An autoimmune disease is where the immune system mistakenly creates antibodies that attack healthy tissue. The underlying processes of antibody production are not clear, although we know it involves a group of cells called B cells. Now, a new study reveals that autoimmune disease may be the result of previously unknown rogue versions of these cells creating autoantibodies.
The study – led by researchers at the Garvan Institute of Medical Research in Sydney, Australia – is published in the journal Immunity.
The discovery surrounds the role of a “death receptor” molecule called FAS that sits on the surface of cells and triggers them to commit suicide when they start to malfunction.
The team suggests that in the case of B cells, when FAS is faulty – perhaps because of mutations in its gene – it allows rogue versions of B cells free reign to produce the wrong kind of antibodies, including some that react with the body’s own tissue – autoantibodies.
Mutated FAS has already been linked to autoimmune disease. Patients with FAS mutations develop autoimmune lymphoproliferative syndrome (ALPS) where the body cannot control the number of immune cells (lymphocytes). This leads to enlarged lymph nodes, liver and spleen.
In a normal immune response, when well-functioning B cells spot a foreign “antigen” such as a virus or bacterium, they rush to “germinal centers” – temporary structures that arise in lymph nodes and tonsils.
Once inside the germinal centers, the B cells rapidly mutate their antibody genes at random until one proves to have a strong match or “high affinity” to the newly-met foreign antigen.
Once the high-affinity antibody gene is found, the B cells then transform into little antibody factories or “plasma cells” to produce large quantities of the new high-affinity antibody and flood the system with them.
However, because of the randomness and speed at which the B cells mutate in their haste to produce a high-affinity antigen, there is a chance that among the candidates will appear some that match some of the body’s own tissue – producing in effect high-affinity “autoantibodies.”
Scientists suspect this is where the FAS receptor kicks in – to ensure the rogue B cells commit suicide before they have a chance to transform into plasma cells and start producing large amounts of autoantibodies.
But when the FAS gene is mutated, the receptor malfunctions, allowing the development of “rogue germinal center B cells” with antibody genes that do not match foreign antigen. These go on to produce large numbers of plasma cells that churn out lots of irrelevant antibodies – as far as the foreign antigen is concerned – but, unfortunately, some of them include autoantibodies.
One of the team leaders, Prof. Robert Brink, who heads Garvan’s B-cell biology lab, explains how they confirmed rogue germinal center B cells emerge when there is no FAS to eliminate them:
“When we removed FAS from a mouse model, we saw the appearance of rogue cells in the germinal center, and the plasma cells they produced, and neither obeyed any of the normal rules.”
He explains that the rogue cells produced a “disproportionately large number of plasma cells” that churned out antibodies you would not expect to see, and:
“Most significantly, many of the antibodies derived from rogue cells turned out to be autoantibodies.”
One of the autoantibodies the researchers found in abundance in the mice without FAS was IgE, a group of antibodies that the immune system makes when it overreacts to an allergen.
In another part of the study, the team looked at records from a large global cohort of patients with ALPS. They found that more than 25% of them have abnormally high blood levels of IgE.
Prof. Brink says this finding provides “provocative evidence” that the result they saw in the mice concerning FAS and rogue germinal center B cells applies to humans.
He notes that high levels of IgE antibodies are coming up in other autoimmune diseases, such as lupus, and IgE is becoming increasingly associated with severe disease. He concludes:
“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.”
Meanwhile, Medical News Today recently learned of another clue about the cause of autoimmune disease, and type 1 diabetes in particular. In a study also reported in the journal Immune, researchers showed that the gene Clec16a is involved in the development of type 1 diabetes. They found that certain cells in the thymus use the cell waste-management process of autophagy – which is influenced by the Clec16a gene – to educate immune system T cells about which proteins belong to the body and which do not.