Ian van Driel
For more information on Ian and his research, visit his 'Find an Expert' page
Research areas
Ian van Driel has two major areas of research:
- Autoimmune disease and immunological tolerance
- Immune responses to pathogenic bacteria
- Cell biology of ion transport proteins
Autoimmune disease & immunological tolerance
- Autoimmune disease occurs when the immune system is directed against the body's own tissues, resulting in destruction or disruption.
- Autoimmune diseases are a major public health problem in industrialized nations. Approximately 5 % of the population suffer from autoimmune diseases. For some autoimmune diseases the symptoms can be treated, but for the most part, specific therapies that cure the underlying immunological disease are unavailable.
- Defining the events and mechanisms that lead to the initiation of autoimmune diseases will lead to an understanding of the processes of immunological tolerance and the development of new predictive, preventative and therapeutic strategies.
- We have concentrated on autoimmune diseases of the stomach - pernicious anaemia and autoimmune gastritis. The prevalence in Western populations of these diseases in people over the age of 60 years is 1.9 per cent. They represent some of the commonest autoimmune diseases and the commonest cause of vitamin B12 deficiency.
Projects
1. Dendritic cells in the generation of tolerance and autoimmunity
Dendritic cells (DC) present self-antigens to T cells and unarguably contribute to extrathymic immune tolerance. However it is not clear how the different subsets of DC contribute to this process, or what changes occur in DC during autoimmune disease
Fig 1 Hypothesis to explain the role of migDC in autoimmunity.
We wish to extend our findings that only a specialsed DC subtype called migratory DC (migDC) from the gastric mucosa present stomach autoantigens to T cells in normal mice and mouse models of autoimmune disease. MigDC arise in tissues and sample the local environment before moving to lymphoid tissues in response to endogenous cues.
This project is designed to reveal the molecular and functional characteristics of migDC and provide an explanation of how they participate in immune tolerance or the initiation and propagation of autoimmune disease. An important strength of this work is that we will examine the presentation of a molecule that is targeted in autoimmune disease in its natural pathophysiological context.
We hypothesise that in normal animals, migDC are tolerogenic and are refractory to further maturation, but when conditions in the tissue favour the development of autoimmune disease, newly arising migDC develop altered cell signalling pathways and patterns of cytokine secretion that promote the differentiation of self-reactive T cells into pathogenic effector cells (see Fig 1).
2. The role of regulatory T cells in the generation of tolerance and autoimmunity
We have shown that Treg cells specific for stomach antigens are generated after contact with antigen presented by DC and that these Treg cells can be highly potent at stopping autoimmune reactions. The aims of this project are to discover the mechanisms by which DC initiate the development of Treg cells. We will also determine the involvement of these autoantigen-specific Treg cells in tolerance.
3. The use of regulatory T cells to cure autoimmune disease
Treg cells show potential in the treatment of inflammatory diseases such as autoimmune disease. We have developed methods for the generation of Treg cells in vitro and to use these 'iTreg' cells to reverse established autoimmune disease. Our aims are now to optimise these methods and discover how the Treg cells reverse the disease process.
Immune responses to pathogenic bacteria
By gaining a better understanding of how the immune system combats bacterial infections, we aim to maximise the chances of developing more effective vaccines and antimicrobial drugs.
The WHO estimates that bacterial infectious diseases account for approximately 10 million deaths annually and acknowledges that the economic impact resulting from bacterial infections is inestimable. While the specific nature of the diseases changes somewhat over time, bacterial infection generally shows no sign of diminishing. Numerous new pathogenic bacteria have emerged in the past three decades at the same time as old ones have re-emerged.
Vaccines for most major pathogenic bacteria are either non-existent or have serious shortcomings. Resistance to commonly used small molecule antimicrobials is on the rise, and modern travel facilitates rapid global dissemination of drug-resistant virulent clones. The combination of human-induced environmental changes and the growing proportion of the aging population with increased susceptibility to infection are predicted to increase morbidity and mortality over this century.
1. The role of plasmacytoid dendritic cells in combating bacterial pathogens
Plasmacytoid dendritic cells (pDC) are well known as the primary source of type I interferons in response to many viral infections. However, their involvement in the fight against other classes of infectious organisms, including bacteria, has not been examined and their other mechanisms of action are poorly understood.
