Gut Feeling

Many illnesses are linked by one common factor - the immune system - so increasing our knowledge of how it works will have wide benefits

WHEN YOU hear the words “immune system”, what springs to mind? Armies of James Bond-like cells coursing through your veins, seeking out and destroying invaders such as bacteria, viruses and parasites?

Well, it paints a good picture, but it turns out there’s a lot more to our bodily defences than that, and dealing with acute infection in the bloodstream is only the tip of the iceberg.

The last couple of decades have blown open the field of immunology with discoveries about how our immune system works at a molecular level to keep us alive and healthy, and what happens when it backfires and gets triggered inappropriately.

And it’s now emerging that conditions which bear little resemblance to each other on the surface – including cancer, diabetes, obesity, arthritis, bowel diseases, multiple sclerosis and even infertility – all share one thing in common: an altered immune system.

Understanding those similarities could be the key to treating not just one, but many of those diseases, according to Cliona O’Farrelly, professor of comparative immunology at Trinity College Dublin.

“People might be studying the inflammatory process in rheumatoid arthritis, in diabetes, in irritable bowel syndrome or in the liver, but the molecules and cells that are responsible for that activity are identical,” she says. “So if you find a way of controlling it in one place, that could be applied elsewhere.”

O’Farrelly’s work has focused on how individual organs have their own specific immune systems – a concept that originally started with the gut, which has its own immune setup in situ to monitor what’s passing through – and identify potentially dangerous bacteria and viruses.

“The appreciation that what was going on in the gut was different to what was going on in the lymph system has been around for 15 to 20 years and is now evolving much more clearly,” she explains.

O’Farrelly has since added to that idea of organ-level immune systems, teasing out clues from the liver and the uterus about how they make their own immune cells – not only to protect themselves from infection and cancer, but also to recognise when they should leave well alone.

“Those organs – the gut, liver and uterus – come into contact with foreign material that is harmless, like dietary antigens in the gut and liver, and foetal antigens in the uterus,” she says.

Mounting an inappropriate immune response to a foetus can result in infertility, while setting off the alarm to a food component like gluten can lead to coeliac disease. And if “good” bacteria trigger inflammation in your gut lining it may underpin bowel disease like Crohn’s, she explains. “It’s really important that you don’t mount an immune response against those.” O’Farrelly is figuring out how the liver’s immune system reacts to chronic infection, such as hepatitis C, and meanwhile her work on the womb suggests it generates its own immune cells, which are altered in women who are infertile. The hope is that such findings could lead to more specific diagnoses or treatments of both conditions, she says.

Even fat is in on the game and has its own immune cells. O’Farrelly’s work with University College Dublin has shown that in obesity a normally protective sheath of belly fat called the omentum turns tail – it becomes inflamed and appears to suppress the cells of the immune system that normally ward off tumours and viruses and promote healing.

“The fat becomes an immune organ – because it’s so big it harbours all these immune cells and seems to have this suppressive effect, and individuals are more prone to cancer and infection and slower to heal.”

And compromised immune systems aren’t just the dubious privilege of humans. Understanding immunity can give animal health a boost too, says O’Farrelly, who has been working with Teagasc and UCD to join the dots between stress in dairy herds and infertility.

“There has been huge emphasis on the milk yields in the dairy herd, and that puts enormous stress on the system. Heavily stressed cows then get an inflammatory response in the uterus which makes them more susceptible to endometritis and that affects fertility,” she says.

Understanding why this happens in the million-strong herd could have enormous economic potential, says O’Farrelly, whose work is funded from a number of sources including Science Foundation Ireland, Department of Agriculture and the Research Stimulus Fund.

Chickens, too, are under the spotlight, thanks to their ability to live happily with a tummy bug called Campylobacter, while humans can suffer gastroenteritis if we ingest it uncooked.

“I’m really interested in what it is about the immune response of chickens that allows them to tolerate [Campylobacter] and yet we can’t,” says O’Farrelly.

Some chickens harbour the bug and don’t fall ill, while others seem genetically endowed with a means to stop it from colonising their guts in the first place, she explains.

