From the Walter and Eliza Hall Institute of Medical Research: Hobbit and Blimp1 May Be Needed for Local Tissue Immune Response
Reporter: Stephen J Williams, PhD
control a molecular program to protect the body.
Melbourne researchers have uncovered genes responsible for the way the body fights infection at the point of ‘invasion’ – whether it’s the skin, liver, lungs or the gut.
Research led by Dr Axel Kalliesand Dr Klaas van Gisbergen at the Walter and Eliza Hall Institute of Medical Research, and Dr Laura Mackay from the University of Melbourne at the Peter Doherty Institute for Infection and Immunity has identified the genes Hobit andBlimp1 and found that they control a universal molecular program responsible for placing immune cells at the ‘front lines’ of the body to fight infection and cancer.
The presence of these organ-residing cells, which differ strikingly from their counterparts circulating in the blood stream, is key to local protection against viruses and bacteria.
Walter and Eliza Hall Institute’s Dr Kallies said the human body was fighting disease-causing pathogens every minute of its life. Dr Kallies said identifying how immune cells remain in the part of the body where they are needed most was critical to developing better ways to protect us from infections such as malaria orHIV.
“Discovering these ‘local heroes’ and knowing how the localised immune response is established allows us to find ways to ensure the required cells are positioned where they are needed most,” Dr Kallies said.
“This research will help us understand how immune cells adapt, survive and respond within the organs they protect. This is critical to rid the body of pathogens even before they are established and may also have implications for understanding how the spread of cancer could be prevented.”
The Doherty Institute’s Dr Laura Mackay, who is also an associate investigator with the Australian Research Council Centre of Excellence in Advanced Molecular Imaging, said the factors that control the ‘tissue-residency’ of immune cells – their ability to locally reside in different organs of the body – was previously unknown.
“These results have major implications for developing strategies to induce immune cells in tissues that protect against infectious diseases,” Dr Mackay said.
“It’s a crucial discovery for future vaccine strategies – Hobit and Blimp1 would be key to placing immune cells in the tissues, which we know are really important for protection.”
The findings have just been published in the journal Science.
This research was supported by the Victorian State Government Operational Infrastructure Support and the Australian Government National Health and Medical Research Council Independent Research Institute Infrastructure Support Scheme.
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(centre) and Associate Professor Tarlinton led a
research team that identified a gene that is
essential for survival of antibody-producing cells.
Scientists have identified the gene essential for survival of antibody-producing cells, a finding that could lead to better treatments for diseases where these cells are out of control, such as myeloma and chronic immune disorders.
The discovery that a gene calledMcl1 is critical for keeping this vital immune cell population alive was made by researchers at Melbourne’s Walter and Eliza Hall Institute. Associate Professor David Tarlinton, Dr Victor Peperzak and Dr Ingela Vikstrom from the institute’s Immunology division led the research, which was published today in Nature Immunology.
Antibody-producing cells, also known as plasma cells, live in the bone marrow and make antibodies that provide a person with long-term protection from viruses and bacteria, Associate Professor Tarlinton said. “Plasma cells are produced after vaccination or infection and are responsible for the immune ‘memory’ that can persist in humans for 70 or 80 years. In this study, we found that plasma cells critically rely on Mcl1 for their continued survival and, without it, they die within two days,” he said.
Dr Peperzak said the team was surprised to find that plasma cells used this as a ‘failsafe’ mechanism in controlling their survival. “One of the interesting things we found is that because plasma cells rapidly destroy Mcl-1 proteins within the cell yet depend on it for their survival, they need continuous external signals to tell them to produce more Mcl-1 protein,” Dr Peperzak said. “This keeps the plasma cells under tight control, with Mcl-1 acting like a timer that constantly counts down and, if not reset, instructs the cell to die.”
Plasma cells are vital to the immune response, but can be dangerous if not properly controlled, Associate Professor Tarlinton said. “As with any immune cell, plasma cells are really quite dangerous in many respects and need to be tightly controlled,” he said. “When they are out of control they continue to make antibodies that can be very damaging if there are too many. This happens in conditions such as myeloma – a cancer of plasma cells – and various forms of autoimmunity, such as systemic lupus erythamatosus or rheumatoid arthritis, where there are excessive levels of antibodies.”
