Molecular Sciences Bldg 21, James Cook University,
Townsville, 4811, Queensland, Australia
Telephone: 61-7-4781 6265 Fax: 61-7-4781 6078
Genomics Group is working to determine the causes of autoimmune
using both cellular and genetic techniques. Current projects study: the
genetics of autoimmune diabetes, gastritis and lupus in mice; the
of mycobacteria on autoimmune diseases; and the role of
NKT cells in childhood diabetes.
A major focus for the group is the study of interactions between genetic and environmental factors in causing autoimmune disease. Our understanding of these genetic and environmental factors has been greatly aided by the inbred NOD mouse model (pictured) which spontaneously develops autoimmune diabetes, but is protected by treatment with Mycobacterium bovis, the BCG vaccine.
NOD mice are a well established model of both type 1 diabetes and systemic lupus erythematosus. They spontaneously develop lymphocytic infiltrates of their islets of Langerhans in the pancreas, and in the majority of females, this pathology progresses to complete destruction of the insulin-producing beta cells, resulting in diabetes. Many genes encoding susceptibility to diabetes in this model have been mapped by us and other groups.
If NOD mice are exposed to mycobacteria between three and ten weeks of age, they are protected from the onset of diabetes, but tend to develop another autoimmune disease, systemic lupus erythematosus. Our group was responsible for all of the original characterisation of this model. Lupus in both patients and NOD mice is characterised by the production of antibodies specific for multiple cellular constituents. This results in antibody clumping and deposition in fine vascular beds (such as those in the kidneys and skin) resulting in the activation of inflammatory processes and tissue damage. About 50% of women with lupus develop kidney failure.
We postulated that the autoimmune diseases diabetes and lupus represented two different expressions of the same basic tendency to autoimmune disease in these mice, and that exposure to the environmental factor mycobacteria was responsible for switching between the two expressions (phenotypes) of this underlying susceptibility.
This hypothesis was disproved in two ways. Firstly, mycobacteria were sonnicated and then subfractionated, and the individual subfractions tested for their abilities to prevent diabetes and precipitate lupus. We have identified a single subcomponent, MAPG, which can prevent diabetes without inducing lupus. This product is in the final stages of preparation for clinical trials in children who are known to be at a high risk of developing type 1 diabetes.
The second way in which we were able to demonstrate that diabetes and lupus were independent in the NOD mouse model, was by performing a whole genome screen of loci encoding susceptibility to lupus induced by mycobacteria. We then compared the genetic locations of the lupus genes with those of the diabetes genes. With the exception of the MHC region on chromosome 17, which is involved in almost all autoimmune diseases, the genes did not co-localise.
NKT cells are a small population of white blood cells that play a critical role in controlling the size and character of immune responses against bacteria, viruses, parasites, tumours and the body's own tissues. Indeed, both diabetes and lupus are associated with numerical deficiencies in these cells; we were responsible for demonstrating this deficiency in NOD mice. When we mapped the genes controlling numbers of NKT cells in mice, only two genetic regions were identified: one was on distal chromosome 1 and mapped to the same location as our previously mapped major lupus gene, and the other was on chromosome 2, and mapped to the same region as an important diabetes susceptibility gene. It seems likely that these two regions play important roles in both autoimmune disease susceptibility and control of NKT cells, and it is possible that disease susceptibility is a consequence of these genes' effects on NKT cell numbers.
Our current work is focussed on identifying the coding sequences responsible for these phenotypes. We have produced congenic mice for each segment in order to narrow down the region under consideration, and are now applying the candidate approach to positional cloning by examining the protein coding regions within these areas that could conceivably play a role in controlling NKT cell numbers. These protein coding regions are being characterised by sequencing the cDNA from both parental strains and characterising the levels of expression of the gene in each strain and the congenic lines by reverse transcriptase PCR.
Genomics Research Group is very grateful for the generous support of
Australia and the National Health and Medical Research Council of
diseases are conditions in which the body's defence (immune) system
part of the body itself. The targeting of this attack is directed
by specialised proteins called antibodies, or else by a subset of white
blood cells called T cells. It is not known why some individuals
these diseases while most do not, but they are relatively common and
cause serious health problems and even death. The most common
|Autoimmune thyroid disease (Hashimoto's Disease, Graves Disease)||2|
One way of discovering
cause of these diseases is to examine the genes associated with them.