We have found pDC to play a central role in the acute response to the intracellular bacterial pathogen Legionella pneumophila. Surprisingly, unlike the pDC response to viral invasion, the ability of the cells to combat bacterial infection was independent of type I interferon production.
Our results have revealed a role for pDC in combating bacterial infections by mechanisms not previously appreciated for this cell type.
Fig 2 Proposed mechanisms of action of pDC in the clearance of bacterial infection. See text for explanation.
Our overall aims are to define both the role of pDC in combating pathogenic bacteria and the mechanisms they use. We hypothesise (Fig 2) that pDC play a significant role in fighting a range of pathogenic bacteria that involves the recognition of bacterial products by toll-like receptors (TLR) and the consequent activation of signalling pathways that result in the secretion of cytokines or chemokines in addition to type I interferon. These cytokines and chemokines attract and activate effector cells, such as macrophages, neutrophils, and NK cells, that secrete cytokines or dispose of the pathogens directly.
2. Regulatory T cells and the control of immune responses to bacteria
It is postulated that one of the important tasks of Treg cells is to control the responses to microorganisms and prevent inappropriate responses to friendly commensal organisms and collateral damage when fighting pathogens.
The investigation of this hypothesis has been held back by the inability to deplete Treg cells efficiently. We have obtained a mouse line in which Treg cells can be rapidly and totally eliminated, offering a robust system in which to examine the role of Treg cells in infection.
In this project we will examine two pathogens. The first is Legionella pneumophila, the major cause of Legionnaire’s disease, an acute form of pneumonia. Infection with L. pneumophila elicits a strong inflammatory response in the lung. The second bacteria is Citrobacter rodentium, which colonises the colon and causes a disease that mimics inflammatory bowel disease. We will deplete Treg cells and determine the effects on disease, clearance of bacteria and immune response.
3. The genetic causes of inflammatory bowel disease
Inflammatory bowel diseases (IBDs) are the result of destructive inflammatory responses in the gut. Chronic IBD, which includes Crohn’s disease and ulcerative colitis, is a common condition in most Western populations. In the US Crohn’s disease and ulcerative colitis afflict about 600,000 people with approximately 50,000 new cases reported each year. In Australia over 61,000 people have IBD and about 1,600 new cases are diagnosed each year.
IBD afflicts people of all ages, many cases presenting in their teens and 20s. The condition is rarely fatal in itself, but is responsible for considerable illness and increases the risk of colorectal cancer. New therapies for IBD achieve remission rates of less than 50% of patients and have potential life-threatening complications, thus the search continues for additional, more effective treatment options.
The overall aim of this project is to discover genes and pathways that control IBD. Our approach will be to produce new mutant mouse strains with random point mutations throughout the genome and determine which genes are associated with IBD-like phenotypes. To identify mice with IBD-like conditions we will screen mice treated with N-ethyl-N-nitrosourea (ENU), a chemical that causes the random introduction of point mutations in DNA.
Such a “forward genetic” approach has the advantage of making no assumptions about the function of genes and their products and has been successfully applied to the discovery of novel gene-phenome relationships in inflammation, immune responses and development of non-gut tissues.
In confirmation of the feasibility of the ENU approach, we have already identified two mutant mouse lines that rapidly and spontaneously develop ulcerative colitis, and the mutations responsible (See Fig 3).Fig 3 A mutation that causes IBD. Mr Hankey mice develop severe colitis. Chromatograms from a sequencing run of Mr Hankey cDNA are shown as is the Mr Hankey versus wildtype sequence. The mutation that causes disease is shown.
Cell biology of ion transport proteins
The localisation and trafficking of membrane proteins, including ion transport proteins, is critical for the control of many biological processes. Our understanding of how membrane proteins are targeted to particular cellular domains in a regulated manner is still at a relatively early stage. To gain knowledge of targeted transport of proteins, we have studied the parietal (oxyntic) cells of the gastric mucosa.
Parietal cells provide an example of a solute transport system in which the regulated trafficking of two independent membrane proteins, namely a proton pump and an ion channel, plays a key role. Parietal cells are highly specialised epithelial cells that line the stomach surface and produce gastric acid: the luminal surface membrane of the cell pumps protons against a concentration gradient greater than seven orders of magnitude. Gastric acid secretion was one of the first regulated secretory activities to be identified and has been extensively studied because of its intrinsic cell biological and biochemical interest as well as the importance of pharmacological intervention in this process. Acid secretion by parietal cells represents a superb and accessible model system for the study of ion homeostasis.
