The Laboratory of Immunogenetics started as the section of Gastrointestinal Immunology when the Chair on Gastrointestinal Immunology was created in 1992. It was part of the Department of Gastroenterology of the University Hospital Vrije Universiteit (AZVU). In 2001 the Board of Directors of the VU University Medical Centre (VUmc) gave the status of “Project” in order to find the best place with the organization for the further development of immunogenetics in the VUmc in Amsterdam.
Since 1998 the research laboratory activities have been expanded to the study of chronic inflammatory and autoimmune diseases according to the priorities established by the Faculty of Medicine, of the Vrije Universiteit, the Hospital of the Vrije Universiteit and the Research Institute for Immunology and Inflammatory Diseases as indicated in the Figure. In 2004 most of the immunogenetic scientific activities will be part of the new research Institute of the VUmc: VU medisch centrum instituut voor kanker en immunologie (V- ICI) within the Department of Pathology of the VUmc.
The Laboratory for Immunogenetics started in 1992 as the Laboratory of Gastrointestinal Immunogenetics at the “VU” University in Amsterdam. Prof A.S. Peña started with Prof S.G.M. Meuwissen a systematic study of cytokine gene polymorphisms in the chronic inflammatory bowel diseases (IBD) -ulcerative colitis and Crohn’s disease. Also together with the group in Leiden of Dr. F. Koning (Leiden University Medical Center) studies, previously initiated there were continued on coeliac disease. These studies were going to supplement the information obtained on the major histocompatibility complex (MHC) known to be associated with these diseases.
It was soon realised that the disturbed balance between the pro-inflammatory and the regulatory cytokines in chronic inflammatory diseases of the intestine was also apparent in multiple sclerosis and other chronic inflammatory diseases and autoimmune diseases.
Collaborative studies in multiple sclerosis were initiated with Prof C.H. Polman from the Department of Neurology. The clinical heterogeneity of this disease mirrors to a certain extent the heterogeneity of diseases such as Crohn’s disease and ulcerative colitis. The identification of patients with both inflammatory bowel disease and multiple sclerosis, as well as several common findings strengthened the collaboration. For example, 40% of the patients with either of these diseases are associated with HLA-DR2.
Studies on cytokine gene polymorphisms were extended to rheumatic diseases. With Prof B.A.C. Dijkmans studies were initiated on ankylosing spondylitis, which is closely correlated to IBD. Recently, two new areas of research have been opened. Other initiative is on the immunogenetics and pathogenesis of periodontitis together with Dr. A.J. van Winkelhoff of the ‘Academisch Centrum Tandheelkunde Amsterdam’ (ACTA) at the start and later with Prof. Bruno Loos and Dr. Marja Laine.
In this multidisciplinary approach the major theme is the systematic mapping of those gene polymorphisms involved in the regulation of the inflammation. Since the MHC plays a major role in this process, techniques have been developed to study genes such as those encoding the cytokines TNFalpha and LTalpha in the central region of the MHC, which are in linkage disequilibrium with HLA genes. The studies on cytokine gene polymorphisms are being performed in our laboratory. The close collaboration on the study of HLA genes that already existed before the establishment of our laboratory was continued with Dr. M. Giphart, Dr. G.Th.M. Schreuder, and Dr. F. Koning from the Department of Immunohaematology, LUMC for several years.
To unravel fully the significance of cytokine gene polymorphisms in the regulation of chronic inflammation and in the natural evolution of these diseases, it is important to study different ethnic groups. Hence an alliance has been established with several centres abroad to study patient groups and well-matched control groups from several continents. Our studies are not only directed towards finding susceptibility genes, but rather to the investigation of gene polymorphisms that may contribute to the understanding of the biological basis of disease heterogeneity. Our laboratory has therefore a direct link with clinical research.
Allele 2 of the interleukin-1 receptor antagonist has been found to be increased in patients with ulcerative colitis, especially in patients with pancolitis. Moreover, recent studies in the United Kingdom and Germany have found that at the intestinal level carriers of this allele produce significantly less interleukin-1 receptor antagonist and cannot properly compensate for the increased amount of interleukin-1beta. However, our recent study on multiple sclerosis suggest that this genetic disbalance also exists in a group of patients with severe prognosis. These observations open the possibility that individuals with chronic inflammatory bowel diseases and several other autoimmune diseases that are carriers of allele 2 of the interleukin-1 receptor antagonist are not high producers of the protein as has been found in the peripheral blood of healthy individuals, but lower secretors favouring a disbalance in the pro-inflammatory cascade. There is some evidence from Finland that individuals carrying this allele have high concentrations of this antagonist in peripheral blood.
The Laboratory of Immunogenetics is in an exciting phase of development. We believe that successful developments will depend on the application of the most modern molecular biological techniques with a well co-ordinated effort between the different disciplines. A proper classification of disease, an intimate collaboration with the clinical experts managing the patients and a careful recording of the evolution of these diseases is of crucial importance for obtaining results. In order to have a greater impact on understanding the pathogenesis of multifactorial diseases several close collaborations were started and have turned into the main projects that have obtained grants.
We expect to find gene polymorphisms that are predictive for the severity or difference in the prognosis of patient subgroups. These studies are especially appropriate to a major development in the therapeutic field directed to restoring the disbalance in the cytokine regulation in many of these diseases. The clearest example of this approach is the observation that one of the most powerful biological therapies at present, the monoclonal anti-TNFalpha treatment, is only effective in a subgroup of patients with rheumatoid arthritis and Crohn’s disease. Preliminary observations suggest that this effect may be to a certain extent genetically determined. This example can be applied to many other new therapies such as interferon-beta in the treatment of multiple sclerosis. This multidisciplinary approach will also provide information on the significance of allelic diversity in determining the functional abnormalities in different diseases.
Present & future development
The main focus of the Laboratory of Immunogenetics is the systematic study of gene polymorphisms that contribute to regulate the chronic inflammatory response with its major emphasis on cytokine gene polymorphisms. Since 2008 the activieties have been focused on the immunogenetics of inflammatory bowel disease, coeliac disease and infectious diseases mainly the long term complications of Chlamydia trachomatis.