Childhood diabetes (type 1, or Insulin dependent diabetes mellitus) is known to be caused by autoimmune mediated destruction of the insulin producing cells in the pancreas. The NOD mouse is a type of mouse which develops a disease equivalent to human type 1 diabetes and has been used as a model for testing new therapies for prevention and treatment of potential value in the human disease. The genes responsible for diabetes in these mice have been well studied, but one hurdle facing future work is our ignorance of the mechanisms whereby they actually affect the immune system.
In many immune responses, one or other pattern of reactivity dominates. In some reactions, a predominantly cellular response occurs and white blood cells (especially T lymphocytes) mediate tissue destruction. This is a common response to viral infections. In other reactions, antibody production predominates, often in response to bacterial infection. These two types of response are counter-regulated so that the cell hormones (lymphokines) which mediate cellular responses tend to ameliorate antibody responses. There are many lines of evidence to suggest that type 1 diabetes is mediated by an inappropriate cellular response to the insulin-producing beta cells (pictured) and may be prevented by an ongoing antibody response. Although NKT cells make up only a tiny proportion of the lymphocytes in the immune system, they have a powerful action and produce large amounts of the lymphokine (IL4) which enhances antibody responses and inhibits cellular responses. Two recent experiments suggest that they are responsible for determining whether a cellular or antibody response is made. NOD mice spontaneously develop type 1 diabetes and we have shown that they have very few NKT cells. Other workers have shown that NOD mice make less IL4 than other strains, which is consistent with their relative lack of NKT cells. We think this defect may result in these mice being more likely to make cellular responses and may partly explain the nature of the autoimmune response to the islets in diabetes. In support of this hypothesis, we have shown that we can prevent diabetes in NOD mice by injecting them with extra NKT cells.
currently trying to find out how these cells prevent diabetes, identify
the genes which control them and examine their role in human diabetes.
Multiple Sclerosis (MS) is a complex genetic trait resulting from the
contributions of multiple genetic and environmental factors (1). It is
a chronic immune-mediated inflammatory/demyelinating disease of the
central nervous system that occurs in young adulthood and is more
common in women. To date, there is no cure or preventative therapy for
MS and the mechanisms underlying the initiation and progression of MS
are still unclear. Genetic and epidemiological studies have identified
some reproducible associations, such as HLA alleles, UV exposure,
cigarette consumption and microbial exposure. The Lions Clubs of
Australia, Charities for MS and the Federal Government ARC Linkage
Scheme are jointly supporting a collaborative network involving the
CGC, Florey Institute (Melbourne), the Royal Melbourne and Box Hill
Hospitals and the Menzies Medical Research Institute (Hobart) to study
gene expression in patients with MS.
lupus erythematosus (lupus) is an autoimmune disease in which the
of antibodies against many normal cell components results in the
of proteins in the small blood vessels, inflammation, and subsequent
to many parts of the body, including the skin, joints, kidneys and
About half of lupus patients develop significant kidney disease (termed
lupus nephritis) and this is a strong predictor of a poor outcome. In
nephritis, immune complexes, consisting of antibody and cell
are deposited in the filtering units of the kidney. This gives a
"lumpy bumpy" pattern when stained with fluorescent reagents that bind
either antibody or the inflammatory mediator complement.
We have found that injecting BCG (the anti-tuberculosis vaccine, M.bovis) into NOD mice prevents diabetes, but causes the onset of lupus. We have been studying what genes are responsible for causing lupus in NOD mice, and comparing them to the genes already known to cause diabetes. We examined the idea that some genes cause both lupus and diabetes because they control how likely the immune system is to attack the body's own tissues. This project was a major undertaking for the group and has taken five years to complete. Approximately 900 female mice were clinically monitored for almost a year after vaccination with BCG. Mice which developed haemolytic anaemia, antinuclear antibodies and lupus nephritis (pictured), as well as a group of unaffected mice were then gene typed at over 150 genetic locations. This linkage analysis localised both genes which are shared with diabetes as well as other genes which are shared with other mouse models of lupus. The identification of these genes will be of great help in understanding what causes lupus and in developing safer ways of treating or preventing diabetes.