“The poultry industry in this country is worth a fortune and if we could come up with a way of breeding chickens that do not carry ‘Campy’, think of what it could save our nation healthwise and think of the money you could make from it. People are inclined to think of research being this esoteric thing carried out in ivory towers, but there’s very real money involved.”

Gut Bacteria - Educating your immune system

BELIEVE IT or not, you carry around a kilo of bacteria inside your gut. And you can hardly have missed the message in every ad break that having the right kinds of bugs in there can contribute to good health.

But what do those “friendly” bacteria actually do? One of their remits is to educate your immune system, according to Dr John MacSharry and Dr Elizabeth Brint from the Alimentary Pharmabiotic Centre (APC) at University College Cork.

“Most people think your immune system is in your blood, but the area of your body with the most immune cells and recognition is your gut,” says MacSharry. “The whole gut – the alimentary canal – is the largest area of the body exposed to the outside world because of the bacteria and food particles there, and it has to constantly monitor what is going through for harmful [pathogens].””

The immunological frisking takes place at the single layer of cells that lines the inside surface of the gut: cross-talk between the bacteria and specific Toll-Like Receptors (tolls) on the gut lining activates biochemical pathways to keep the gut lining robust if all is well, or to trigger inflammation if a pathogen is starting to invade.

“The bacteria inside your gut aren’t just sitting there,” says Brint. “They are educating your underlying immune system through these [tolls] and that’s allowing your gut immune system to become more aware of what is going on in the gut lumen – is it normal or is there a pathogen there?”

If the communication goes awry and you mount an inappropriate immune response to the “good” bacteria, it could underpin conditions like Crohn’s disease and irritable bowel syndrome (IBS).

So, research at the Science Foundation Ireland-funded APC is looking at how changing the gut flora can help restore harmony in inflamed bowels and possibly even improve non-gut conditions such as asthma. A spin-out company, Alimentary Health, has marketed a UCC-developed probiotic supplement for IBS, and the push is on now to pinpoint more targeted molecules that could be used therapeutically.

“We are looking at what component of the bacteria stimulates the immune system in this way,” she says. “Because it’s one thing to feed the whole bug to someone, it’s another to give a little compound which is really going to affect the immune system.”

Swine Flu - efficiency in vaccines

WITH SWINE flu infecting the headlines, talk is buzzing about impending vaccines, which are undergoing trials and due to be rolled out over coming months.

One of the tricks of the trade is to use agents called “adjuvants” to make vaccines more efficient, meaning that lower doses can be given and existing stocks can be stretched.

The recent bird flu (H5N1) threat and the swine flu (H1N1) pandemic have boosted research in the area, says Dr Ed Lavelle, head of the adjuvant research group at Trinity College Dublin.

“Adjuvant is a generic term for any substance that can enhance the immune response to an antigen, and an antigen is anything you can get an antibody against – most vaccines will contain either one antigen or a mixture,” he says.

“In some cases the vaccine by itself gives you a strong response but in most cases you have to add something to it to enhance the immune response so you get protection against the disease.”

The approach is particularly relevant for the pandemic H1N1 or swine flu vaccine, adds Lavelle. “We don’t have immunity against swine flu so you are starting at a lower level of immunity, and it’s unlikely that we can make enough vaccine to immunise everyone fast enough, so you need to do something to enhance the response.”

Aluminium hydroxide, or alum, is often used as a vaccine-boosting adjuvant, but more recently oil and water mixtures have been proving their mettle too, explains Lavelle.

In the meantime, research is continuing into how adjuvants actually work. “Particles have been known to activate the immune system for around 100 years but we haven’t known specifically how they do it,” says Lavelle.

His own research group, which collaborates with Novartis and receives funding from Science Foundation Ireland, Enterprise Ireland and Sigmoid Pharma, looks at how various adjuvants affect inflammatory pathways in cells and animal models.

“Depending on what type of adjuvant you use, you can get different effects. So the key thing now is trying to understand how adjuvants modulate these effects.”