International Psoriasis Council

Advancing Knowledge. Enhancing Care.

Advancing Knowledge. Enhancing Care.

In the Lab with IPC Councilor Nicole Ward

Dr. Ward is a Professor of Dermatology and Neurosciences at Case Western Reserve University and University Hospitals Case Medical Center in Cleveland, Ohio. She has spent the past 16 years developing mouse models to help identify the cellular and molecular mechanisms underlying inflammatory skin disease and its associated comorbidities, including atherothrombosis, psoriatic arthritis, inflammatory bowel disease, and depression. She employs a systems biology approach using CyTOF, multi-color FACS, RNASeq, and ScSeq to better understand how chronic skin-contained inflammation has the capacity to drive distant organ injury.

TELL US WHAT YOU ARE CURRENTLY INVESTIGATING

Dr. Ward: “Our lab is studying how chronic skin inflammation can initiate arthritis in distant joints and tendons using the Klk6+ mouse. Kallikrein-related peptidase 6 (KLK6) is a member of a family of serine proteases that are emerging as prevalent biomarkers of inflammatory disease. The Klk6+ mouse model spontaneously develops psoriasis-like skin inflammation and, importantly, PsA-like symptoms, including joint and tendon inflammation and changes to the bones. We know that suppressing KLK6 gene expression eliminates the skin inflammation and improves the arthritis-like changes. We are now trying to identify the cellular and molecular mechanisms underlying how skin-initiated inflammation causes the damage we observe in the tendons, joints and bones.”

ANY THEORIES YET?

Dr. Ward: “We think that an atypical cell in terms of psoriasis pathogenesis may be involved, possibly a B cell or plasma B cell.”

WHAT’S YOUR NEXT STEP?

Dr. Ward: “We are collaborating with clinician scientists to make sure our findings in the mouse model will translate to psoriasis patients. We feel this is a critical step in everything we study. When we observe something that looks potentially interesting in a mouse model, we always return to psoriasis patients and look at their skin, or circulating blood, or synovial tissues to confirm that what we have observed in the mouse model is also present in psoriasis patients. Our work is all about modeling human disease. We don’t just want a mechanism of action (MOA) in a mouse model. We want to make sure the MOA in the mouse is recapitulated in the psoriasis patient population.”

WHAT HAS YOUR PAST RESEARCH IN THE AREA OF PSORIASIS COMORBIDITIES REVEALED?

Dr. Ward: “We have done a lot of work looking at how chronic skin-initiated inflammation observed in our psoriasis models promoted atherothrombosis. We had hypothesized that the chronic skin inflammation seen in our psoriasis models modulated circulating proinflammatory monocytes that contributed to shortened clotting times we were observing in an experimental thrombosis assay. We spent seven years trying to demonstrate that these proinflammatory monocytes were critical in driving the prothrombosis. They aren’t. Instead, we determined that chronic skin inflammation elevated circulating neutrophils and platelets, and that these correlated best with the thrombosis. In addition, we found that anti IL-23 and IL-17 biologics decreased platelets and neutrophils and improved the prothrombosis. Our goal now is to validate these observations in psoriasis patients and identify how neutrophils and platelets interact to promote thrombosis preclinically in our animal models and clinically in psoriasis patients.”

WHY IS THIS LINE OF INVESTIGATION IMPORTANT?

Dr. Ward: “We are interested in using our preclinical mouse models of psoriatic disease to identify novel pathways, and mechanisms of psoriasis-related comorbidities. We have three mouse models of psoriasis in the lab currently – the KC-Tie2, Klk6+ and Il17c+ models. All develop cardiovascular comorbidities, one develops arthritis and two develop inflammatory bowel-like disease. Currently we are generating sequence libraries of skin, blood, skin draining lymph nodes, and stool and are using bioinformatic and systems biology approaches to identify similarities and differences across the different phenotypes that we hope will provide insight into the unique mechanisms of the co-morbidity. We then align our findings with those observed in psoriasis patient cohorts with similar comorbidities. The ultimate goal is to translate our preclinical findings to patients and potentially identify novel biomarkers of disease so that we can identify and/or predict which patient is at highest risk for developing which comorbidity. This would then impact how the patient is treated. This type of personalized medicine is the future of psoriasis.”

WHAT QUESTIONS REMAIN?

Dr. Ward: “Biologics are so effective, and we know so much about the pathways of disease in large part because of the efficacy of biologics. Questions remain, including what biologic will work best in which individual? Can we identify biomarkers for disease treatment responsiveness? Can we generate diagnostic tools or biomarkers to identify comorbidities before their onset? If we could identify in advance which psoriasis patients will develop arthritis, or who is at high risk of stroke or heart attack, or who will develop concomitant inflammatory bowel disease, then treatment of each person’s disease would become personalized.  As a basic scientist, my interest is in helping to address these gaps in the field and to contribute to a better understanding of the pathophysiology behind psoriasis comorbidities and potentially personalized medicine. It’s my hope that the work we do in the lab helps psoriasis patients feel better and live longer, healthier, happier lives.”
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