We are now using the genetic information obtained in the gene mapping study to produce mice carrying only one or two disease susceptibility genes on a normal genetic background, in order to study the interactions between them and the environmental disease trigger, BCG.
is a disease in humans which destroys the acid-producing cells in the
and is associated with the development of pernicious anaemia (vitamin
deficiency) and cancer of the stomach. The thymus is the organ that
T cells, which are the white blood cells that provide the cellular
from infections and cancer. If the thymus is removed from some kinds of
mice while they are still very young, the few T cells that have left
thymus start to damage the host's own tissues. Together with
in Dr Ian van Driel's laboratory at the University of Melbourne, we are
using this experimental approach to study the BALB/c inbred strain of
These mice, after removal of the thymus, develop T cell-mediated damage
of the acid-producing cells of the stomach, resulting in a disease that
closely resembles autoimmune gastritis in humans. We have identified
locations of four genes which are responsible for causing gastritis amd
one of them appears to be especially important, because it has the
effect and may also be involved in diabetes and lupus. We currently
this gene in more detail by locating it more exactly and by examining
effect on mice not normally prone to gastritis.
Germ Warfare: Breakthroughs in Immunology
Warfare is a popular science book about immunology. The aim of
the book was to explain, in a reasonably accessible way, a little about
how the immune system works. It was targeted at intelligent lay people
- particularly those in the latter years of high school and the early
of their undergraduate education. The primary goal of the book was to
the science palatable by placing it in a human context - by embedding
in anecdotes told by those who actually did the work.
Those who are interested in finding out more about the book may wish to visit its web site, which contains chapter outlines and the reviews published to date.
Asimov's Elephant is a collection of the
from Radio National's acclaimed science program 'Ockham's Razor'.
Razor' is a wide-ranging and popular Radio National series that is
as part of the Science Show. It features prominent speakers from a
of scientific fields who talk about aspects of their work. The talks
contemporary social and philosophical issues in conjunction with recent
research in areas such as health, agriculture, the environment,
genetics, mathematics and more.
Many of the subjects which were introduced on the Science Show during the last seven years have particular currency today. Issues such as cloning technology and its implications for humanity; biological warfare and what can be done to eliminate the dangers; the ramifications of salinity and the need for sustainability; the importance of vaccination; and the reasons behind people's reluctance to use public transport are just a few being actively debated. Other subjects are fascinating in their own right. Robyn Williams provides a lively, provocative and stimulating collection.
Flanders, Karl Landsteiner and a Belief in Fairies
Beer of Revenge
Secrets of the
Immune System Fly
A piece of my Mind
SOON TO COME:
Photo copyright: Nicole Fraser
POSITIONS IN THE MEDICAL GENOMICS GROUP:
Students interested in undertaking a PhD or Masters project in the Medical Genomics Group should contact Alan Baxter to discuss projects of mutual interest. Most higher degrees students would be expected to eligible for a scholarship through the Australian Postgraduate Award (APA) scheme, the James Cook University Postgraduate Research Scholarship or an equivalent national or international scholarship.
The Australian Postgraduate Award (APA) and James Cook University
Research Scholarship (JCUPRS) are open to applicants with, or who
to hold, a first class honours degree or equivalent by the end of the
and who wish to undertake full-time research Masters or PhD program. In
2005 the stipends for an APA were $18,484 pa (full time) or $9,906
Additional funds are available for relocation expenses, travel and
preparation. APA applicants must be Australian citizens or have been
permanent resident status and lived in Australia continuously for 12
prior to 31 October of the year of application. Follow
this link for further details.
Information and application forms can
be obtained from the Research Scholarships Officer or from the
Closing Date: 31 October of each year
Students who have completed their undergraduate training in a BSc, BBiomedSc, BMedlabSc or equivalent program and are interested in participating in the Biochemistry and Molecular Biology Honours Program are encouraged to contact Alan Baxter for a description of currently available projects. Honours studies require a full-time commitment for one year (two semesters) and can start in either February or August. Follow this link for details.
There are two main opportunities for undergraduates to participate in the ongoing research of the Medical Genomics Group.
Students enrolled in BC3203 (Special Topics in Biochemistry and Molecular Biology - second semester) could ask that they undertake their research project in the Medical Genomics Laboratory. Research projects will be in the area of environment/gene interactions and immunogenetics of autoimmune disease.Students can apply for a Comparative Genomics Centre Vacation Scholar Award. The successful applicants receive instruction in the latest genetic and immunological techniques, receiving a stipend of $200 per week for a full-time commitment of between 6 and 10 weeks over the summer break. Applications for the CGC Vacation Studentships are announced in September each year and close in late October. Contact Alan Baxter for further details.