Excited to share our study in @SciImmunology dissecting the immune landscape of psoriatic arthritis (PsA)—with a new finding: immunoproteasome overactivity drives treatment resistance🧵 .Led by Reut Tzemach,Chamutal Gur,@TgSanPhan,Eyal David & team. (1/11).

At the Weizmann Institute, Zelig was not only a groundbreaking scientist but also a generous mentor, a sharp thinker, and a beloved colleague. His passion, curiosity, and kindness touched everyone who had the privilege to work with him. He will be deeply missed.

Zelig’s research on engineered T cells laid the foundation for CAR-T therapy and led to the creation of Kite Pharma, a global leader in CAR-T therapy. His impact on science and biopharma will be felt for generations. His legacy inspires us to develop life-saving immunotherapies.

We mourn the loss of our beloved department member, Prof. Zelig Eshhar — a visionary immunologist and pioneer of CAR-T cell therapy. His groundbreaking work revolutionized cancer treatment and gave hope to countless patients.

RT @TheColonnaLab: Our new study by @DuSiling reveals how CSF1R mutations in adult-onset leukoencephalopathy with axonal spheroids and pigm….

Many have asked what is our secret recipe for recovery. In reality there is only one way- you start as fast as you can and slowly accelerate

We are coming out of our cocoon -

Thank you everyone for the amazing support, we will definitely need your help down the road. We will rebuild everything that is broken - because we are not done.

RT @RTNconference: Have you registered yet for #ReThinkNeuroimmunology in October? .Organizers, @QuintanaLabHMS @Stevens1Lab @JonyKipnis @I….

RT @neuroimmune_usp: Hey #Neuroimmunology enthusiasts: DO NOT MISS THIS ! Fantastic event #ReThinkNeuroimmunology organized by simply the b….

RT @SciImmunology: A new Science #Immunology study provides insight into how elevated gene expression related to immunoproteasome and MHC I….

Excited about the potential of this proposal to improve colon cancer immunotherapy!.

Thanks to our collaborators @YMerbl, clinical partners-Prof. @OriElkayam & the rheumatology team at @tasmc1, and the @SciImmunology editorial team. @WeizmannScience. (11/11).

📍Takeaways:.🧬 Refractory PsA is marked by a distinct immunoproteasome-MHC-I signature. 🛑 Targeting this axis with selective inhibitors could dampen inflammation where biologics fail. 🧪 A step towards precision immunotherapy in PsA. (10/11).

A possible mechanism behind PsA treatment resistance: .🔁 IFN-γ → immunoproteasome → MHC-I → CD8+ T cell activation → more IFN-γ.A self-sustaining inflammatory loop, especially in cDC2. Further investigation is needed as PsA autoantigen remains elusive. (9/11)

Next, we treated synovial cells from refractory PsA patients ex vivo with ONX-0914. Notably, monocytes & macrophages with IFN-γ expression dropped significantly✅. In contrast, responder-derived cells were largely unaffected. Indicating a selective effect. (8/11)

To test this, we used an immunoproteasome/LMP7-selective inhibitor ONX-0914 in a mouse model of psoriasis. Treatment reduced psoriatic skin inflammation and silenced the inflammatory signature in monocyte-derived cells. (7/11)

Why does this matter?.The immunoproteasome is a specialized complex that degrades proteins into peptides for MHC-I presentation. But its hyperactivity may also fuel chronic inflammation. (6/11).

Stratifying PsA patients by treatment response, we found a distinct resistance signature in cDC2s, MØ & Mo at RNA/protein levels:. 🔹Immunoproteasome genes (e.g., PSMB8/9). 🔹MHC-I pathway genes (e.g., TAP1, TAPBP).→ Suggesting increased antigen processing & presentation. (5/11)

Compared to OA, PsA synovial fluid exhibited an expansion of diverse T and myeloid cells, with striking IFN-induced inflammatory signature in type 2 conventional dendritic cells (cDC2s), monocyte (Mo) and macrophages (MØ). (4/11)

We used single-cell RNA-seq to analyze synovial fluid from 41 PsA patients and 9 osteoarthritis (OA) controls. This gave us a high-resolution immune map of active joint inflammation. (3/11)