Investigating the role of synovial glycome in the interplay between systemic and joint inflammation.

Normal inflammation is needed for fighting infections, but when this process becomes uncontrolled, it can last for months or even years, leading to severe chronic conditions. Cardiovascular disease, cancer, diabetes, chronic kidney disease, neurodegenerative disorders, and a large group of autoimmune conditions, like Rheumatoid Arthritis (RA) are only a few examples. (RA) is an extended chronic inflammatory disease, causing pain, stiffness, and swelling on the body's joint.

However, RA affects not only the joints, as inflammation also affects some patients in areas as diverse as the eyes, gut, skin, or heart. Why some people suffer from these non-joint pathologies, and some others do not, is unknown. There are many biological mechanisms described in RA, and we still do not fully understand the genetic and environmental factors that contribute to the activation of these disease-leading routes.

As a result, not all the drugs work for all people and clinicians must follow a trial-and-error approach. Furthermore, reliable diagnostic features that can be used to measure disease progression and outcomes have not yet been determined.

Our objective is to investigate how chronic inflammation is consolidated, with a special focus on the mechanisms leading to disease variability and inflammation in multiple organs. Based on our preliminary results, we think that different kinds of inflammation are a consequence of unbalanced expression of glycans, a specific type of molecules found in all cells and organs in the body.

Glycans, or complex sugars, are expressed on all cell surfaces. Due to this privileged location, they are a fundamental part of any process involved in cell communication, including inflammation. We have previously discovered that joint inflammation is increased when glycans are modified by inflammatory mediators.

Building on these results, we have formulated the hypothesis that specific changes in glycan composition can induce different inflammatory routes, which in turn, can start disease in other organs. Our goal is to validate this hypothesis in human RA and identify how glycan changes in the joint of patients can induce inflammation in other parts of the body.

We plan to achieve this goal by exploiting the clinical diversity observed in RA. Samples will be obtained from joint replacement surgery, in which we will analyze the glycan composition. Blood samples will be also collected to correlate glycan expression with general inflammation away from the joint.

We will correlate molecular details (glycan structure, inflammatory factors) with clinical parameters (type of inflammation, inflamed organs). Understanding the molecular details of distinct inflammatory glycans will allow us to find predictive markers to apply the right treatment, to the right person, at the right time. We expect to generate new ideas to better understand inflammation, something that can benefit not only people with arthritis, but also many other patients suffering from other chronic inflammatory and autoimmune disorders.

Although glycans have been overlooked in research due to their complexity, recent technological advances, like some of the techniques to be used in our project, have clearly demonstrated that these molecules are at the center of many diseases, sparking the possibility of using them for therapeutic and diagnostic purposes.

The project will be conducted by a multidisciplinary team, including clinicians, biologists, and chemists to explore new ideas involving academic institutions and NHS hospitals and clinics in Glasgow, Birmingham, and London. Together, we aim to find answers to unsolved challenges using an overlooked area of human health, which will reveal new methods to identify effective medical interventions.