is some form of ratio that has to be met and since they do that, all of the sudden one even gets more B-cells that heal the wounds and repair previous wrong doings. Without any knowledge on the subject, that seems a bit fairy-tale like, which does make me a bit sceptical.

Apparently a drug called Anifrolumab already exists which can restore this balance by blocking interferon. However, since this drug is already in use to treat Lupus, and doesn’t provide a cure, is any of this really new? I’m guessing other drugs that also block interferons exist and haven’t been the cure yet?

Moreover if you do all of this just to bring down the number of B-cells and this should provide a cure, then wouldn’t the existing B-cell targeting drugs also provide a cure or possibly even CAR-T cell therapies? If it has to do with getting things into the right tissue or something like CNS penetration, is their approach better?

I wonder why they were the first to discover this deficiency in AHR Receptor Ligands. Were they? Should genetic studies not have found such a signal? What about the recent study claiming Lupus can be tracked to a single gene change, are the findings related?