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Rogier Q. Hintzen, MD, PhD

Hintzen-51x53px Professor and Head of MS Center ErasMS,
 Department of Immunology

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 Neuroimmunology Brain Research Group 

Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system (CNS), which is characterized by ongoing autoimmunity and demyelination, eventually leading to neuronal deficits. Although the cause of MS is unknown, the central dogma is that pathogenic B- and T-cell subsets are activated in the periphery to mediate inflammation in the CNS. The prime focus of our group is to unravel the mechanisms, subsets and antigen specificity of B and T cells in MS. Our research covers the following topics: 1) functional immunogenetics, 2) functional immunophenotyping, 3) immune control by the Epstein-Barr virus, and 4) antigenic targets of local immune responses. These topics are strongly interrelated with one ultimate goal: to understand the selective regulation of B- and T-cell immunity in MS patients.

Functional immunogenetics
In this part of research, we are particularly interested in genes identified by genome-wide association studies that control the biology of HLA class II (HLA-II), the major genetic factor in MS. The success of B-cell depletion therapy in MS points to B cells as most the important antigen-presenting cells. We use model and primary blood human B cells in stimulation and RNAi assays to analyze gene function in relationship to the HLA-II pathway using qPCR, flow cytometry, cell sorting and high-resolution microscopy. Our aim is to identify disease-related genes that are selectively regulated to control B-cell antigen presentation in MS.

Picture2Functional immunophenotyping
An important goal in this research line is to specify which functional properties and subsets of peripheral blood B and T cells are associated with the course of MS. We use different combinations of lineage and maturation markers in multicolor flow cytometry panels to screen for subset-specific aberrancies in functional B- and T-cell parameters. Our group has a large collection of PBMC from the peripheral blood of different cohorts of MS patients and controls. Identified markers and subsets will provide implications for functional assays, but can also be used to define clinical subgroups and to predict MS development and treatment outcome.



Immune control by the Epstein-Barr virus
Epstein-Barr virus (EBV) is a prime MS risk factor that establishes lifelong latency in B cells. We argue that EBV is a key factor for breaking immune tolerance, causing activation of pathogenic B- and T-cell subsets in MS. Using high-throughput molecular arrays (expertise by Dr. Menno van Zelm and Dr. Mirjam van der Burg), we focus on the distribution of EBV in B-cell subsets and how this selectively affects their development and survival in MS. Additionally, T-cell clones from distinct MS brain compartments are studied for (cross-)reactivity to autologous, HLA- and (auto)antigen-restricted EBV+ B-LCL. We make use of advanced cell isolation and (co-)culture systems, cytokine and proliferation assays as well as in situ analyses.  

Antigenic targets of local immune responses
Intrathecal Ig production and somatic hypermutations within variable regions of Ig suggest antigen-driven B cell activation in MS brain. However, knowledge on the antigens that are recognized is far from complete. To overcome hurdles related to EBV-mediated immortalization, we use a novel EBV-independent method (Prof. Hergen Spits, UvA/AIMM Therapeutics, Amsterdam) to immortalize intrathecal B cells from patients with MS, NMO and ADEM. Using this technology, the original function and specificity of B-cell clones are maintained. This gives us the unique opportunity to assess Ig reactivity against CNS autoantigens and viruses using ELISA and cell-based assays.

 Group members

NIB-Groepsfoto-300x200Rogier Hintzen, MD, PhD, Group leader 
Marvin van Luijn, PhD
Liza Rijvers, PhD student
Malou Janssen, PhD student
Jamie van Langelaar, PhD student
Annet Wierenga-Wolf, Research Assistant
Marie-José Melief, Research Assistant
Hatice Orhan, MSc student

 Selected Publications

(See for all publications Rogier Hintzen and Marvin van Luijn in Pubmed)

van Luijn MM, Kreft KL, Jongsma ML, Mes SW, Wierenga-Wolf AF, van Meurs M, Melief MJ, der Kant RV, Janssen L, Janssen H, Tan R, Priatel JJ, Neefjes J, Laman JD, Hintzen RQ.
Multiple sclerosis-associated CLEC16A controls HLA class II expression via late endosome biogenesis.
Brain. 138(Pt 6):1531-47, 2015.

van Luijn MM, van den Ancker W, van Ham SM, van de Loosdrecht AA.
Class II-associated invariant chain peptide as predictive immune marker in minimal residual disease in acute myeloid leukemia.
Oncoimmunology. 3(12):e941737, 2015.

Kreft KL, van Meurs M, Wierenga-Wolf AF, Melief MJ, van Strien ME, Hol EM, Oostra BA, Laman JD, Hintzen RQ.
Abundant kif21b is associated with accelerated progression in neurodegenerative diseases.
Acta Neuropathol Commun. 3;2:144, 2014.

