Antibody Target for Autoimmune Diseases
First Published: Flinders University - February 2012
A revolutionary medical breakthrough by researchers at Flinders University could pave the way to a cure for two debilitating autoimmune diseases.
PhD student Rhianna Lindop has developed a world-first technique in conjunction with Flinders proteomics experts Dr Georgia Arentz and Dr Tim Chataway to analyse a type of antibody that contributes to the disease progression of lupus and Sjogren's syndrome, resulting in vital new information that could ultimately lead to targeted therapies.
Lupus and Sjogren's syndrome are autoimmune diseases caused when the body mistakenly considers healthy tissue to be a harmful substance and, as a result, produces antibodies that actually attack the body's own organs.
"We all have proteins in our body but in people with autoimmune diseases the body recognises these 'self' proteins to be foreign and responds to them by producing antibodies that attack and destroy healthy tissues and organs," Ms Lindop (pictured with Flinders Professor Tom Gordon) said.
"Usually when you're sick the body produces antibodies to fight off the infection but it has the opposite effect in people with autoimmune diseases," she said.
Using a mass spectrometry machine, the researchers have - for the first time - analysed the antibody's molecular structure in 10 patients with lupus and Sjogren's to determine its sequence at a "protein level" rather than just on the genomic, or DNA scale, as previous research has done.
The findings have shown that all patients with the particular antibody demonstrated a common molecular signature.
"People always thought these antibodies were too complex to characterise but we found the antibody was restricted and common to all of the patients and specified by unique features," Ms Lindop said.
"This means that we can now focus on developing novel targeted therapies aimed at removing the antibody in people with lupus or Sjogren's - and the same research could also be applied to other antibodies associated with other autoimmune diseases."
With no cure for the two conditions, Ms Lindop said her groundbreaking research could lead to a "next generation of diagnostics and therapeutics".
"Current immunosuppressive treatments are aimed at reducing the effects of the disease but they don't actually alter the antibody so this research could allow us to develop a drug that specifically targets the antibody," she said.
"It's really exciting because it fits into the bench to bedside concept - we're doing research at the bench that actually translates to the hospital bed to improve lives."
Ms Lindop was a recent winner in Flinders University's Best Student Paper Award, a new initiative which aims to recognise, reward and promote excellence in student research.
Seeking Solutions for Scleroderma
First Published: ENews - February 2010
February is national Scleroderma month, and as home to Australia’s only population-based register of scleroderma sufferers Flinders is at the forefront of research which is helping patients with this rare disease live longer.
About 25 South Australians are diagnosed each year with scleroderma, a disorder which causes damage to and loss of the capillaries which deliver oxygen to the skin. This leads to hardening skin, ulcerations over joints and impaired mobility.
Scleroderma’s most serious form can also severely shorten the sufferer’s life by causing fibrosis (thickening of the tissue) of the internal organs.
Established in 1993 by Professor Peter Roberts-Thomson and his team in the Department of Immunology, Allergy and Arthritis, the South Australian Scleroderma Register tracks the prevalence and incidence of the disease in South Australia.
Recently, the database has been expanded to include autoantibodies (specific blood markers) for scleroderma and survival data. Clinicians can now use this information to determine the type of scleroderma the patient has, prognosis, and how best to proceed with treatment.
“Patients are now living longer because of better management,” Prof Roberts-Thomson said.
Prof Roberts-Thomson and his team hope to determine the cause of the disease and whether its progress can be halted by looking at the capillaries which are damaged in its early stages.
Honours student Karen Patterson is using video imaging of the blood vessels at the base of the fingernail (one of the first places to show signs of damage) to track the changes that occur over time.
It is hoped the project will lead to a better understanding of the pathological processes that cause the loss of capillaries.
“If we could understand why the blood vessels are being damaged we could hopefully interfere with that process and block it,” Prof Roberts-Thomson said.
Scleroderma - Unlocking The Mystery
First Published: Investigator - January 2003
Scleroderma is an uncommon immune disorder where the skin becomes hard and thickened and the patient literally becomes entrapped in their own skin. The sufferer's life is frequently shortened due to the thickening or fibrotic process also impairing internal organs.
South Australia has one of the highest scleroderma prevalence figures in the world with around 350 sufferers registered. The usual age of onset is between 40 and 60 years.
Unfortunately the cause of scleroderma is unknown and there is no specific treatment.
At Flinders Medical Centre, Professor Peter Roberts-Thomson and his team in the Department of Immunology, Allergy and Arthritis are investigating the reasons behind why the body turns against itself and produces hardened skin with distressing joint contractures.
They have recently completed an epidemiological study into the genetic component of the disease to ascertain whether sclerodema can be inherited. The study showed that the disease is more common in immigrants born Europe (particularly Greece and Italy) as well as people that may have been exposed to silica dust. However there is not enough evidence to show that any particular job is more likely to cause the disease.
However the study has been unable to explain why the disease is also more prevalent in women than men with a ratio of 4:1.
In addition to using the epidemiological study, the team is also researching the disease on a micro-vascular level. A microscopic examination of the skin's blood vessels, will then be carefully examined to hopefully determine how they are being damaged.
