Research Programe: “Adaptive immunomics”

In many autoimmune diseases, but also in immunity against infections and cancer cells, adaptive immune responses play a key role. Adequate monitoring of these responses and selective targeting offers hope of personalized, more selective and effective therapies with less side effects, and potentially cure. 

The adaptive responses mentioned above are driven by specific immune cells, T- and B-lymphocytes.  These cells are unique in that each individual lymphocyte has its own unique specificity, encoded within the antigen receptor, which is shared only with cells from the same clone. Dr de Vries and his team developed a novel tools that quantitatively fingerprint millions of individual lymphocyte receptors in blood or tissues, both in vitro and in vivo. This can be used to show which lymphocytes get activated and proliferate to form clones that dominate a given immune response. By comparing clonal expansion across tissues and across timelines, and combining these observations with results from in vitro assays, we are identifying and characterizing those clones that play a key role in health and specific disease states, with a focus on autoimmune disease. Detailed analysis of these clones helps to develop novel diagnostics, predictors and therapeutic targets.

Using this technology we developed:

1. a validated novel diagnostic marker for IgG4-related disease, which may prevent misdiagnosis of this relatively benign disease as cancer and lead to unnecessary surgery

• Doorenspleet ME, Hubers LM, Culver EL, Maillette de Buy Wenniger LJ, Klarenbeek PL, Chapman RW, Baas F, van de Graaf SFJ, Verheij J, van Gulik TM, Barnes E, Beuers U, and N. de Vries. Immunoglobulin G4+ B-Cell Receptor Clones Distinguish Immunoglobulin G4-Related Disease From Primary Sclerosing Cholangitis and Biliary/ Pancreatic Malignancies. Hepatology 2016; 64(2):501-7.These results were validated in independent cohorts

2. a validated novel predictive marker that identifies a subgroup of individuals with autoantibody-positive arthralgia in which 91% of the individuals developed arthritis within 3 years. This patented technology might be used to prevent onset of arthritis in these individuals and reassure other patients who are not at imminent risk.

• Tak PP, Doorenspleet ME, de Hair MJH, Klarenbeek PL, van Beers-Tas MH, van Kampen AHC, van Schaardenburg D, Gerlag DM, Baas F, de Vries N. Dominant B cell receptor clones in peripheral blood predict onset of arthritis in individuals at risk for rheumatoid arthritis. Ann Rheum Dis. 2017; 76(11):1924-30. doi: 10.1136/annrheumdis-2017-211351.

3. a novel diagnostic marker that identifies patients with active vasculitis

• Al-Soudi A, M Doorenspleet, R. Esveldt, S. Tas, R, van Vollenhoven, P. Klarenbeek, N. De Vries. The IgG4:IgG RNA ratio is a new and promising disease activity marker in granulomatosis with polyangiitis. [abstract FRI0303]. EULAR June 16th 2017, Madrid, Spain. DOI: 10.1136/annrheumdis-2017-eular.5088.

Prospects

1. We are currently  expanding our analysis to other autoimmune diseases and happy to collaborate. Examples are rheumatoid arthritis, vasculitis, myositis, chronic inflammatory demyelinating polyneuropathy, Crohn's disease and IgG4-related disease. We also use our technologies to study related immune responses, e.g. anti-drug responses, or to get more insight into the development of immune responses in general. Many of these studies are performed in collaboration with local, national and international partners.

2. Also in collaboration with our partners we are characterizing the clones identified using single cell technologies. The ultimate goal is to develop tools that selectively downregulate disease-associated immune responses in autoimmune disease, thus providing the opportunity to intensify treatment of these diseases without the potential side-effects of standard immunosuppressive therapy, like infection or the slightly increased rates of tumor development. We think this approach will help to develop curative therapy in these diseases. 

3. In collaboration with partners we are aiming to implement our markers in health care in order to prevent autoimmune diseases, diagnose early and improve treatment results in our patients.