Background/Purpose: Interleukin 12 (IL-12) and 23 (IL-23) may play a pivotal role in the pathogenesis of inflammatory diseases, including Spondyloarthritis (SpA). In mice, the deubiquitinase Trabid, encoded by Zranb1, participates to the epigenetic regulation of IL-12 and IL-23 genes via the stabilization of the histone demethylase JMJD2D. TRABID also regulates the methyltransferase EZH2, involved in the epigenetic control of the inflammatory response in human.
This study aims to assess the expression and the functional relevance of TRABID in controlling the inflammation and activation of IL-12/IL-23 axis in SpA.

Methods: TRABID expression was assessed in synovial tissue (ST) (n=10), Peripheral blood (PBMCs) (n=10), Bone Marrow (BM) (n=5) and Gut (n=20) of SpA patients with active disease and matched healthy by immunohistochemistry (IHC) and quantitative PCR.
Gene expression of ZRANB1, JMJD2D, EZH2, IL-23, IL-12a, IL-17a  in ST was further investigated in the Pathobiology of Early Arthritis Cohort (PEAC) in DMARDs naïve RA (n= 91) and SpA (n=14) patients via RNA sequencing.
Ultrasound-guided synovial biopsies of clinically active joints from twenty-five patients (11 males) with active (DAS: mean 4.3; SD 1.1) SpA, were also studied. The degree of synovitis was histologically assessed by hematoxylin and eosin staining. Immunohistochemistry (IHC), followed by semi-quantitative scoring, was also performed to determine the degree of CD20⁺ B cells, CD3⁺ T cell, CD68⁺ macrophage and CD138⁺ plasma cell infiltration.
Accordingly, STs were categorized STs into fibroid, myeloid and lymphoid-myeloid pathotypes and TRABID, IL-23p19 and IL-23R expression were assessed by IHC.

Results: The expression of ZRANB1 was increased in SpA PBMCs and ileal samples (p< 0.001). In particular, the highest expression of ZRANB1 was observed in chronic inflamed gut samples of SpA patients, being its expression directly correlated with IL-23p19 (r=0.49, p< 0.05) and IL-23R (r=0.67, p< 0.001). Within the early arthritis cohort the expression of ZRANB1 in STs was higher in PsA versus Rheumatoid arthritis (RA) (p< 0.05) and expression of the TRABID target EZH2 correlated with the levels of IL12A (r= 0.46; padj < 10-5), IL23A (r= 0.45; padj< 10^-5) and IL-17A (r= 0.23; padj< 0.05). The number of TRABID⁺ cells was significantly increased in SpA ST (p< 0.001), gut (p< 0.001) especially among infiltrating inflammatory mononuclear cells, and BM (p< 0.001). In ST the number of TRABID⁺ cells was particularly increased in the lymphoid and myeloid pathothypes compared to the pauci-immune fibroid (p< 0.01) and correlated with the synovitis score (r= 0.48; p< 0.05), CD68 in the sub-lining (r= 0.69; p< 0.001), CD3 (r= 0.57; p< 0.01), and CD20 (r= 0.64; p< 0.01). Finally, TRABID⁺ cells were enriched in the STs rich in IL-23p19 versus the low expressing IL-23p19 STs (p< 0.05) and correlated with the number of IL-23R expressing cells (r= 0.58; p< 0.05).

Conclusion: ZRANB1/TRABID levels are increased in the synovial tissue, bone marrow and gut of SpA patients and correlated with specific histologic pathothypes, the degree of synovitis and the levels of IL-23 and IL-23R. In conclusion, this study may pave the way for future TRABID therapeutic inhibition in the treatment of SpA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-deubiquitinase-trabid-is-a-potential-therapeutic-target-in-spondyloarthritis/