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Novel Drug Targets and Early Biomarkers of Psoriatic Diseases

Husni Lab focuses on transforming management and treatment

Researchers standing in laboratory

By M. Elaine Husni, MD, MPH; Unnikrishnan M Chandrasekharan, PhD; Vincent Del Signore, BS; and Shashank Cheemalavagu, MD

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In the Husni Laboratory, our translational research encompasses two primary objectives: identification of safer drug targets for individuals afflicted with psoriatic disease, and the discovery of precise biomarkers capable of forecasting treatment outcomes and the onset of disease comorbidities.

The Husni Lab has been focused on the mission to transform psoriatic disease management and treatment.

TNFR2 in Psoriatic Disease

Our research aims to elucidate the distinct roles of two tumor necrosis factor alpha (TNF-α) receptors in the pathogenesis of psoriatic disease. Utilizing murine models treated with imiquimod (IMQ), we have identified the crucial role of TNF-α receptor-2 (TNFR2), as opposed to TNFR1, in orchestrating the pathogenesis of psoriatic disease. Our investigations have revealed that TNFR2-dependent activation of dendritic cells (DCs) serves as a pivotal driving force in the manifestation of psoriasis (PsO). Dendritic cells, which are upregulated in psoriatic disease, play a central role in the polarization and activation of naïve T cells into psoriatic disease-promoting effector Th1 and Th17 cells. 1,2

Our murine models have demonstrated an increase in various DC subtypes during PsO, with this surge significantly inhibited in TNFR2 knockout mice (Figure 1). In addition, recent findings indicate that genetic depletion of TNFR2 in DC alone can curtail psoriatic arthritis (PsA)-like disease in mice. We are currently pursuing studies using preclinical models and human PBMC-derived DC to understand mechanisms that underlie the TNFR2-dependent regulation of DC subtype expansion during psoriatic disease. Our findings underscore TNFR2 as a promising new target for combating psoriatic diseases. By selectively targeting TNFR2 while preserving TNFR1 function, we anticipate reduced adverse effects compared to conventional anti-TNF therapies, which often affect TNFR-1-dependent host-defense mechanisms.

PsO to PsA transition

In approximately 30% of cases, PsO can progress into PsA3,4. Unfortunately, reliable biomarkers for predicting this transition are lacking. The temporal gap between the onset of PsO and PsA presents an opportunity to identify biomarkers that can predict which PsO patients are prone to developing PsA.

To this end, we employed single-cell RNA sequencing (scRNAseq) technology on PBMCs obtained from treatment-naïve patients categorized into three groups, based on clinical assessments. We divide our clinical cohorts into low risk, high risk and established PsA.

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Our unbiased scRNA-seq transcriptomic analysis enabled the stratification of specific immune cell subtypes in PBMCs (Figure 2A), leading to the identification of certain immune cell types that are enrichedwith marked differences in gene expression across the three groups (Figure 2B). Ongoing immunophenotyping on patients’ PBMCs and skin samples aims to validate our findings. We believe that the insights gleaned from this study have the potential to facilitate the development of bioassays capable of predicting psoriatic arthritis years before clinical detection.

This research has been made possible by funding from NIH RO1, the Arthritis Foundation and the National Psoriasis Foundation.

Notes

1. Kamata, M. & Tada, Y. Dendritic Cells and Macrophages in the Pathogenesis of Psoriasis. Front Immunol 13, 941071, doi:10.3389/fimmu.2022.941071 (2022); PMCPMC9274091.

2. Wang, A. & Bai, Y. Dendritic cells: The driver of psoriasis. J Dermatol 47, 104-113, doi:10.1111/1346-8138.15184 (2020).

3. Rech, J., Sticherling, M., Stoessel, D., Biermann, M. H. C., Haberle, B. M. & Reinhardt, M. Psoriatic arthritis epidemiology, comorbid disease profiles and risk factors: results from a claims database analysis. Rheumatol Adv Pract 4, rkaa033, doi:10.1093/rap/rkaa033 (2020); PMCPMC7585407.

4. Zachariae, H. Prevalence of joint disease in patients with psoriasis: implications for therapy. Am J Clin Dermatol 4, 441-447, doi:10.2165/00128071-200304070-00001 (2003).

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