Myeloma is a blood cancer that affects more than 1200 Australians each year, and is more common in people over 60. It is caused by the uncontrolled production of abnormal plasma cells in the bone marrow and the build up of damaging antibodies in the blood. Rheumatoid arthritis and lupus are autoimmune diseases in which the antibodies produced by plasma cells attack and destroy the body’s own tissues.
Associate Professor Tarlinton said that his hope was that the discovery could be used to develop new treatments for these conditions. “Myeloma in particular has a very poor prognosis, and is generally considered incurable,” Associate Professor Tarlinton said. “Now that we know Mcl1 is the one essential gene needed to keep plasma cells alive, we have begun ‘working backwards’ to identify all the critical molecules and signals needed to switch on Mcl1 and keep the cells alive. Our hope is that we will identify some point in the internal cell signalling pathway, or a critical external molecule, that could be blocked to stop Mcl-1 being produced by the cell. This would be an important new platform for diseases that currently have no specific or effective treatment, such as myeloma, or offer new treatment options for people who don’t respond well to existing treatments for diseases such as lupus or rheumatoid arthritis.”
This research was supported by the Australian National Health and Medical Research Council, Multiple Myeloma Research Foundation, European Molecular Biology Organization and the Victorian Government.
Read the article in Nature Immunology: Mcl-1 is essential for the survival of plasma cells.
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Liz Williams
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Australian researchers find immune ‘kill switch’
as reported in http://www.abc.net.au/am/content/2012/s3649437.htm
Martin Cuddihy reported this story on Friday, December 7, 2012 08:12:00
TONY EASTLEY: For want of a better description we all apparently have an immune system ‘kill switch’.
Melbourne researchers have discovered why the body reacts the way it does when under stress from a severe infection.
They’ve found that the immune system switch destroys blood stem cells, and they’ve also discovered how to turn it off.
The discovery could mean a faster recovery rates from blood infections and from bouts of chemotherapy.
Martin Cuddihy reports.
MARTIN CUDDIHY: Worldwide, sepsis or blood poisoning is one of the leading causes of death in the intensive care units of hospitals.
When someone develops the condition the body goes into shock and blood stem cells start dying.
SETH MASTERS: You can think about it like suicide. The cells know that they should die to try and get rid of the infection but if the infection is overwhelming as it is with sepsis, then we need them to stay alive to help fight any infection.
MARTIN CUDDIHY: Dr Seth Masters from the Walter and Eliza Hall Institute in Melbourne is part of a research team that’s discovered the kill switch that tells cells when they should die.
Normally that’s a good thing, except when there’s a massive infection.
SETH MASTERS: You have to repopulate those immune cells somehow and these come from progenitor cells in the bone marrow and we think that this cell death pathway is something we can block to try and help the new cells regenerate to fight the infections better.
MARTIN CUDDIHY: So what does this cell receptor normally do?
SETH MASTERS: We are not entirely clear about that. We think that when a progenitor cell gets infected it’d be really bad if it stayed alive for too long cause it would pass that infection along to all of its daughters and sons.
So instead of staying infected, it just commits suicide and dies via this new pathway.
MARTIN CUDDIHY: Dr Masters is part of an international research team that’s found blocking a certain cell receptor stops blood cells from dying.
The researchers hope the discovery could lead to a treatment for sepsis and a way to help boost the immune system of cancer patients undergoing chemotherapy.
SETH MASTERS: I think that probably the most likely avenue where it could be of use is in trying to help recovery from chemotherapy. That’s a period during which we really need as many cells to mobilise out of the bone marrow into the periphery as possible to try and fight any potential infections that might be coming along.
And so we think that this cell death pathway might be stopping that from happening quickly and if we can inhibit it, we can make it go faster.
MARTIN CUDDIHY: Does that mean then that someone could be subjected to a more intense round of chemotherapy if this was to work and therefore you could boost their immune system following that round of chemo?
SETH MASTERS: Yeah, that does seem like a relatively attractive proposal. It is not something we have actually validated just yet but that would have to be on the cards if we can do some more research down those lines.
MARTIN CUDDIHY: The findings are published today in the medical journal Immunity.
TONY EASTLEY: Martin Cuddihy.
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