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Trigger identified that likely unleashes autoimmune disease

deleder2k

Senior Member
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Australian researchers believe they have discovered a group of cells that trigger autoimmune disease, as well as the molecular 'trigger guard' that normally holds them in check.

Source: ScienceDaily.com

Published in the respected journal "Immunity" (impact factor 19.748 as of 2013)

Australian researchers believe they have discovered a group of cells that trigger autoimmune disease, as well as the molecular 'trigger guard' that normally holds them in check.

Dubbed 'rogue germinal centre B cells', these previously undetected cells are renegade versions of the germinal centre B cells that make the 'high affinity' antibodies required for long-term immunity.

When we develop an infection, or are vaccinated, we create antibodies that attack invading microbes. When we develop an autoimmune disease, we create antibodies that attack ourselves.

During a normal immune response, B cells that encounter foreign 'antigen' (such as a virus or bacteria) migrate to germinal centres, transient microstructures that form in lymph nodes and tonsils. Once inside, B cells mutate their antibody genes randomly until they produce an antibody with high affinity to the invader.

At that point, successful B cells transform into small antibody factories known as 'plasma cells', which multiply and flood the system with new antibodies.

Unfortunately, the urgency and speed at which B cells mutate, as well as the random nature of the process, sometimes creates B cells with high affinity 'autoantibodies' that happen to match 'self'. Such cells must be inactivated in order to avoid autoimmune disease.

The process by which autoantibody-producing B cells are prevented from developing in the germinal centre remains unknown. The FAS molecule, a 'death receptor' present at high levels on these cells, has been a prime suspect in their control.

A research team led by Danyal Butt, Dr Tyani Chan and Professor Robert Brink, from Sydney's Garvan Institute of Medical Research, now demonstrates that FAS has a very important, but entirely unexpected, role in preventing autoantibody production.

FAS mutations were found to enable the development of a subclass of 'rogue germinal centre B cells', with antibody genes that in no way recognise foreign antigen. These rogue cells produce large numbers of plasma cells that in turn produce unexpected and damaging antibodies, including autoantibodies. The findings are published in the journal Immunity.

"In very simple terms, we believe FAS prevents rogue germinal centre B cells from developing, and we suspect that is its primary role," said Professor Brink.

"When we removed FAS from a mouse model, we saw the appearance of rogue cells in the germinal centre, and the plasma cells they produced, and neither obeyed any of the normal rules.

"A disproportionately large number of plasma cells were formed by these rogue cells, producing antibodies you wouldn't expect to see, very high numbers of IgE antibodies in particular.

"Instead of getting better at binding foreign antigen, rogue cells got worse -- the opposite of what is supposed to happen in the germinal centre!

"Most significantly, many of the antibodies derived from rogue cells turned out to be autoantibodies."

Patients with a mutation in FAS develop an autoimmune disease known as Autoimmune Lymphoproliferative Syndrome (ALPS) in which the body cannot control the number of immune cells (lymphocytes). This results in enlargement of the lymph nodes, liver and spleen.

Through collaborators at the National Institutes of Health in the US, Brink and colleagues gained access to a database containing disease information from the largest cohort of ALPS patients in the world. They found that over 25% of ALPS patients have abnormally high levels of IgE in the blood.

Professor Brink believes that the patient data provides "provocative evidence" that his group's findings about FAS and rogue germinal centre B cells in mice also apply to humans.

"High levels of IgE antibodies are being found in other autoimmune diseases, such as lupus, and IgE is becoming increasingly associated with severe disease," he said.

"The fact that these rogue cells produce both autoantibodies and IgE antibodies, provides a compelling association with the more severe forms of autoimmunity.

"We do not yet know how rogue B cells arise -- mutation of FAS is certainly one way, but there are likely to be others. Defining these mechanisms promises to advance our understanding of the genesis of autoimmune disease and will point the way towards new diagnosis and treatment strategies."

Story Source:

The above story is based on materials provided by Garvan Institute of Medical Research. Note: Materials may be edited for content and length.