Stern JN, Yaari G, Vander Heiden JA, Church G, Donahue WF, Hintzen RQ, Huttner AJ, Laman JD, Nagra RM, Nylander A, Pitt D, Ramanan S, Siddiqui BA, Vigneault F, Kleinstein SH, Hafler DA, O'Connor KC.
B cells populating the multiple sclerosis brain mature in the draining cervical lymph nodes.
Sci Transl Med. 6;6(248):248ra107, 2014.

Patsopoulos NA, Barcellos LF, Hintzen RQ, Schaefer C, van Duijn CM, Noble JA, Raj T; IMSGC; ANZgene, Gourraud PA, Stranger BE, Oksenberg J, Olsson T, Taylor BV, Sawcer S, Hafler DA, Carrington M, De Jager PL, de Bakker PI.
Fine-mapping the genetic association of the major histocompatibility complex in multiple sclerosis: HLA and non-HLA effects.
PLoS Genet. 9(11):e1003926, 2013.

International Multiple Sclerosis Genetics Consortium (IMSGC), Beecham AH, Patsopoulos NA, Xifara DK, Davis MF, Kemppinen A, Cotsapas C, Shah TS, Spencer C, Booth D, Goris A, Oturai A, Saarela J, Fontaine B, Hemmer B, Martin C, Zipp F, D'Alfonso S, Martinelli-Boneschi F, Taylor B, Harbo HF, Kockum I, Hillert J, Olsson T, Ban M, Oksenberg JR, Hintzen RQ et al.
Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.
Nat Genet. 45(11):1353-60, 2013.

Kreft KL, Verbraak E, Wierenga-Wolf AF, van Meurs M, Oostra BA, Laman JD, Hintzen RQ.
Decreased systemic IL-7 and soluble IL-7Rα in multiple sclerosis patients.
Genes Immun. 13(7):587-92, 2012.

Kreft KL, Verbraak E, Wierenga-Wolf AF, van Meurs M, Oostra BA, Laman JD, Hintzen RQ.
The IL-7Rα pathway is quantitatively and functionally altered in CD8 T cells in multiple sclerosis.
J Immunol. 188(4):1874-83, 2012.

Kreft KL, Verbraak E, Wierenga-Wolf AF, Laman JD, Hintzen RQ.
Role of CD8 regulatory T-cells in multiple sclerosis.
Ann Neurol. 69(3):593; author reply 593-4, 2011.

van Luijn MM, van den Ancker W, Chamuleau ME, Zevenbergen A, Westers TM, Ossenkoppele GJ, van Ham SM, van de Loosdrecht AA.
Absence of class II-associated invariant chain peptide on leukemic blasts of patients promotes activation of autologous leukemia-reactive CD4+ T cells.
Cancer Res. 71(7):2507-17, 2011.

Peferoen LA, Lamers F, Lodder LN, Gerritsen WH, Huitinga I, Melief J, Giovannoni G, Meier U, Hintzen RQ, Verjans GM, van Nierop GP, Vos W, Peferoen-Baert RM, Middeldorp JM, van der Valk P, Amor S.
Epstein Barr virus is not a characteristic feature in the central nervous system in established multiple sclerosis.
Brain. 133(Pt 5):e137, 2010.

Hoppenbrouwers IA, Aulchenko YS, Janssens AC, Ramagopalan SV, Broer L, Kayser M, Ebers GC, Oostra BA, van Duijn CM, Hintzen RQ.
Replication of CD58 and CLEC16A as genome-wide significant risk genes for multiple sclerosis.
J Hum Genet. 54(11):676-80, 2009.

Aulchenko YS, Hoppenbrouwers IA, Ramagopalan SV, Broer L, Jafari N, Hillert J, Link J, Lundström W, Greiner E, Dessa Sadovnick A, Goossens D, van Broeckhoven C, Del-Favero J, Ebers GC, Oostra BA, van Duijn CM, Hintzen RQ.
Genetic variation in the KIF1B locus influences susceptibility to multiple sclerosis.
Nat Genet. 40(12):1402-3, 2008.

Stoop MP, Dekker LJ, Titulaer MK, Burgers PC, Sillevis Smitt PA, Luider TM, Hintzen RQ.
Multiple sclerosis-related proteins identified in cerebrospinal fluid by advanced mass spectrometry.
Proteomics. 8(8):1576-85, 2008.

Buljevac D, Flach HZ, Hop WC, Hijdra D, Laman JD, Savelkoul HF, van Der Meché FG, van Doorn PA, Hintzen RQ.
Prospective study on the relationship between infections and multiple sclerosis exacerbations.
Brain. 125(Pt 5):952-60, 2002.