foto

Prof. dr. N. de Vries MD PhD

Position
Professor
Main activities
Research, Patient care, Teaching
Specialisation
Rheumatology
Focus of research

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.


 

Key publications
  • 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):1924-1930 [PubMed]
  • Doorenspleet ME, Hubers LM, Culver EL, Maillette de Buy Wenniger LJ, Klarenbeek PL, Chapman RW, Baas F, van de Graaf SF, Verheij J, van Gulik TM, Barnes E, Beuers U, de Vries N, Immunoglobulin G4(+) B-cell receptor clones distinguish immunoglobulin G 4-related disease from primary sclerosing cholangitis and biliary/pancreatic malignancies. HEPATOLOGY 2016;64 (2):501-507 [PubMed]
  • Doorenspleet ME , Klarenbeek PL, de Hair MJH, van Schaik BDC, Esveldt REE, van Kampen AHC, Gerlag DM, Musters A, Baas F, Tak PP, de Vries N, Rheumatoid arthritis synovial tissue harbours dominant B-cell and plasma-cell clones associated with autoreactivity. ANN RHEUM DIS 2014;73 (4):756-762 [PubMed]
  • Maillette de Buy Wenniger LJ, Doorenspleet ME, Klarenbeek PL, Verheij J, Baas F, Elferink RPO, Tak PP, de Vries N, Beuers U, Immunoglobulin G4+ clones identified by next-generation sequencing dominate the B cell receptor repertoire in immunoglobulin G4 associated cholangitis. HEPATOLOGY 2013;57 (6):2390-2398 [PubMed]
  • Klarenbeek PL, de Hair MJH, Doorenspleet ME , van Schaik BDC, Esveldt REE, van de Sande MGH, Cantaert T, Gerlag DM, Baeten D, van Kampen AHC, Baas F, Tak PP, de Vries N, Inflamed target tissue provides a specific niche for highly expanded T-cell clones in early human autoimmune disease. ANN RHEUM DIS 2012;71 (6):1088-1093 [PubMed]
All Publications
Curriculum Vitae

NAME: De Vries Niek, MD, PhD
BIRTH: 3/5/1960
 

EDUCATION/TRAINING

  • Propaedeuse Geneeskunde, Ghent University, Belgium
  • MD, Nijmegen University, The Netherlands
  • PhD, Nijmegen University, The Netherlands
  • Rheumatologist
  • BROK, BKO, Examiner Master Phase Medicine

POSITIONS

  • Staff member UMCU, dept Rheumatology & Clinical Immunology, Utrecht, The Netherlands from 1/2/2000-31-12-2001
  • Staff member AMC, dept Clinical Immunology & Rheumatology, Amsterdam, The Netherlands from 1/1/2002
  • Associate professor AMC, dept Clinical Immunology & Rheumatology, Amsterdam, The Netherlands from 1/2/2003
  • Head outpatient clinic Rheumatology from 2004
  • Program Director Rheumatology from 2011
  • Principle Investigator AMC from 2013
  • Teacher in "Teach the Teacher" Program AMC from 2013
  • Member Redactiecommissie advising regarding implementation of clinical protocols from 2013
  • Advising member research Council READE, Amsterdam from 2016
  • Location head Dept Clinical Immunology & Rheumatology, AMC | Amsterdam UMC from 2018


