van Zelm - B Cell Differentiation Laboratory
- Key terms | The group | Research overview | Research aims | Current research | Student projects | Major achievements | Jeffrey Modell Foundation | Publications | Training possibilities | Collaborations | Alumni
- B cell, memory B cell, T cell, Ig, epigenetics, Jeffrey Modell Foundation, PAD, predominantly antibody deficiency, allergy, COVID-19 immunity
van Zelm group L-R: Mrs Simone Reinwald, Ms Gemma Hartley, Dr Craig McKenzie, Professor Robyn O'Hehir AO, Ass/Prof Menno van Zelm, Ms Pei Mun Aui, Dr Emily Edwards, Mrs Neeru Varese
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. To tackle the challenges for studying the human immune system, we have developed unique tools for examining antigen-specific B cells, B-cell replication history and functional signalling pathways. In collaboration with multiple (inter)national collaborators, we have direct access to samples from patients with specified disease, as well as those undergoing targeted treatment.
Current research lines include:
- Defining the contribution of rare and common genetic variants to the severity and heterogeneity of disease in patients with predominantly antibody deficiency;
- 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);
- Abnormal IgE responses and memory B cells in bee venom and rye grass allergies, and how IgG induced by allergen-specific immunotherapy inhibits IgE-mediated effector cell activation.
- Diversity, specificity and longevity of B-cell memory following vaccination or natural infection with zoonotic viruses (influenza, SARS-CoV2)
Research projects for students
Bachelor of Medical Science (Honours) 2021 Projects:
Beyond rare monogenetic variants in predominantly antibody deficiency
In collaboration with Prof Robyn O’Hehir, Dr. Julian Bosco (Alfred Hospital) and Dr Samar Ojaimi (Monash Health)
We have established a large cohort of patients with predominantly antibody deficiency (PAD), the most prevalent symptomatic form of primary immunodeficiency. Even though advancements in next-generation sequencing (NGS) have yielded an increase in new causative gene identification, the diagnostic rate for patients with PAD remains low (<20%). This highlights the complexity of the genetic causes of this disease.
We have taken a unique approach beyond identification of rare genetic variants, in which we include functional analysis of immune cell function, and disease-modifying effects of common gene variants. The project will involve functional studies of B-cell, T-cell and monocyte activation, as well as genetic analysis of inherited gene variants. The student will have their own research project to examine the disease-causing immunological mechanism in a subgroup of patients through flowcytometric, in vivo functional, and genetic analyses.
Specificity and memory in allergic responses to aeroallergens
In collaboration with Prof Robyn O'Hehir and Prof Mark Hogarth (Burnet Institute)
In our laboratory, we devised new tools to study allergen-specific B-cells that will enable us to unravel specificity and memory of allergic responses, and how this is changed during immunotherapy. The project involves recombinant longitudinal analysis of antigen-specific B cells before and after allergen immunotherapy for house dust mite (HDM) or ryegrass pollen (RGP). The student will be directly involved in blood sample processing, multiparameter flowcytometry and single cell transcriptomics and Ig gene transcript analysis.
Longevity of B-cell memory following natural infection or vaccination
In collaboration with Prof Robyn O'Hehir and Prof Mark Hogarth (Burnet Institute)
The COVID19 pandemic has re-emphasised the need for a good understanding of immune memory and its longevity. Our technology to detect antigen-specific B cells has enabled us to quantify and immunophenotype influenza-specific and SARS-CoV2-specific memory B cells. Our previous work on influenza vaccination indicated that memory B cell numbers remain stable over many months.
In this project, we will longitudinally examine memory B cells following natural infection with SARS-CoV2, and examined their immunophenotype and transcription profiles. This work will inform us on the nature of these memory B cells, and whether the virus elicits a unique type of response, or if this is in line with the current understanding of immune memory.
Learning objectives in B-cell differentiation laboratory
In each of these projects, the student will have a unique opportunity to study important processes in the human immune system, will be exposed to basic and clinical research, and will apply advanced molecular biology techniques and state-of-the-art conventional and imaging flowcytometry.
Major achievements in the past years
- Dissecting stepwise differentiation of precursor-B cells in bone marrow, the regulation of Ig gene rearrangements including the roles of IL7R signaling and ID2 (J Immunol 2005;175:5912-5922; Cell 2008;133:265-79; Cell 2009;238:435-448; Blood 2011;118:2116-2127 ; J Immunol 2013;191:1210-1219; Nucleic Acids Res 2016;44(1):175-86; Sci Rep. 2016;6:33924).
- Elucidating the genetic and immunological bases of primary antibody deficiencies (N Engl J Med 2006;354:1901-1912, J Clin Invest 2010;120:1265-1274, Front Immunol. 2019;10:2084, Front Immunol. 2019;10:768 , Front Immunol. 2019;10:2593).
- Unraveling the origin of diverse human memory B cell subsets from T-cell independent, T-cell dependent, and recurrent immune responses (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 ; Immunol Cell Biol. 2017;95(9):744-752; J Immunol. 2018;201(7):1928-1935).
- Showing dysregulation of B-cell memory in allergy, and how this is affected by treatment (J Allergy Clin Immunol. 2014;134(6):1346-1353.e9; Allergy. 2018;73(6):1331-1336; Clin Exp Allergy. 2018;48(6):679-690, Allergy. 2019;74(12):2394-2405 , Allergy. 2019;74(12):2342-2354, Allergy. 2020;75(5):1121-1132)
- Shaping of adaptive immunity in young children by non-genetic factors (J Infect Dis. 2016;213(2):233-42; J Pediatr. 2016;170:126-134; J Leukoc Biol. 2017;101(4):949-956; J Allergy Clin Immunol. 2017;139(6):1923-1934 )
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: email@example.com)
Associate members in collaborative projects
- Sanne Beth, MD: PhD student (the Netherlands)
- Kirsten Looman: MD, PhD student (the Netherlands)
- Dr. Paul A. Gill, PhD
PhD thesis: “Investigating Immune Effects of Short-Chain Fatty Acids in Healthy Humans” (2016-2020)
- Dr. Simone Reinwald, PhD
Research Assistant 2018-2020
- Ms. Eliza Watson
Research Assistant 2017-2019
- Dr Jorn J. Heeringa, MD, PhD
PhD thesis: “The B-cell side of Allergy and Chronic Inflammatory Disease: Studies on the source of IgE and IgG4” (2012-2018)
- Dr W.M. (Marieke) Timmermans, MD, PhD
PhD thesis: "Immunopathogenesis of Granulomas in Chronic Inflammatory Diseases: Relevance to diagnostics, biomarkers and treatment” (2013-2018)
- Dr Michelle A.E. Jansen, MD, PhD
PhD thesis: "Shaping of Adaptive Immunity and Celiac Disease Autoimmunity in a Population based Childhood Cohort: The Generation R Study" (2010-2017)
- 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
Hons and MSc students
- Sabina Masinovic 2020
- Charlotte Leijten 2019-2020
- Gemma Hartley 2019
- Rosalyn Cao 2018
- Adam Nelson 2018
- Tarnia Fischer 2018
- Janice Klingenberg 2018
- Floor Vissers 2018
- Samuel de Jong 2016
- Eliza Watson 2016
- 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
- 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