B Cell Differentiation Laboratory
Key words: B cell, T cell, Ig, epigenetics
Bottom L-R: Ms Rosalyn Cao, Ms Pei Mun Aui, Ms Janice Klingenberg, Ms Floor Vissers, Ms Simone Reinwald
B cells contribute to the immune response by recognition of pathogens with their unique B-cell antigen receptor (BCR) and the production of soluble forms of this receptor: immunoglobulins (Ig), which neutralize the pathogen. Their role in the immune system is crucial, as B-cell deficiencies lead to serious infections. Furthermore, impaired B-cell function is a main causative factor in several autoimmune diseases.
Precursor-B cells are generated throughout life from hematopoietic stem cells in bone marrow, where they each assemble a unique BCR. There is heavy selection for B cells with functional BCRs that show limited autoreactivity before they migrate to peripheral lymphoid organs.
After leaving the bone marrow, B cells recirculate and only enter the second stage of differentiation into memory B cells and plasma cells once they recognize antigen with their unique receptor.
The research of our group aims to unravel the processes that underlie differentiation and selection decisions at important checkpoints in human B-cell differentiation. Whereas it is challenging to study human immunology, this approach will allow direct translation into patient care and diagnostics. To tackle the complexity of these basic and translational studies, we work closely together with multiple (inter)national collaborators.
Current research lines include:
- Studies on the epigenetic regulation of ordered rearrangements of the Ig heavy and Ig light chain genes;
- Dissection of B-cell antigen receptor and T-cell co-stimulation signaling pathways in patients with primary immunodeficiencies to study the regulation of somatic hypermutation, class switch recombination, and differentiation into memory B cells and plasma cells;
- The impact of persistent viral infections and intestinal microbiota in young children on T-cell and B-cell memory, and immune-mediated diseases (esp. Celiac disease and allergies);
- Elucidating the involvement of B cells and plasma cells in chronic inflammatory disease (esp. Periodontitis, Sarcoidosis, Crohn's disease and Behçet's disease);
- The pathophysiology of IgE- and IgG4-expressing B cells in allergies, and the impact of immunotherapy on these cells.
Research projects for students
Major achievements in the past years
Dissecting precursor-B cells in human bone marrow, and elucidating the roles of IL7R signaling and ID2 on Ig gene rearrangements (J Immunol 2005;175:5912-5922; Blood 2011;118:2116-2127; J Immunol 2013;191:1210-1219).
- Demonstrating how genomic DNA is organized in three-dimensional space and how locus contraction and nuclear localisation regulate ordered gene rearrangements (Cell 2008;133:265-79; Cell 2009;238:435-448; Nucleic Acids Res 2015;44(1):175-86).
- Elucidating the functions of CD19 and CD81, and how mutations in these genes underlie a novel antibody-deficiency syndrome in humans (N Engl J Med 2006;354:1901-1912, Genes Immun. 2007;8:663-670, J Clin Invest 2010;120:1265-1274, Genes Immun 2010;11:523-530, Hum Mol Genet. 2011;20:1854-63 and J Allergy Clin Immunol. 2014;28(7):1560-4).
- Dissecting human memory B cell subsets expressing IgM, IgG, IgA or IgE using novel molecular assays (J Exp Med 2007; 204:645-655; Blood 2011;118:2150-8; J Allergy Clin Immunol. 2014; 34(3):688-697.e6; J Immunol 2015;195(4):1417-26).
- Showing dysregulation of B-cell memory in immune-mediated diseases (Blood 2011;118:6814-23; Am J Respir Crit Care Med. 2013;187:406-16; Leukemia. 2014;28(7):1560-4; J Allergy Clin Immunol. 2014;134(6):1346-1353.e9)
- Elucidating how breastfeeding and persistent viral infections shape adaptive immunity in young children (PLoS One. 2015;10(5):e0126019; AIDS. 2015;29(14):1745-56; J Infect Dis. 2016;213(2):233-42; J Pediatr. 2016;170:126-134)
Jeffrey Modell Foundation Centre for Primary Immunodeficiencies Melbourne
A/Prof van Zelm is the director of the JMF Centre for Primary Immunodeficiencies, opened in June, 2018.
Training possibilities in the group
The group offers training possibilities for Honours and PhD students. Together with the student a specific research topic will be determined within one of the research lines of the group. Depending on the exact research project, applied techniques include several of the following techniques: flow cytometric immunophenotyping, cell sorting, AMNIS ImageStream, (RT-)PCR amplification, Sanger sequencing, recombinant DNA technology, DNA micro-array analysis, 3D Fluorescence in situ hybridization (FISH) and CRISPR-Cas9 mediated mutagenesis. During the training period students learn multiple principles and theories in the fields of immunology, genetics and cell biology, and learn to design, (safely) perform, interpret and document experiments in the field of Molecular Immunology.
For more information, please contact A/Prof. Menno C. van Zelm (tel: +61 39903 0834, or e-mail: firstname.lastname@example.org)
Associate members in collaborative projects
- Michelle A.E. Jansen, MD: PhD student (the Netherlands)
- Marieke Timmermans, MD: PhD student (the Netherlands)
- Tim van der Houwen, MD: PhD student (the Netherlands)
- Sanne Beth, MD: PhD student (the Netherlands)
- Dr Gavin Brooks, PhD
- Dr Lieke S.J. Kamphuis, PhD
PhD thesis: "The Many Faces of Sarcoidosis Novel insights into pathogenesis, diagnostics and therapy" (2009-2016)
- Dr Magdalena B. Rother, PhD
PhD thesis: "Formation of the Immunoglobulin Repertoire in Precursor-B-cell Development" (2010-2015)
- Dr Diana van den Heuvel, PhD
PhD thesis: "The Immune System out of Shape? Shaping of adaptive immunity by persistent viral infections in young children" (2010-2015)
- Dr Ruud H.J. Verstegen, MD, PhD
PhD thesis: “Humoral Immunity in Children with Down Syndrome: relevance to respiratory disease” (2015)
- Dr Magdalena A. Berkowska, PhD
PhD thesis: “Generation of an immunocompetent B-cell repertoire” (2008-2012)
- Dr Katharina Nothelfer, PhD
- Benjamin Bartol, BSc
- Halima Charif, BSc
- Edwin F.E. de Haas, BSc
- Kevin A.M. van Kester, BSc
- Fatemeh Ahmadi 2015
- Liza Rijvers 2013-2014
- Kyra Smit 2013-2014
- Hessel van der Weide 2013
- Sanne van de Bovenkamp 2012-2013
- Ingrid Snijdewind 2011-2012
- Samuel de Jong 2016
- Eliza Watson 2016
- Nicole Borggreven 2015
- Lemelinda Marques 2014-2015
- Jasper Rip 2014
- Roel Kroek 2013-2014
- Rachid Bouzid 2013-2014
- Marleen Hoozemans 2012-2013
- Dan Zhao 2012-2013
- Michael Vermeulen 2009-2010
- Abdullah Tarique 2010