Journal Reference:

  1. Danyal Butt, Tyani D. Chan, Katherine Bourne, Jana R. Hermes, Akira Nguyen, Aaron Statham, Lorraine A. O’Reilly, Andreas Strasser, Susan Price, Peter Schofield, Daniel Christ, Antony Basten, Cindy S. Ma, Stuart G. Tangye, Tri Giang Phan, V. Koneti Rao, Robert Brink. FAS Inactivation Releases Unconventional Germinal Center B Cells that Escape Antigen Control and Drive IgE and Autoantibody Production. Immunity, 2015; DOI: 10.1016/j.immuni.2015.04.010

@Jonathan Edwards, what do you think of the research conducted Down Under? Are they into something, and is it plausible that rogue germinal centre B cells could pave the way for ME?
 
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Marco

Grrrrrrr!
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Near Cognac, France
Does this then suggest a genetic/epigenetic element to some autoimmune diseases even though the production of rogue germinal B cells is random?
 

Snow Leopard

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Does this then suggest a genetic/epigenetic element to some autoimmune diseases even though the production of rogue germinal B cells is random?

Yes, of course.

The model that these researchers developed however, generated a lot of IgE antibodies rather than IgG, and so this particular finding may only be relevant to autoimmune conditions where IgE antibodies are implicated in the disease.
 

msf

Senior Member
Messages
3,650
It seems to be an explanation for some autoimmune diseases rather than all autoimmune diseases. From what I've just read, ALPS is usually diagnosed early in life, which would seem to make FAS mutations a unlikely cause of autoimmune diseases that develop later in life.
 

Jonathan Edwards

"Gibberish"
Messages
5,256
Australian researchers believe they have discovered a group of cells that trigger autoimmune disease, as well as the molecular 'trigger guard' that normally holds them in check.

Source: ScienceDaily.com

Published in the respected journal "Immunity" (impact factor 19.748 as of 2013)

@Jonathan Edwards, what do you think of the research conducted Down Under? Are they into something, and is it plausible that rogue germinal centre B cells could pave the way for ME?

A bit odd really. My own group suggested that autoimmunity was due to rogue germinal centre B cells in 1999 so that does not seem very new! And Fas defects causing autoimmunity in mice with lymphoproliferation has been around since the lpr gene was found in MRL/lpr mice around 1982. Maybe this group have not realised they have re-invented a well known spontaneous mutant model.

As Snow Leopard points out, the difficulty in relating this to human autoimmunity is the focus on IgE. IgE is not really a feature of human autoimmunity. You can find IgE autoantibodies if you look hard but none of the autoimmune disease I know of use IgE effector mechanisms. And at a simpler level, humans with autoimmunity do not have Fas defects. I think we told a rather better story in 1999 that makes a bit more sense than this. What immunological colleagues never seemed to 'get' is that the rogue cells in autoimmunity are completely normal in all respects except the antibody they make. Colleagues would hold up there hands in horror and say 'why should their be rogue mutating cells in autoimmunity - what would cause it?'. The simple answer is that mutating is what B cells do for a living so you do not need any special cause or trigger. You just need the antibody to crash the regulatory system.

So the title of this piece is certainly wrong I think - this is not the trigger for human autoimmune disease - because humans don't have the Fas defect and there ain't no trigger.
 

Jonathan Edwards

"Gibberish"
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5,256
Another point is that Fas defect animals get every autoimmune problem under the sun. Humans get one at a time - or occasionally a couple of associated ones.
 

Marco

Grrrrrrr!
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Location
Near Cognac, France
So basically this is a FAS defect disease that affects apoptosis of cells which may include rogue B cells rather than an autoimmune disease per se?

Maybe I've got the wrong end of the stick.
 

Jonathan Edwards

"Gibberish"
Messages
5,256
So basically this is a FAS defect disease that affects apoptosis of cells which may include rogue B cells rather than an autoimmune disease per se?

Maybe I've got the wrong end of the stick.

Seems more towards the right end to me. It becomes semantic, but these poor animals have a lot more problems than just autoantibodies.