SELECTED PEER-REVIEWED PUBLICATIONS

  • Musters A, Klarenbeek PL, Doorenspleet ME, Balzaretti G, Esveldt REE, van Schaik BDC, Jongejan A, Tas SW, van Kampen AHC, Baas F, de Vries N. In Rheumatoid Arthritis Synovitis at Different Inflammatory Sites is Dominated by Shared but Patient-specific T-cell Clones. J Immunol 2018 in press
  • 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.
  • Doorenspleet ME, Klarenbeek PL, de Hair MJH, van Schaik BDC, Esveldt REE, van Kampen AHC, Gerlag DM, Baas F, Tak PP, de Vries N. Rheumatoid arthritis synovial tissue harbours highly dominant B-cell and plasma cell clones associated with autoreactivity. Annals Rheum Dis 2014 Apr;73(4):756-62.
  • Maillette de Buy Wenniger LJ, Doorenspleet ME, Klarenbeek PL, Baas F, Oude Elferink RP, Tak PP, de Vries N*, Beuers U*. IgG4+ clones dominate the B-cell receptor repertoire of patients with IgG4-associated cholangitis. Hepatology 2013 Jun;57(6):2390-8.
  • Klarenbeek PL, Remmerswaal EBM, ten Berge IJM, Doorenspleet ME, van Schaik BDC, Esveldt REE, Koch SD, ten Brinke A, van Kampen AHC, Bemelman FJ, Tak PP, Baas F, de Vries N, van Lier RAW. Deep Sequencing of Antiviral T-Cell Responses to HCMV and EBV in Humans Reveals a Stable Repertoire That Is Maintained for Many Years. PLoS Pathog 8(9): e1002889. doi:10.1371/journal.ppat.1002889
  • Klarenbeek PL, de Hair MJH, Doorenspleet ME, van Schaik BDC, Esveldt REE, van de Sande MGH, Cantaert T, Gerlag DM, Baeten D, van Kampen AHC, Baas F, Tak PP, N de Vries. Inflamed target tissue provides a specific niche for highly expanded T-cell clones in early human autoimmune disease. Annals Rheum Dis 2012;71:1088-93.
  • Klarenbeek PL, Tak PP, van Schaik BD, Zwinderman AH, Jakobs ME, Zhang Z, van Kampen AH, van Lier RA, Baas F, de Vries N. Human T-cell memory consists mainly of unexpanded clones. Immunol Lett. 2010 Sep 6;133(1):42-8. Epub 2010 Jul 6.
  • Stahl EA, Raychaudhuri S, Remmers EF, Xie G, Eyre S, Thomson BP, Li Y, Kurreeman FA, Zhernakova A, Hinks A, Guiducci C, Chen R, Alfredsson L, Amos CI, Ardlie KG, BIRAC Consortium, Barton A, Bowes J, Brouwer E, Burtt NP, Catanese JJ, Coblyn J, Coenen MJ, Costenbader KH, Criswell LA, Crusius JB, Cui J, De bakker PI, De jager PL, Ding B, Emery P, Flynn E, Harrison P, Hocking LJ, Huizinga TW, Kastner DL, Ke X, Lee AT, Liu X, Martin P, Morgan AW, Padyukov L, Posthumus MD, Radstake TR, Reid DM, Seielstad M, Seldin MF, Shadick NA, Steer S, Tak PP, Thomson W, Van der helm-van mil AH, Van der horst-bruinsma IE, Van der schoot CE, Van riel PL, Weinblatt ME, Wilson AG, Wolbink GJ, Wordsworth BP, YEAR Consortium, Wijmenga C, Karlson EW, Toes RE, De Vries N, Begovich AB, Worthington J, Siminovitch KA, Gregersen PK, Klareskog L, Plenge RM. Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat Genet. 2010 Jun;42(6):508-14. Epub 2010 May 9.
  • Bonarius HPJ, Baas F, Remmerswaal EBM, Van Lier RAW, Ten Berge IJM, Tak PP, De Vries N. Monitoring the T-cell receptor repertoire at single-clone resolution. PLoS ONE. 2006 Dec 20;1:e55.
  • De Vries N, Van Riel PL, Van de Putte LBA. Research in complex disease. Lancet 2002:359:1243-5.
  • De Vries N, Tijssen H, Van Riel PLCM, Van de Putte LBA. Reshaping the shared epitope hypothesis. HLA-encoded risk for rheumatoid arthritis is encoded by amino acid substitutions at positions 67-74 of the HLA-DRB1 molecule. Arthritis Rheum 2002:46(4);921-8.
  • Wilson AG, De Vries N, Pociot F, di Giovine FS, van de Putte LBA, Duff GW. An allelic polymorphism within the human Tumor Necrosis Factor a promotor region is strongly associated with HLA A1, B8, and DR3 alleles. J Exp Med 1993: 177: 557-560

 

Research programmes

“Adaptive immunomics”: Immunogenomic approaches to selectively monitor and target adaptive immune responses in immune-mediated inflammatory disease

The research program “Adaptive immunomics” aims to unravel disease-associated adaptive immune responses in immune-mediated inflammatory disease. In these adaptive responses specificity is often encoded by only a few lymphocyte clones, each encoding a unique B- or T-lymphocyte receptor. To identify, track, monitor and selectively target these cell clones we developed molecular and bioinformatic approaches to fingerprint these receptors. Thus we identify and quantitatively monitor such clones over time, both in vivo and in vitro, and assess their tissue distribution, e.g. in diseased individuals. Based on the observed distribution of clones in time and place we are able to make inferences regarding the disease-relatedness of individual clones.


Detailed analysis of these clones regarding cellular phenotype and genomic make-up in the different phases of the disease helps to develop novel diagnostics, predictors and therapeutic targets. For instance, based on clonal markers we were able to develop a validated marker for IgG4-related disease, and developed a marker that identifies a subgroup of individuals with autoantibody-positive arthralgia in which 82% of the individuals developed arthritis within 3 years. These results were validated in independent cohorts.


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.
Many of these studies are performed in collaboration with local, national and international partners. Our primary focus is on autoimmune disease, e.g. rheumatoid arthritis, vasculitis, myositis, chronic inflammatory demyelinating polyneuropathy, Crohn's disease and IgG4-related disease, and on related immune responses, e.g. anti-drug responses.

 

Faculty
Prof. dr. N. de Vries MD PhD

Postdocs
Dr. M.E. Doorenspleet MSc (-)
Dr. P.L. Klarenbeek MD PhD
Dr. R.M. Thurlings MD

PhD Students
Drs. A. Al-Soudi MSc
D.C. Anang
Drs. G. Balzaretti
R. Garcia Valiente
Drs. A. Musters MD
Drs. S. Pollastro MSc
M. Stratigopoulou
L. van der Weele

Others
M.J.G. Backer
R.E.E. Esveldt-van Lange
I.T.G. Niewold

Prof. dr. P.P. Tak (The pathogenesis of rheumatic disease and development of innovative therapies)

Other research related activities
  • Contribution to training of professionals, University of Amsterdam
  • Membership of medical or scientific committee, Reade, Amsterdam, Research Council Reade
  • Membership of medical or scientific committee, EULAR, EULAR Synovitis Study Group (ESSG)
  • Membership of medical or scientific committee, EULAR, EULAR Study Group for Risk Factors for RA
  • Membership of medical or scientific committee, Dutch Network of B-cell Immunologists, Dutch Network of B-cell Immunologists
  • Membership of medical or scientific committee, EFIS, European Network of B-cell Immunologists
  • Membership of editorial board / Editorship, ARTHRITIS & RHEUMATOLOGY
  • Membership of editorial board / Editorship, HELIYON
Current research funding
  • AMC
  • AMC (Vrijgesteld)
  • Europese Unie
  • NIEUWE DEB IND
  • NIEUWE DEB SO
  • Stichting ReumaNederland
  • ZonMw
  • ZonMw (Vrijgesteld)