Our ultimate aim is to understand the molecular mechanism and functional implications of trafficking events in parietal cells. This project will analyse trafficking of the functionally important “cargo” molecule, the apical K+ channel. The parietal cell apical K+ channel plays an essential role in gastric acid secretion by supplying the luminal K+ required for the activity of the H+/K+ ATPase proton pump.
The apical K+ channel in parietal cells has recently been identified as kcnq1 complexed with the smaller modulatory subunit kcne2. Our recent data indicate that in resting parietal cells, kcnq1 resides in a previously unrecognised intracellular membrane compartment, distinct from that of the H+/K+ ATPase-containing compartment, that resembles the recycling endosome. The kcnq1 K+ channel traffics to the apical membrane upon activation of parietal cells to secrete acid (Fig 4). This novel observation is important as it suggests that trafficking of the kcnq1 K+ channel is crucial to the control of acid secretion in parietal cells.
In this project we will further characterise the kcnq1 K+ channel-containing membrane compartments, the trafficking of this protein in parietal cells and the trafficking sequences that lead to regulated subcellular localisation. Importantly, we will establish the functional significance of the regulated trafficking of the kcnq1 K+ channel.
Fig 4. Intracellular localisation of K channel kcnq1 and H+/K+ ATPase in resting and activated gastric units from wildtype mice:
(A) Gastric units were probed with phalloidin or antibodies against Q1 or H+/K+ ATPase. (B) Areas of co-localisation between Q1, H+/K+ ATPase or actin positive membranes. An increase in Q1 and H+/K+ ATPase at the secretory canaliculi is observed in activated parietal cells. Bars = 10 µm
Lab personnel
Head
Associate Professor Ian van Driel
Research staff
Dr Dorothee Bourges (Research Officer)
Dr Desmond Ang ( Research Officer)
Nhung Nguyen (Research Officer)
Graduate students
Stacey Allen
Priscilla Gunn (jointly with Paul Gleeson)
Ellen Ross
Eric Tu
Selected publications
- Ang DK, Oates CV, Schuelein R, Kelly M, Sansom FM, Bourges D, et al. (2010) Cutting edge: Pulmonary Legionella pneumophila is controlled by plasmacytoid dendritic cells but not type I IFN. J Immunol, 2010, 184(10):5429-5433.
- Newton HJ, Ang DKY, van Driel IR, and Hartland EL. (2010). The molecular pathogenesis of infections caused by Legionella pneumophila . Clin Microbiol Rev, 2010, 23(2):274-298. (IF: 17.3)
- Tennant SM, Hartland EL, Phumoonna T, Lyras D, Rood JI, Robins-Browne RM, and van Driel IR (2008) The influence of gastric acid on the susceptibility to infection with ingested bacterial pathogens. Infect Immun, 76(2):639-645 (IF: 4.0)
- Read S, Hogan T, Zwar T, Gleeson PA, and van Driel IR (2007) Prevention of autoimmune gastritis in mice requires extra-thymic T cell deletion and suppression by regulatory T cells, Gastroenterology, 133(2):547-558 (IF: 12.5)
- Rudge G, Barrett SP, Scott B, and van Driel IR (2007) Infiltration of a mesothelioma by interferon γ-producing T cells and tumour rejection following depletion of regulatory T cells, J Immunol, 178(7):4089-4096 (IF: 6.4)
- Zwar TD, Read S, van Driel IR, and Gleeson PA. (2006) CD4+CD25+ regulatory T cells inhibit the antigen-dependent expansion of self-reactive T cells in vivo, J Immunol, 176(3):1609-1617. (IF: 6.9)
- van Driel IR, Read S, Zwar TD, and Gleeson PA (2005) Shaping the T cell repertoire to a bona fide autoantigen: lessons from autoimmune gastritis, Curr Opin Immunol, 17(6):570-576. (IF: 9.1)
- Allen S, Read S, DiPaolo R, McHugh RS, Shevach EM, Gleeson PA, and van Driel IR. (2005) Promiscuous thymic expression of an autoantigen gene does not result in negative selection of pathogenic T cells, J Immunol, 175(9):5759-5764.(IF: 6.9)