Professor Roberts-Thomson said that the establishment of a South Australian register for scleroderma sufferers has had many benefits for the advancement of knowledge about the disease.
"Having a register allows continuous in-depth research work as well as the trial of new therapies in controlled studies. Because of this, we have been able to recently study a new treatment called anti-endothelin which neutralises one of the substances released from the small blood vessels. In time we hope to be able to unlock the mystery surrounding this disease and offer some form of life-saving treatment for its sufferers."
Genetic Discovery For Multiple Sclerosis
First Published: Investigator - June 2009
An Australasian multiple sclerosis (MS) study has discovered variations in two genes which could contribute to the development of the disease.
MS is an inflammatory disorder of the brain and spinal cord and affects almost 20,000 people in Australia. It is the most common cause of neurological disability in young people; however its cause is a mystery.
The research is one of the largest genetic studies in MS ever to be undertaken. It involved scanning the DNA of more than 5,000 people – 1,600 with MS and 3,400 without MS.
The study was conducted by The Australian and New Zealand Multiple Sclerosis genetics consortium (ANZGENE). ANZGENE is a collaboration of MS clinicians and scientists, supported by Multiple Sclerosis Research Australia and the Australian Research Council.
Dr Mark Slee, Neurologist from the Flinders Multiple Sclerosis Service and Department of Neurology, is part of the consortium. He said findings from the research provide a platform to target new therapies aimed at early treatment or disease prevention.
‘The chance of developing MS comes from environmental factors acting on a genetically susceptible person,’ he said.
The ANZGENE study, recently published in the prestigious scientific journal Nature Genetics, found that people with MS are more likely to have several genetic variants on Chromosome 12 and Chromosome 20 which are linked to immune function and contribute to the development of MS. Previous genetic studies in MS have implicated other immune related genes in MS susceptibility.
On Chromosome 12, one of the genetic variations contributing to MS risk was found to be involved in the metabolism in Vitamin D (the CYP27B1 gene). Other auto-immune diseases, such as Type 1 Diabetes are also associated with changes in the same gene.
‘The new gene variation associated with Vitamin D metabolism is very important,’ Dr Slee said. ‘This gene variation may provide a link between genetic risk and environmental factors which determine MS susceptibility.’
On Chromosome 20, a further MS susceptibility gene was found – the CD40 gene.
Variations in this gene are also associated with other autoimmune diseases such as Rheumatoid Arthritis and Graves’ disease. This gene is important in regulating activity in many parts of the immune system and how immune cells become activated to cause inflammation in the nervous system.
Researchers will now ‘fine map’ the newly discovered genes to gain a better understanding of their role in MS which could lead to the development of new therapies for treatment of the disease.
First Published: Investigator - March 2009
Health Talk speaks to Professor Malcolm Smith, Regional Director of Rheumatology for the Southern Adelaide Health Service about the symptoms, causes and treatment for Lupus.
Lupus is an inflammatory autoimmune disease that causes tissue in the body to become inflamed, swollen and painful. The body’s immune system, which is designed to produce antibodies to destroy viruses or bacteria, mistakenly produces antibodies to attack healthy tissue.
There are several types of Lupus, including systemic lupus erythematosus (SLE), discoid and drug-induced lupus. SLE is the most common type.
Depending on which tissues are attacked, lupus can be anything from mild to life threatening.
Who does it affect?
Lupus can affect people of all ages and sexes, but most commonly it tends to affect women of childbearing age. Lupus affects around one in 700 Australians.
What causes lupus?
The cause of lupus is unknown; however it does appear to have a genetic component. Once a person is diagnosed with lupus they can expect to experience episodes of it throughout their life. In between episodes they may be symptom free.
What are the symptoms?
Episodes of lupus can cause pain and tiredness. Lupus can cause inflammation in many parts of the body including:
- The joints. Joints may become swollen and painful
- The skin, causing a rash, ulcers (over the body and in the mouth ulcers) and possibly hair loss
- Major organs such as the kidneys or lungs. Symptoms may include pain and affected function of the organ.
Lupus can cause a range of symptoms, but sufferers generally don’t have all of them. Symptoms can include:
- Joint or muscle pain
- Fever (often low grade)
- Mouth ulcers
- Chest pain
- Extreme tiredness
- Skin rash
- Hair loss
- Sunlight sensitivity
- Kidney problems
- Clotting problems
- Unexplained headaches, migraines or mood swings.
How is lupus diagnosed?
Lupus is diagnosed by a combination of sight, symptoms and testing for the presence of certain antibodies in the blood.
How is lupus treated?
There is no cure for lupus, but it can be controlled with medication. Medications used to treat lupus and its symptoms include:
- Non-steroidal anti-infl ammatory drugs (NSAIDs)
- Oral cortisone
- Oral plaquenil
- Disease-modifying anti-rheumatic drugs (DMARDs).
Sources: Professor Malcolm Smith; Health Insite www.healthinsite.org.au and Better Health Channel.
Researchers Revolutionise The Treatment Of Rheumathoid Arthritis
First Published: Investigator - August 2003
After ten years of international collaboration, Flinders researchers have helped to develop a new therapy for the treatment for rheumatoid arthritis - a debilitating disease that effects 2% of the population.
Designed for chronic sufferers, this new therapy is hoped to revolutionise the treatment of rheumatoid arthritis by inhibiting the production of the chemical substances in the body which cause this disease.
Enbrel, has been released onto the PBS Scheme but due to the high cost ($25,000) will only be administered by rheumatologists to patients who meet the very strict criteria and there are long term side effects.
Unfortunately it isn't the cure but is a major improvement of what is currently available to chronic sufferers of rheumatoid arthritis.
Further to this breakthrough, Flinders investigators continue to work on early diagnosis and pain management of rheumatoid arthritis to help slow the progression of the disease. The FMC Arthritis Tissue Bank, established in 1996 by Dr Malcolm Smith, provides a rich resource for researchers wanting to understand the impact of existing and new drug therapies.
"If we can identify early that a treatment is not working and therefore change the treatment, it will spare the patient great discomfort," said Dr Smith.
"At present our research efforts are establishing whether taking a biopsy before someone starts treatment will direct what their outcome will be or, alternatively, by taking the biopsy during treatment we can determine whether the treatment is working or not, and if so change the therapy. Ultimately, we want to avoid treating people unnecessarily," he said.
Rheumatoid arthritis is the commonest form of inflammatory arthritis in the western world effecting most small joints in the body. There is no cure, but the work of Dr Malcolm Smith is a positive step toward the pain management and slowing the progression of this devastating disease.
First Published: Investigator - June 2009
Scleroderma literally means ‘hard skin’ and is a disease of the body’s connective tissue. It is thought to be an example of an auto-immune disorder where the body’s immune system starts to attack the body.
Professor Peter Roberts-Thomson, Clinical Director of Immunology for SA Pathology and Bachelor of Science Honours student Karen Patterson discuss the disease and their latest research.
What is scleroderma?
Scleroderma (also called Systemic Sclerosis) is a disease of the body’s connective tissue. The human body is held together by meshes of connective tissue. These ‘nets’ consist of a strong, fibrous collagen, stretchy elastin and a substance called proteoglycan. People who develop scleroderma overproduce collagen, which can result in the connective tissue and skin becoming hard and tight. Scleroderma can affect just the skin, or more seriously, internal organs including the heart, lungs and kidneys.
How common is it?
Up to one in 5,000 Australians may have one of the different forms of scleroderma. It is more common in people aged between 20 and 50 and affects women more than men.
What causes scleroderma?
The cause of scleroderma is unknown. However, the strongest risk factor is a family history of scleroderma but other risk factors are believed to include occupational exposure to silica dust (which is commonly seen with miners) and chemicals like polyvinyl chloride (PVC).
How do you know if you have it?
One of the most common symptoms of scleroderma is thickening and hardening of the skin, often on the hands and face. Other symptoms can include:
- fingers and toes going white, blue and then red in response to cold and heat (a condition called Raynaud's phenomenon)
- pain, stiffness, and swelling of fingers and joints
- tight mask-like skin on the face, and shiny skin on the arms
- ulcers on fingertips or toes
- shortness of breath
Are there different types of Scleroderma?
Yes. Scleroderma is broadly classified according to the amount of skin and internal organs affected by the condition – limited scleroderma and diffuse scleroderma. The latter is a more serious form of the disorder as there is more extensive skin involvement and the internal organs are more severely affected.
How can it be treated?
There is currently no cure for scleroderma but it is possible to successfully manage many of the symptoms of the disease. A number of clinical trials are currently underway involving exciting new drugs but it will 1-2 years before the results are made public (as scleroderma is an uncommon disease and it takes time to recruit sufficient patients for these trials).
How is scleroderma diagnosed?
Scleroderma is diagnosed using a range of medical tests including history and physical examinations, blood tests including a test for autoantibodies (antinuclear antibodies or ANA) and tissue biopsies.
How is scleroderma managed?
Managing the disease depends on its severity, but may include medications such as immunosupressives, lifestyle changes, gentle exercise, stress management and various aids and equipment.
Is there any new research in the area?
Flinders is at the forefront of research into scleroderma. Over the last 15 years Prof Roberts-Thomson and his team have established the South Australian Scleroderma Register which attempts to identify every new patient in SA with this condition. From analysing data common to each patient it has been found that the important risk factors for this disease in SA include a positive family history, being female and being born in Europe (as compared with being born in Australia).
Investigations have also focussed on the specific auto-antibodies in the blood characterising this condition and their help in making an early diagnosis and their prediction for future disease outcome.
Damage to small blood vessels is an early and prominent feature in scleroderma. For her BSc (Hons) Karen Patterson is investigating this vascular damage at the base of the finger nail (nail fold capillaroscopy) using video-microscopy (combining a microscope with a computer) and investigating factors which may accelerate or inhibit this damage.
Such studies are increasing our understanding of the basic pathology of this disease and may help us develop specific tests for early diagnosis and for medication which may inhibit this vascular damage.